Pathological splenic rupture: a rare complication of chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is an uncommon disorder characterized by monocytosis of the peripheral blood, absence of the Philadelphia chromosome, fewer than 20% blasts, and one or more lineages showing dysplastic features. Splenomegaly is frequently seen and may be massive. A 56-year-old man with stable CMML and moderate splenomegaly presented to the emergency department with generalized abdominal pain and abrupt drop in hemoglobin. Abdominal imaging revealed splenic rupture and emergency splenectomy was undertaken, with complete recovery. Atraumatic rupture of the spleen has rarely been reported as a complication of CMML or other myelodysplastic disorders. This report should alert physicians to consider this diagnosis in patients with CMML and acute abdominal pain.     

Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: Case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome

If chronic myelomonocytic leukemia (CMML) transforms into an acute leukemic phase, the blast crisis is invariably myeloid. Occasionally, the other subtypes of myelodysplastic syndrome (MDS) (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation) have been noted to transform into acute lymphoblastic leukemia (ALL). We now report a case of CMML that transformed into ALL and we review the literature of 13 other cases of MDS with ALL transformation. Such cases provide suggestive clinical evidence that MDS can involve a pluripotent stem cell. © 1955 Wiley-Liss, Inc.     

Cytogenetic risk stratification in chronic myelomonocytic leukemia

Background

The prognostic value of cytogenetic findings in chronic myelomonocytic leukemia is unclear. Our purpose was to evaluate the independent prognostic impact of cytogenetic abnormalities in a large series of patients with chronic myelomonocytic leukemia included in the database of the Spanish Registry of Myelodysplastic Syndromes.

Design and Methods

We studied 414 patients with chronic myelomonocytic leukemia according to WHO criteria and with a successful conventional cytogenetic analysis at diagnosis. Different patient and disease characteristics were examined by univariate and multivariate methods to establish their relationship with overall survival and evolution to acute myeloid leukemia.

Results

Patients with abnormal karyotype (110 patients, 27%) had poorer overall survival (P=0.001) and higher risk of acute myeloid leukemia evolution (P=0.010). Based on outcome analysis, three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). Overall survival at five years for patients in the low, intermediate, and high risk cytogenetic categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed that this new CMML-specific cytogenetic risk stratification was an independent prognostic variable for overall survival (P=0.001). Additionally, patients belonging to the high-risk cytogenetic category also had a higher risk of acute myeloid leukemia evolution on univariate (P=0.001) but not multivariate analysis.

Conclusions

Cytogenetic findings have a strong prognostic impact in patients with chronic myelomonocytic leukemia.     

Chronic myelomonocytic leukemia in childhood

A four-year-old child with recurrent infections and increasing hepatosplenomegaly over a three-year period was evaluated. Increased numbers of myeloid precursors packed the bone marrow and infiltrated the peripheral blood. A diagnosis of chronic myelogenous leukemia (CML) was considered but could not be confirmed by laboratory studies appropriate for the types of CML usually observed in childhood. Examination of the patient's peripheral blood smears revealed many atypical monocytoid cells with unipolar hairy projections. Scanning electron microscopy showed these to be leukemic monoblasts with characteristic broad-based ruffles on the cell surface. A population of myeloid precursors possessing narrow ridge-like profiles was also observed. Progressive infiltration of the spleen caused hypersplenism which necessitated splenectomy. Subsequently, massive liver and bone marrow involvement led to the patient's death. Terminally, the proliferating blast cells were demonstrated to be leukemic monoblasts by analysis of cytochemical staining patterns, surface immunoglobulins, serum lysozyme levels, and monocyte-mediated antibody-dependent cellular cytotoxicity studies. The findings in this case are most compatible with a diagnosis of chronic myelomonocytic leukemia (CMML), a condition not previously described in childhood. Several myeloproliferative disorders with prolonged survival have been reported in children, but special studies were not performed to determine which cell lines were abnormally proliferating. The similarities between these children and our patient with CMML suggest that monocyte studies may be useful in the diagnosis of these unusual disorders, provide insights into their pathogenesis, and aid in the selection of appropriate therapy.     

Megakaryoblastic transformation of chronic myelomonocytic leukemia presenting with severe bone pain

A 77-year-old woman, who had suffered from osteoporosis with compression fractures of vertebrae, was admitted to our hospital because of increasing bone pain. She had anemia and monocytosis, and was diagnosed as chronic myelomonocytic leukemia (CMML). Although chemotherapy was initiated, she died from pneumonia. Autopsy revealed multiple tumors composed of megakaryoblastic cells in her bone marrow and extramedullary organs and, therefore, the pathological diagnosis was made as megakaryoblastic transformation of CMML. Severe bone pain was considered to be a symptom of megakaryoblastic transformation of CMML.     

Erythrophagocytosis by dysplastic neutrophils in chronic myelomonocytic leukemia and subsequent transformation to acute myeloid leukemia

Erythrophagocytosis by neutrophils is a rare phenomenon in myeloid malignancies, and its clinicopathologic significance is not fully understood. We report a unique case of erythrophagocytosis by dysplastic neutrophils in chronic myelomonocytic leukemia (CMML) and subsequent transformation to acute myeloid leukemia (AML). Review of multiple marrow samples, both pretreatment and post-treatment, demonstrated a correlation between percentage of dysplastic neutrophils and degree of erythrophagocytosis. Erythrophagocytosis was observed only in dysplastic forms of neutrophils. Post-transplant marrows with engraftment of donor cells showed no neutrophilic dysplasia or erythrophagocytosis. Possible mechanisms of neutrophilic erythrophagocytosis in myeloid malignancies are discussed.     

Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher‐risk myelodysplastic syndromes or chronic myelomonocytic leukemia

In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration. This is important as prognosis postrelapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one patient) while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections, and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS.     

TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia

Background

Acquired somatic deletions and loss-of-function mutations in one or several codons of the TET2 (Ten-Eleven Translocation-2) gene were recently identified in hematopoietic cells from patients with myeloid malignancies, including myeloproliferative disorders and myelodys-plastic syndromes. The present study was designed to determine the prevalence of TET2 gene alterations in chronic myelomonocytic leukemias.

Design and Methods

Blood and bone marrow cells were collected from 88 patients with chronic phase chronic myelomonocytic leukemia and from 14 with acute transformation of a previously identified disease. Polymerase chain reaction analysis and direct sequencing were used to sequence exons 3 to 11 of the TET2 gene. Annotated single nucleotide polymorphisms were excluded. Survival curves were constructed by the Kaplan-Meier method.

Results

We detected TET2 mutations in 44 of 88 (50%) patients with chronic myelomonocytic leukemia, which suggests that TET2 gene mutations are especially frequent in this myeloid disease. A TET2 gene alteration was identified in 18 of the 43 patients studied at diagnosis and was associated with a trend to a lower overall survival rate; confining the analysis to the 29 patients with chronic myelomonocytic leukemia-1, according to the WHO classification, the difference in overall survival between patients with or without TET2 gene mutations became statistically significant.

Conclusions

TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients’ outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.     

Hematopoietic progenitor cell colony growth differentiates chronic myelomonocytic leukemia from reactive monocytosis

In the absence of a cytogenetic abnormality or overt dysplasia, chronic myelomonocytic leukemia (CMML) may be difficult to be distinguished from reactive monocytosis. We have previously described a typical growth pattern in CMML patients, i.e., 'pseudonormal' colonies resembling granulocytic colonies but consisting entirely of monocytic cells when stained. To study the utility of the colony forming unit cell assay (CFU-C) as a diagnostic tool in patients with monocytosis, we analyzed a cohort of 48 consecutive patients referred to our institution with peripheral blood monocytosis. Thirty-six patients fulfilled the WHO criteria for CMML; 12 were diagnosed with reactive monocytosis. Of the patients with CMML, 28 showed pseudonormal growth with or without leukemic cluster growth, another four showed exclusively leukemic growth. None of the patients with reactive monocytosis showed either leukemic or pseudonormal growth. With a specificity of 100% and a sensitivity of 89%, the CFU-C assay has a unique potential to distinguish CMML from reactive monocytosis.     

A case of chronic myelomonocytic leukemia complicated with spondyloarthritis

Chronic myelomonocytic leukemia (CMML), a clonal hematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap feature, is frequently associated with autoimmune diseases, such as vasculitis, polyarthritis, and neutrophilic dermatosis. We herein report the first case of CMML complicated with spondyloarthritis (SpA). A 64-year-old female patient, admitted to our hospital with buttock pain alternating left and right, was found to have sacroiliitis and spondylitis by contrast magnetic resonance imaging. Peripheral blood test and bone marrow biopsy revealed an increase of monocytes with trilineage dysplasia. We made a diagnosis of CMML. Although arthritic symptoms and imaging findings initially improved by azacitidine, CMML was thereafter transformed into acute myeloid leukemia. She is scheduled to hematopoietic stem cell transplantation. The concomitant onset of sacroiliitis with CMML suggested that her SpA feature was a paraneoplastic phenomenon of CMML. Thus, we must be aware that myelodysplastic syndrome including CMML can manifest as SpA.     

慢性粒单核细胞白血病的临床特点和预后分析

目的:本研究探讨慢性粒单核细胞型白血病(CMML)的临床特点及影响其预后的相关因素,评估IPSS、WPSS及MDAPS3个积分系统在CMML预后中的应用意义。方法:选取我院2003年5月-2009年7月CMML病例18例,选取同期急性单核细胞白血病(AML-M5)58例作为对照。结果:CMML伴有明显的多系病态造血。干细胞相关抗原CD34、CD117的表达较低,HLA-DR、CD117、CD14抗原表达均低于AML-M5(P<0.05),CD11b抗原表达高于AML-M5(P<0.05)。结论:WPSS积分系统对CMML的预后评估较为理想;CMML时干细胞相关抗原的表达均较低;CD11b高表达可能与CMML的预后不良有关;常规化疗对CMML的治疗效果不佳,造血干细胞移植是目前惟一有可能治愈CMML的方法。     

Allogeneic bone marrow transplantation as primary therapy for chronic myelomonocytic leukemia

Summary This is the first report of a successful bone marrow transplantation for chronic myelomonocytic leukemia. A 41-year-old woman with chronic myelomonocytic leukemia received, as primary treatment, a novel preparatory regimen consisting of high dose fractionated total body irradiation and high dose VP-16 chemotherapy followed by allogeneic marrow transplantation from her histocompatible brother. The patient is now more than two years after marrow transplantation with normal blood counts and a normal bone marrow which is of donor type. For younger patients with this disease who have a histocompatible sibling donor, bone marrow transplantation may represent a valid therapeutic option with curative potential.This investigation was supported by PHS Grants CA 30206 and CA 33572 awarded by the National Cancer Institute, DHHS     

In vitro and in vivo effects of JAK2 inhibition in chronic myelomonocytic leukemia

In chronic myelomonocytic leukemia (CMML), colony‐forming units granulocyte/macrophage (CFU‐GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM‐CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML. We investigated the in vitro effects of the specific JAK2 inhibitor TG101209 on the autonomous CFU‐GM formation from peripheral blood mononuclear cells of patients with CMML. TG101209 was found to either block or strongly inhibit spontaneous CFU‐GM growth in all 10 patients tested. This inhibitory effect was dose dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU‐GM growth from normal individuals. In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU‐GM formation ex vivo. Pharmacological JAK2 inhibition may be an interesting approach to be systematically studied in patients with CMML.     

Flow cytometry immunophenotypic findings in chronic myelomonocytic leukemia and its utility in monitoring treatment response

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis. Due to the lack of unique surface markers expressed by neoplastic monocytes and the frequent CD34‐negative blast immunophenotype, the diagnostic value of flow cytometric immunophenotyping (FCI) in CMML is rarely studied. In this study, by using a multicolor FCI assay, we assessed bone marrow (BM) immunophenotypical alterations in 118 CMML patients and follow‐up BM samples in 35 of these patients. The median BM monocytes as determined by FCI were 14% (1–63%), correlated with morphologic count (P = 0.0004). FCI alterations in monocytes were observed in 96% and granulocytes in 83% of cases. The percentage of CD34⁺ myeloblasts by FCI was low [median 0.6% (0.02–12.6%)], but exhibiting frequent aberrancies [median 6 (2–12)]. CD34⁺ B‐cell precursors were absent in 93% of cases. In 35 patients with follow‐up BM samples assessed, the CD34⁺ myeloblasts showed persistent FCI aberrancies in all 29 patients treated with hypomethylating agents and 3 patients on observation, but became normal in 3 patients following stem cell transplant. In conclusion, CMML exhibit numerous FCI alterations in monocytes, granulocytes, and more profound/frequent in CD34⁺ myeloblasts. These findings provide solid evidence for using FCI as an ancillary test in CMML diagnosis and also, in assessment of treatment responses.     

Chronic myelomonocytic leukemia with nucleophosmin (NPM1) mutation

Nucleophosmin (NPM1) mutations in chronic myelomonocytic leukemia (CMML) are extremely uncommon, and the clinicopathologic features of these neoplasms are poorly characterized. Over a 10‐yr interval, NPM1 mutation analysis was performed in 152 CMML at our institution. NPM1 mutations were identified in 8 (5.3%) patients, five men and three women, with a median age of 72 yr (range, 27–87). In all patients, the bone marrow was hypercellular with multilineage dysplasia, monocytosis, and retained maturation supporting a diagnosis of CMML. NPM1 mutation allele burden was <5% in two patients and >10% in six patients. Four (50%) patients, all with >10% NPM1, progressed AML with a median interval of 11 months (range, 1–21). Compared with 144 CMML without NPM1 mutations, CMML patients with NPM1 mutation presented with more severe anemia (P = 0.053), higher BM monocyte percentage (P = 0.033), and an increased tendency for AML progression (P = 0.088) and an inferior overall survival (P = 0.076). Mutations involving NRAS/KRAS (2/7), TET2(2/5), ASXL1(1/5,) and FLT3(0/8) were not significantly different between these two groups. In summary, CMML with NPM1 mutation shows histopathological features of CMML, but patients appear to have a high probability for AML progression and may require aggressive clinical intervention, especially in patients with a high mutation burden.