Ocular infiltration as initial presentation of acute monocytic leukaemia transformed from chronic myelomonocytic leukaemia associated with BRAF V600E mutation.

Acute monocytic leukaemia (French-British-American classification: AML-M5b) is characterised by a predominance of cells of the monocytic lineage on bone marrow examination. Furthermore, a discerning feature is its tendency for tissue infiltration. While gum hypertrophy and hepatosplenomegaly are common, ocular involvement is rare. Here, we present a case of a 75-year-old man referred with proptosis and monocytosis-subsequently diagnosed as AML-M5b, whose disease course was distinguished by extensive tissue invasion (ocular, pulmonary, liver, spleen). Cytogenetics and molecular tests were consistent with blastic transformation of previously undiagnosed chronic myelomonocytic leukaemia, supported by the presence of long-standing, low-grade monocytosis. Notably, a BRAF V600E mutation was also detected-an oncogenic driver previously reported in de novo and therapy-related, but not chronic myelomonocytic leukaemia-transformed, AML-M5b. While an initial response to cytoreductive treatment was observed, his tissue-invasive disease soon progressed with worsening pulmonary infiltrates, disseminated intravascular coagulation and renal failure, resulting in death.

Opioid toxicity with underlying tumour lysis syndrome in a patient with CMML: a diagnostic and therapeutic challenge.

Use of strong opioids like morphine as analgesics for painful conditions in haematological malignancies is a challenging task. We report a unique case of chronic myelomonocytic leukaemia presenting with opioid toxicity overlapping with tumour lysis syndrome. The patient was on hydroxyurea-based chemotherapy for the primary disease. She was receiving oral morphine for abdominal pain due to splenomegaly. She was brought to the emergency in unresponsive state with pinpoint pupils. Opioid overdose leading to unconsciousness was suspected as the first diagnosis. Further workup revealed a final diagnosis of tumour lysis syndrome overlapping with opioid overdose. The patient was ventilated and started on naloxone infusion, and supportive measures for managing tumour lysis were added. The patient gradually improved and was extubated on the fifth day of ventilation. This case presents several learning points for the treating physician. Haematological malignancies have a dynamic course of disease with waxing and waning tumour burden during the course of chemotherapy. This fact should be kept in mind when prescribing strong opioids like morphine on outpatient basis to these patients. Massive tumour cell lysis during the course of chemotherapy may precipitate tumour lysis syndrome and may lead to renal dysfunction which makes the patient susceptible to morphine-related adverse effects. Pain physician should keep a watch for therapy-related adverse effects to avoid diagnostic and therapeutic dilemma associated with coexisting features of these two fatal conditions.

A case of type B lactic acidosis as a complication of chronic myelomonocytic leukaemia: a case report and review of the literature.

INTRODUCTION: Type B lactic acidosis represents a rare and often lethal complication of haematological malignancy. Here, we present a patient who developed a type B lactic acidosis presumably due to a concurrent chronic myelomonocytic leukaemia. Upon swift initiation of cytoreductive chemotherapy (doxorubicin), the lactic acidosis was rapidly brought under control. This case adds to the literature reporting other haematological malignancies that can cause a type B lactic acidosis and its successful treatment. CASE PRESENTATION: We report the case of a 77-year-old Caucasian man brought to our Accident and Emergency department following an unwitnessed collapse; he was found surrounded by coffee-ground vomit. Although haemodynamically stable on admission, he rapidly deteriorated as his lactic acid rose. An initial arterial blood gas revealed a pH of 7.27 and lactate of 18mmol/L (peaking at 21mmol/L). CONCLUSIONS: A high degree of clinical suspicion for haematological malignancy should be held when presented with a patient with lactic acidosis in clinical practice, even without evidence of poor oxygenation or another cause. Treatment with emergency chemotherapy, in lieu of a definitive diagnosis, was rapidly successful at lowering lactate levels within 8 hours. This may suggest a causal and perhaps direct relationship between lactic acid production and the presence of leukemic cells. Veno-venous haemofiltration had no apparent effect on reducing the lactic acidosis and therefore its benefit is questioned in this setting, especially at the cost of delaying chemotherapy. In the face of a life-threatening lactic acidosis, pragmatic clinical judgement alone may justify the rapid initiation of chemotherapy.

Leucemia mielomonocítica crónica / Chronic myelomonocytic leukemia

La leucemia mielomonocítica crónica es un desorden clonal de las células progenitoras hematopoyéticas clasificado como neoplasia mielodisplásica mieloproliferativa. Se caracteriza por la presencia de monocitosis absoluta y persistente en la sangre periférica (> 1.0 x 10 9/L) con la presencia de displasia celular y mieloproliferación en la médula ósea. Los pacientes presentan síntomas relacionados a las citopenias y al estado de hipercatabolismo y al examen físico se encuentra esplenomegalia. El diagnóstico se establece con la combinación del examen de la lámina de sangre periférica, el aspirado medular y la biopsia de médula ósea, el inmunofenotipaje y el estudio molecular de las anomalías que se presentan. El pronóstico de la enfermedad es malo. El tratamiento de elección es el trasplante alogénico de progenitores hematopoyéticos con régimen de acondicionamiento de toxicidad reducida. En alrededor del 30 por ciento de los pacientes la enfermedad se transforma en una leucemia mieloide aguda...

Chronic myelomonocytic leukemia is a clonal hematopoietic stem cell disorder classified as a myelodysplastic/myeloproliferative neoplasm. It is characterized by absolute monocytosis (>1.0 x 10(9)/ L) in the peripheral blood that persists for at least 3 months, with dysplastic and myeloproliferation in the bone marrow. Patients may show symptoms related to cytopenias and hypercatabolic state with splenomegaly. The diagnosis is established by combination of complete blood count, peripheral blood smear, bone marrow aspirate, bone marrow biopsy, immunophenotypic profile and study of molecular abnormalities. The prognosis is bad. The treatment of election is the hematopoietic allogeneic stem cell transplantation with regimen of reduced toxicity. In around 30 percent of these patients the disease transforms to acute myeloid leukemia...

Leucemia mielomonocítica crónica / Chronic myelomonocytic leukemia

La leucemia mielomonocítica crónica es un desorden clonal de las células progenitoras hematopoyéticas clasificado como neoplasia mielodisplásica mieloproliferativa. Se caracteriza por la presencia de monocitosis absoluta y persistente en la sangre periférica (> 1.0 x 10 9/L) con la presencia de displasia celular y mieloproliferación en la médula ósea. Los pacientes presentan síntomas relacionados a las citopenias y al estado de hipercatabolismo y al examen físico se encuentra esplenomegalia. El diagnóstico se establece con la combinación del examen de la lámina de sangre periférica, el aspirado medular y la biopsia de médula ósea, el inmunofenotipaje y el estudio molecular de las anomalías que se presentan. El pronóstico de la enfermedad es malo. El tratamiento de elección es el trasplante alogénico de progenitores hematopoyéticos con régimen de acondicionamiento de toxicidad reducida. En alrededor del 30 por ciento de los pacientes la enfermedad se transforma en una leucemia mieloide aguda(AU)

Chronic myelomonocytic leukemia is a clonal hematopoietic stem cell disorder classified as a myelodysplastic/myeloproliferative neoplasm. It is characterized by absolute monocytosis (>1.0 x 10(9)/ L) in the peripheral blood that persists for at least 3 months, with dysplastic and myeloproliferation in the bone marrow. Patients may show symptoms related to cytopenias and hypercatabolic state with splenomegaly. The diagnosis is established by combination of complete blood count, peripheral blood smear, bone marrow aspirate, bone marrow biopsy, immunophenotypic profile and study of molecular abnormalities. The prognosis is bad. The treatment of election is the hematopoietic allogeneic stem cell transplantation with regimen of reduced toxicity. In around 30 percent of these patients the disease transforms to acute myeloid leukemia(AU)

Lenalidomide and metronomic melphalan for CMML and higher risk MDS: a phase 2 clinical study with biomarkers of angiogenesis.

Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.

Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review.

Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap features, and an inherent tendency to transform to acute myeloid leukaemia. Approximately 30% of patients present with clonal cytogenetic abnormalities, while almost 90% have molecular aberrations involving epigenetic regulation, the spliceosome component machinery, tumour suppressor genes and transcription factors/regulators. Numerous prognostic models exist for CMML, with more recent models incorporating prognostic mutations, such as those involving ASXL1. Other variables that seem to consistently affect outcomes include the degree of leucocytosis/monocytosis, anaemia and thrombocytopenia. Allogeneic stem cell transplant remains the only curative option for CMML, while hypomethylating agents can be used for transplant-ineligible patients or those without suitable stem cell sources. Targeting biological pathways activated in CMML offers potential hope for more effective and less toxic therapies.

Chronic myelomonocytic leukemia: 2013 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is classified as a myelodysplastic/myeloproliferative neoplasm by the 2008 World Health Organization classification of hematopoietic tumors. It is characterized by absolute monocytosis (>1 × 109/L) in the peripheral blood that persists for at least 3 months. DIAGNOSIS: The diagnosis of CMML rests on a combination of morphologic, histopathologic and chromosomal abnormalities in the bone marrow. It is important to exclude other myeloproliferative neoplasms and infectious/autoimmune conditions that can cause monocytosis. RISK STRATIFICATION: Several CMML-specific prognostic models incorporating novel mutations have been recently reported. The Mayo prognostic model classified CMML patients into three risk groups based on: increased absolute monocyte count, presence of circulating blasts, hemoglobin <10 gm/dL and platelets <100 × 109/L. The median survival was 32 months, 18.5 months and 10 months in the low, intermediate, and high-risk groups, respectively. The Groupe Francophone des (GFM) score segregated CMML patients into three risk groups based on: age >65 years, WBC >15 × 109/L, anemia, platelets <100 × 109/L, and ASXL1 mutation status. After a median follow-up of 2.5 years, survival ranged from not reached in the low-risk group to 14.4 months in the high-risk group. RISK-ADAPTED THERAPY: The Food and Drug Administration has approved azacitidine and decitabine for the treatment of patients with CMML. An allogeneic stem cell transplant can potentially offer a curative option to a subset of CMML patients. It is hoped that with the discovery of several novel mutations, targeted therapies will become available in the near future.

An evolutionary perspective on chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) shares with other myeloid diseases a number of somatic gene mutations. These mutations can now be integrated within the framework of evolution theory to address the mechanisms of the disease. Several evidences indicate that the disease emerges in adult hematopoietic stem cells (HSC) through the age-dependent accumulation of DNA damage, leading stochastically to a driver mutation that confers a competitive advantage to the cell. A mutation in TET2 gene could be one of these driver mutations provoking the emergence of clonality. After a long latency, secondary lesions, such as mutations in the SRSF2 gene, contribute to progression to full-blown malignancy, with abnormal differentiation. Additional mutations accumulate and branching arising mostly through mitotic recombination generates clonal heterogeneity. Modifications in the microenvironment probably affect this clonal dynamics, whereas epigenetic alterations, such as hypermethylation of the TIF1γ gene promoter, may generate phenotypic diversification of otherwise clonal populations. The preserved although deregulated myeloid differentiation that characterizes CMML, with granulomonocyte expansion and various cytopenias, may depend on early clonal dominance in the hematopietic cell hierarchy. Progression to acute myeloid leukemia observed in 25-30% of the patients may arise from the massive expansion of a clone with novel genetic lesions, providing a high fitness to previously minor subclones when in chronic phase of the disease. This review discusses the various models of disease emergence and progression and how this recent knowledge could drive rational therapeutic strategies.

Adult leukemic synovitis is associated with leukemia of monocytic differentiation.

BACKGROUND: Leukemic synovitis is a rare complication of adult myeloid leukemias characterized by joint pain and swelling. It is important to recognize this diagnostic challenge as it may be the initial manifestation of leukemia or of relapse. METHODS: A retrospective search of patient files from 2 teaching hospitals identified 4 adult patients who presented with large joint arthritis and concurrent or subsequent leukemic synovitis. All patients presented with inflammatory arthritis of large joints, and leukemic synovitis was identified by the presence of leukemic cells in the synovial fluid or infiltrating the synovial membrane seen at biopsy. RESULTS: A leukemia of monocytic origin-acute myelomonocytic leukemia or chronic myelomonocytic leukemia-was diagnosed in all 4 patients. In 2 cases, leukemic synovitis was the initial manifestation of leukemia. In the third case, it was the first sign of relapse, and in the remaining case, it developed shortly after diagnosis of leukemia. All patients had either osteoarthritis or rheumatoid arthritis. One patient was diagnosed simultaneously with osteoarthritis and leukemia. The remaining patients had a prior history of arthritis. CONCLUSIONS: Adult leukemic synovitis occurs in association with leukemias of monocytic differentiation. Data presented here, and review of isolated case reports, support this association. The finding of large joint arthritis as a comorbidity in these 4 cases raises questions about the role of antecedent arthritis as a predisposing factor in the pathophysiology of leukemic synovitis.

Lipoid pneumonia with chronic myelomonocytic leukemia.

A case of lipoid pneumonia with chronic myelomonocytic leukemia is reported. A 61-year-old man was autopsied after suffering from myelodysplastic syndrome (chronic myelomonocytic leukemia) for 13 years. Interstitial lesions of the lungs were suspected as infiltration of leukemia cells before the autopsy. However, blastic leukemia cells were not observed in the lung, although they were seen in the bone marrow and spleen at autopsy. Instead, an unusual amount of cholesterol deposits was observed with mucormycosis and aspergillosis in the lungs. Cholesterol deposition was observed not only in perihilar but also in subpleural regions without apparent bronchial obstruction in both lungs. It is thought that malfunction of monocytes/macrophages resulted in repeated fungal infection and storage of cholesterol caused by tissue destruction and impaired tissue repairing.

Transformation of cytogenetically normal chronic myelomonocytic leukaemia to an acute myeloid leukaemia and the emergence of a novel +13, +15 double trisomy resulting in an adverse outcome.

A 58-year-old man was admitted with symptoms of lethargy and easy bruising for four months duration. Peripheral blood (PB) analysis revealed a white blood cell count (WBC) of 15.9 x 10(9)/l with monocytes 5.4 x 10(9)/l. Bone marrow (BM) was hypercellular with 15% blasts, monocytosis and trilineage dysplasia. Conventional cytogenetic analysis (G-banding) detected an apparently normal male karyotype (46,XY). A diagnosis of chronic myelomonocytic leukaemia (CMML) was made. After 3 years, PB analysis revealed a WBC count of 22 x 10(9)/l and a predominance of blasts. BM aspirate analysis also revealed 89% myeloid blasts and G-banding detected the emergence of an abnormal clone harbouring an extra copy of chromosomes 13 and 15. A diagnosis of disease transformation to acute myeloid leukaemia (AML) was made. Post chemotherapy BM aspirate was very hypocellular and the abnormal +13, +15 clone was still present suggesting primary refractory disease. A second course of chemotherapy was only administered for 24 hours due to complications. The abnormal +13, +15 clone was still present and it was decided that no further treatment apart from palliative care could be offered. The patient died 11 weeks later, five months after AML transformation. This is the first description of a cytogenetically normal CMML patient transforming to AML with the emergence of a unique +13, +15 double trisomy resulting in an adverse outcome.

Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used array-based comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

Chronic myelomonocytic leukaemia after platinum-based therapy for non-small cell lung cancer: case report and review of the literature.

Chronic myelomonocytic leukaemia (CMML) is a preleukaemic condition with myeloproliferative features, and classified as a part of myelodysplastic syndrome (MDS). Other than alkylating agents and topoisomerase II inhibitors, there is less evidence that chemotherapeutic drugs are associated with therapy-related CMML, acute leukaemia or MDS. We present a patient who developed CMML within 2 years of platinum-based chemotherapy for a metastatic non-small cell lung cancer. He received a cumulative dose of 240 mg/m(2) of cisplatin, and 1123 mg/m(2) of carboplatin before developing CMML. The cytogenetic study revealed trisomy 8. This is the first reported case that links platinum-based therapy with development of CMML with trisomy 8. Although the relationship between platinum therapy and the development of CMML is difficult to assess due to combinational nature of therapy in most cases, physicians should consider the possibility of CMML in patients with symptoms or signs suggestive of haematologic malignancy after platinum therapy.

Inherited predispositions and hyperactive Ras in myeloid leukemogenesis.

Identifying the molecular basis for inherited cancer predispositions reveals genes that when mutated, play a critical role in the earliest stages of tumorigenesis. Although rare, inherited predispositions to myeloid leukemias have led to a greater understanding of pathways important for myeloid proliferation and maturation. In particular, elucidating why children with neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are predisposed to juvenile myelomonocytic leukemia (JMML) has uncovered a critical role of hyperactive Ras signaling in normal myeloid growth and leukemogenesis. Here, we review studies of human samples and experiments performed in genetically engineered strains of mice investigating the molecular and biochemical basis of aberrant growth in JMML. These strains model human disease features and provide an opportunity to investigate novel therapeutic strategies that may ultimately cure JMML and other myeloid malignancies characterized by hyperactive Ras.

Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells.

PTPN11 encodes the protein tyrosine phosphatase SHP-2, which relays signals from growth factor receptors to Ras and other effectors. Germline PTPN11 mutations underlie about 50% of Noonan syndrome (NS), a developmental disorder that is associated with an elevated risk of juvenile myelomonocytic leukemia (JMML). Somatic PTPN11 mutations were recently identified in about 35% of patients with JMML; these mutations introduce amino acid substitutions that are largely distinct from those found in NS. We assessed the functional consequences of leukemia-associated PTPN11 mutations in murine hematopoietic cells. Expressing an E76K SHP-2 protein induced a hypersensitive pattern of granulocyte-macrophage colony-forming unit (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) that was dependent on SHP-2 catalytic activity. E76K SHP-2 expression also enhanced the growth of immature progenitor cells with high replating potential, perturbed erythroid growth, and impaired normal differentiation in liquid cultures. In addition, leukemia-associated SHP-2 mutations conferred a stronger phenotype than a germline mutation found in patients with NS. Mutant SHP-2 proteins induce aberrant growth in multiple hematopoietic compartments, which supports a primary role of hyperactive Ras in the pathogenesis of JMML.

Complete remission of TEL-PDGFRB-induced myeloproliferative disease in mice by receptor tyrosine kinase inhibitor SU11657.

The TEL-PDGFRB fusion oncogene is associated with chronic myelomonocytic leukemia (CMML) and results in the expression of a constitutively active tyrosine kinase. SU11657 is a multitargeted selective inhibitor of class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors KIT and FLT3. SU11657 inhibited TEL/PDGFbetaR kinase activity at nanomolar concentrations and inhibited TELPDGFRB-mediated factor-independent growth in myeloblastic 32D cells. Daily oral administration of SU11657 at 40 mg/kg suppressed myeloproliferation and significantly prolonged survival in TELPDGFRB mice treated prior to disease development, as well as in those with large tumor burdens. Our findings suggest that SU11657 or similar agents may have therapeutic potential in humans with hematologic malignancies expressing PDGFR fusion oncogenes.

Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia.

Neurofibromatosis type one (NF1) is a common genetic disorder affecting 1:4000 births and is characterized by benign and malignant tumors. Children with NF1 are predisposed to juvenile myelomonocytic leukemia. The Nf1 gene encodes neurofibromin, which can function as a Ras GTPase-activating protein. Neurofibromin deficiency in mice leads to mid-gestation lethality due to cardiovascular defects. We have previously shown that conditional inactivation of Nf1 using Tie2-Cre recapitulates the heart defects seen in Nf1(-/-) embryos. Tie2-Cre transgenic mice express Cre recombinase in all endothelial cells. Here, we show that Tie2-Cre-mediated deletion of Nf1 also leads to excision of Nf1 in the hematopoietic lineage. Surviving mice exhibit a myeloproliferative disorder similar to juvenile myelomonocytic leukemia seen in NF1 patients. These mice provide a useful model to study neurofibromin deficiency in hematopoiesis. Furthermore, defects in Tie2-Cre-expressing progenitors that result in heart and blood defects suggest that related heart and blood disorders in NF1 and other syndromes represent disorders of the hemangioblast.