Granulomatous dermatitis in the context of chronic myelomonocytic leukemia: More than just reactive infiltrates. An illustrative case report with literature review.

Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous dermatitis included in the latter group. More recently, the true nature of the myeloid cells present in the cutaneous infiltrates of this theoretically reactive dermatitis is being clarified with the use of new molecular techniques such as next-generation sequencing. The same mutations in bone marrow (BM) myeloid neoplastic cells and in the cells of cutaneous infiltrates have been found. We present the case of a 77-year-old man who presented with spread and treatment-resistant skin granulomatous lesions previous to the diagnosis of CMML. The same clonal mutations in SRSF2, IDH1, and RUNX1 were found in both skin and BM with resolution of the lesions after the initiation of azacytidine. In conclusion, we report an exceptional case in which specific granulomatous cutaneous lesions have preceded and allowed the earlier diagnosis of an underlying CMML and a review of all previous similar cases in the literature, including molecular alterations.

Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.

Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide (Lena) to act synergistically with Aza/DLI to improve outcome. We, therefore, prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia. Patients were scheduled for eight cycles Aza (75 mg/m2 day 1-7), Lena (2.5 or 5 mg, days 1-21) and up to three DLI with increasing T-cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of myelodysplastic syndromes (n=24), acute myeloid leukemia (n=23) or chronic myelomonocytic leukemia (n=3) received a median of seven (range, 1-8) cycles including 14 patients with 2.5 mg and 36 with 5 mg Lena daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lena dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade 2-4 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lena can be safely added to Aza/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse (clinicaltrials gov. Identifier: NCT02472691).

Germline CSF3R Variant in Chronic Myelomonocytic Leukemia: Linking Genetic Predisposition to Uncommon Hemorrhagic Symptoms.

Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by monocytosis, splenomegaly, thrombocytopenia, and anemia. Moreover, it is associated with SRSF2 mutations and, rarely, with CSF3R variants. We present the case of an 84-year-old patient with persistent anemia and monocytosis. Due to the presence of dysmorphic granulocytes, monocyte atypia, and myeloid precursors in the peripheral blood cells, the patient was subjected to a bone marrow examination. The diagnosis was consistent with CMML type 2. The Hemocoagulative test showed an increase in fibrinolysis markers. Next-generation targeted sequencing showed TET2 and SRSF2 mutations, along with an unexpected CSF3R germline missense variant, rarely encountered in CMML. The patient started Azacitidine treatment and achieved normal hemostatic process values. In conclusion, we identified a heterozygous germline mutation that, together with TET2 and SRSF2 variants, was responsible for the hemorrhagic manifestation.

Significance of abnormal blood coagulation in patients with chronic myelomonocytic leukemia.

In a retrospective study, we analyzed the prevalence of subnormal prothrombin time (PT) values in 104 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with clinicolaboratory features. Reduced PT values (< 70%) were found in 45/104 (43%) patients. The median survival of patients with reduced PT values was significantly shorter than in patients with normal PT (19 vs. 49 months, p = 0.006). Patients with reduced PT had higher leukocyte counts, a higher proportion of circulating blast cells, and lower platelet counts. In patients for whom clinical information was available, there was no difference in the incidence of bleeding complications between patients with or without reduced PT. Our results show a high prevalence of plasmatic coagulation abnormalities in patients with CMML, which were associated with laboratory features of advanced disease. Moreover, subnormal PT values were identified as a new prognostic marker. Reduced PT values do not seem to have a clinical impact regarding bleeding complications.

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Myelodysplasia cutis as the presenting sign of chronic myelomonocytic leukaemia.

We describe an unusual case of myelodysplasia cutis in a patient with chronic myelomonocytic leukaemia.

Blastic Indeterminate Dendritic Cell Tumor Associated With Chronic Myelomonocytic Leukemia.

ABSTRACT: Indeterminate dendritic cell tumor (IDCT) is an exceedingly rare neoplasm that can be associated with hematopoietic malignancies. We report a case of multifocal cutaneous blastic indeterminate dendritic cell tumor (BIDCT) in a 75-year-old man with chronic myelomonocytic leukemia showing blastic histiocytoid morphology, positivity for CD1a and S100, and no expression of langerin. We present a literature review on the 11 reported cases of IDCTs/BIDCTs associated with chronic myelomonocytic leukemia (CMML), including this case. The clinicopathological characteristics have been summarized. The IDCT and CMML cells are clonally related in 4 tested cases. Patients with IDCT/BIDCT associated with CMML seem to have worse clinical outcomes compared with patients with IDCT not associated with CMML.

Clinical spectrum, outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.

Atypical cutaneous histiocytic eruption in a patient with chronic myelomonocytic leukemia: A case report.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy with features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. We present a case of 72-year-old man with CMML who presented with generalized hemorrhagic papules and plaques which on histopathology showed a peculiar infiltrate of atypical mature histiocytes. The immunohistochemical markers for Langerhans cells, indeterminate dendritic cells, and plasmacytoid dendritic cells were negative. Next generation sequencing performed on the paraffin block of the leg biopsy specimen revealed identical ASXL1, SRSF2, and KRAS mutations as seen in the CMML clone of the peripheral blood. Along with recent literature, this case illustrates the spectrum of histiocytic and dendritic cell proliferations in CMML, many of which may be clonally related to the hematopoietic malignancy.

Probable catastrophic antiphospholipid syndrome secondary to chronic myelomonocytic leukaemia in an adult patient and a mini review.

Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening form of antiphospholipid syndrome (APS), which could be triggered by malignancy. Chronic myelomonocytic leukaemia (CMML) is an uncommon hematologic malignancy. We report a case of a 49-year-old male patient who presented multiple thromboses with a high titre of anti-ß2-glycoprotein-I antibody. Unexpectedly, there was persistent monocytosis combined with <20% blasts in his bone marrow. Thus, a diagnosis of probable CAPS and CMML was made. After treatment with prednisone, hydroxychloroquine and warfarin, the thromboses dissolved, and an improved presentation of peripheral blood and bone marrow was observed. Here, we also provide a mini review of cases of APS complicated with CMML identified from searches of MEDLINE, EMBASE and Web of Science databases. The review describes the clinical characteristics, laboratory data, treatments and outcomes.

[Lysozyme-induced nephropathy: A rare cause of renal failure in chronic myelomonocytic leukemia]. / La néphropathie induite par le lysozyme : une cause rare d'insuffisance rénale dans la leucémie myélomonocytaire chronique.

INTRODUCTION: Lysozyme-induced nephropathy is a rare and unknown complication of chronic myelomonocytic leukemia with overproduction of lysozyme by tumoral cells leading to proximal tubular cells injuries. The present case reports a lysozyme nephropathy secondary to chronic myelomonocytic leukemia. OBSERVATION: We reported a case of a 82-years-old woman who presented an acute renal failure in a context of diarrhea and vomiting. Her background was characterized by untreated chronic myelomonocytic leukemia and high blood pressure. Despite rehydration, renal function deteriorated. Renal biopsy revealed a tubulo-interstitial lysozyme-induced nephropathy with a vacuolization of the tubular epithelium by eosinophilic droplets stained by anti-lysozyme antibody, without tumoral infiltration of the renal parenchyma. CONCLUSION: Lysozyme-induced nephropathy is a rare disease which can be suspected biologically and needs histologic confirmation. Other causes of renal failure secondary to chronic myelomonocytic leukemia have to be eliminated first in these patients. The treatment is symptomatic and is associated with treatments of the underlying hematologic pathology.

Impact of primary disease on outcome after allogeneic stem cell transplantation for transformed secondary acute leukaemia.

Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)-identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3-year progression-free (PFS) and overall survival (OS) for the entire group was 36% (34-37%) and 41% (40-43%), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) was 37% (35-39%) and 27% (26-29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo-HSCT.

Splenectomy in patients with chronic myelomonocytic leukemia: Indications, histopathological findings and clinical outcomes in a single institutional series of thirty-nine patients.

In a 28-year period, 39 (7%) patients with chronic myelomonocytic leukemia (CMML) (median age 66 years, 64% male) underwent a splenectomy at our institution. Primary indications for splenectomy were refractory thrombocytopenia (36%), progressive spleen related symptoms (33%), emergent splenectomy for splenic rupture (21%), refractory anemia (8%), and prior to allogeneic stem cell transplant (3%). Eleven (28%) patients had anemia at the time of splenectomy, of which 3 (27%) were autoimmune. The median time to splenectomy from CMML diagnosis was 6 months (0-40); perioperative morbidity and mortality rates were 43% and 13%, while the median postsplenectomy survival was 25 months (11-38). Durable remission in spleen related symptoms, thrombocytopenia, complications from splenic rupture, and anemia were achieved in 85%, 50%, 62%, and 21% of patients, respectively. Perioperative morbidity (n = 30) included infections/sepsis in 6 (20%), intraabdominal bleeding in 4 (13%), venous thromboembolism (VTE) in 3 (10%), and acute lung injury in 2 (7%) patients. The median duration of hospital stay was 6 days (1-25), with 5 deaths occurring secondary to respiratory failure (n = 2), multiorgan dysfunction (n = 2) and hemorrhagic shock (n = 1). There was no difference in overall survival between CMML patients that underwent splenectomy, in comparison to those that did not. Unlike in myelofibrosis, portal hypertension was not an indication for splenectomy and no patients developed post-splenectomy thrombocytosis. In conclusion, apart from being a lifesaving emergent modality in the event of splenic rupture, splenectomy has an important palliative role in patients with CMML, with significant and durable improvements in spleen related symptoms and refractory cytopenias.

Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: Case report and review of fungal pericarditis.

Cryptococcus neoformans is a saprophytic fungal pathogen that can cause serious illness in immune-compromised hosts and it presents with a wide variety of clinical symptoms. We present a fatal case of fulminant C. neoformans infection presenting as pericardial tamponade in a 71-year-old male with chronic myelomonocytic leukaemia undergoing chemotherapy with the JAK-STAT inhibitor ruxolitinib. We also review the published cases of fungal pericarditis/tamponade. In addition to illustrating an atypical presentation of C. neoformans, this case highlights the risk for opportunistic fungal infections in patients with haematological malignancies, especially the ones treated with small molecule kinase inhibitors.

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.

[Blastic plasmacytoid dendritic cell neoplasm accompanied by chronic myelomonocytic leukemia successfully treated with azacitidine].

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease that develops with a skin lesion and is often accompanied by leukemic transformation. The normal counterparts of BPDCN tumor cells are progenitors of plasmacytoid dendritic cells, whereas the origins are thought to be hematopoietic stem cells. Approximately 10%-20% of BPDCN patients develop other hematologic malignancies, including chronic myelomonocytic leukemia (CMML). Mutations in epigenetic regulators are frequently observed in both BPDCN and CMML tumors. Azacitidine, a drug that targets epigenetic dysregulation, is known to be an effective treatment for CMML. However, it has been used in few BPDCN patients. Here, we report a BPDCN patient with skin lesions, bone marrow infiltration, and lymphadenopathy. CMML also developed during the course of BPDCN. Azacitidine had positive effects on CMML; however, BPDCN aggressively relapsed during treatment. Two TET2 mutations were found in both BPDCN and CMML tumors; one of which was commonly identified in both tumors.