Ruxolitinib for the treatment of myelofibrosis: its clinical potential

Ruxolitinib is an orally bioavailable, selective Janus kinase (JAK) 1 and 2 inhibitor approved for the treatment of myelofibrosis (MF), a bone marrow disease in which the JAK pathway is dysregulated, leading to impaired hematopoiesis and immune function. By inhibiting JAK1 and JAK2, ruxolitinib modulates cytokine-stimulated intracellular signaling. In a phase II clinical trial in patients with MF, ruxolitinib recipients exhibited durable reductions in spleen size, reductions in circulating pro-inflammatory cytokines, improvements in physical activity, weight gain, and alleviation of symptoms (including constitutional symptoms) in patients with and without JAK2 mutation. These findings were confirmed by two phase III clinical MF studies, in which a greater proportion of ruxolitinib recipients achieved a spleen volume reduction of ≥35% from baseline at week 24, compared with placebo in one study (41.9% versus 0.7%; P < 0.0001) and with best available therapy in the other (31.9% versus 0%; P < 0.0001). Alleviation of MF symptoms and improvements in quality of life were also significantly greater in ruxolitinib recipients. Overall survival of patients treated with ruxolitinib was significantly longer than of those receiving the placebo. Owing to risks of potentially serious adverse effects, eg, myelosuppression, ruxolitinib should be used under close physician supervision. Longer follow-up of the phase III MF studies is needed to reach firm conclusions regarding ruxolitinib’s capacity to modify the natural disease course

Miastenija gravis udružena s timomom i aplastičnom anemijom: prikaz slučaja

Myasthenia gravis is associated in 10 to 15 percent of patients with thymic tumors, rarely with aplastic anemia. We report a 45-year-old male diagnosed with myasthenia gravis ­associated with thymoma. We started treatment with pyridostigmine. After thymectomy, the patient ­received 30 irradiation sessions. In the postoperative course, he had mild worsening of myasthenia gravis, which improved with prednisone. Five months later, he developed severe aplastic anemia. He was dependent on blood supplement. After allogeneic transplantation of bone marrow, he improved but later he ­developed graft versus host disease. Myasthenia gravis was under good control with 480 mg of ­pyridostigmine per day.Miastenija gravis (MG) je u 10% do 15% bolesnika udružena s tumorima timusa, rijetko s aplastičnom anemijom. Prikazujemo 45-godišnjeg bolesnika s MG udruženom s timomom. Liječenje je započeto piridostigminom. Nakon timektomije je provedeno 30 zračenja. Poslijeoperacijski je imao blago pogoršanje MG koje se povuklo uz terapiju prednizonom. Pet mjeseci kasnije je razvio tešku aplastičnu anemiju. Postao je ovisan u krvnim derivatima. Nakon alogenične transplantacije koštane srži došlo je do poboljšanja, ali je kasnije razvio reakciju transplantata protiv primatelja. MG je bila dobro kontrolirana uz 480 mg piridostigmina na dan

The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation

Arsenic trioxide (ATO) has potent clinical activity in the treatment of patients with acute promyelocytic leukemia (APL), but is much less efficacious in acute myeloid leukemia (AML) lacking t(15;17) translocation. Recent studies have indicated that the addition of mammalian target of rapamycin (mTOR) inhibitors may increase the sensitivity of malignant cells to ATO. The aim of the present study was to test for possible synergistic effects of ATO and rapamycin at therapeutically achievable doses in non-APL AML cells. In HL-60 and U937 cell lines, the inhibitory effects of low concentrations of ATO and rapamycin were synergistic and more pronounced in U937 cells. The combination of drugs increased apoptosis in HL-60 cells and increased the percentage of cells in G(0)/G(1) phase in both cell lines. In U937 cells, rapamycin alone increased the activity of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the addition of ATO decreased the level of phosphorylated ERK, Ser473 phosphorylated Akt and anti-apoptotic Mcl-1 protein. Primary AML cells show high sensitivity to growth-inhibitory effects of rapamycin alone or in combination with ATO. The results of the present study reveal the mechanism of the synergistic effects of two drugs at therapeutically achievable doses in non-APL AML cells

Post-thaw Viability of Cryopreserved Hematopoietic Progenitor Cell Grafts: Does It Matter?

Cell viability in peripheral blood progenitor cell (PBPC) grafts and its influence on the clinical course following transplantation was evaluated in 81 consecutive transplantations (72 autologous, 9 allogeneic) performed in patients with hematological diseases. Viability of cells in PBPC grafts immediately upon collection was 98.6±3.5%, after addition of dimethyl sulfoxide (DMSO) 73.3±21.8%, and post-thaw 65.2±16.1%. It did not differ significantly between patients with different diagnoses, gender, age, type of priming used, dose of G-CSF administered or number of CD34+ cells collected. However, grafts stored for more than 60 days showed lower post-thaw viability compared to the ones thawed in the 60 days following cryopreservation (56.6±15.2% vs. 67.6±15.5%, p=0.04). Post-thaw graft viability did not influence engraftment time, but there was a predisposition towards infectious complications in the post-transplant period in patients receiving grafts with lower percentage of viable cells. They developed febrile neutropenia more often (72.2% vs. 50% of patients, p=0.05) and had more febrile days (2.4±2.6 vs. 1.5±2.3, p=0.05) following transplantation. We have demonstrated that PBPC grafts are capable of long term engraftment regardless of the graft storage time or percentage of viable cells post-thaw, which confirms the robustness of CD34+ cells during the freeze/thaw procedures carried out in daily clinical practice. Granulocyte concentration in PBPC grafts could have an influence on infectious complications following transplantation and needs to be further investigated on a larger number of patients

Amniotic membrane transplantation for severe ocular graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Allogeneic stem cell transplantation (allo-SCT) offers cure to otherwise incurable hematologic malignancies, but can also lead to many infectious and immune complications, most importantly graft-versus-host disease (GVHD). Ocular GVHD (oGVHD) occurs in 40-60% of allo-SCT patients and can result in severe ocular surface disease causing vision impairment and deterioration of quality of life. Amniotic membrane transplantation (AMT) is an established technique in the treatment of various diseases of the ocular surface. This method could provide new options in the management of otherwise disabling severe oGVHD We describe a young female patient with myeloproliferative neoplasm who underwent allo-SCT from an unrelated donor and suffered from numerous post-transplant complications. In the early post-transplant period she developed acute skin and liver GVHD, requiring introduction of immunosupressive treatment with steroids. Steroid treatment was then complicated with miopathy, iatrogenic diabetes and many infections. She developed serious herpes virus (HSV) ophtalmitis followed by severe GVHD of the eye. Despite multiagent local therapy, oGVHD progressed to ocular ulcers with threatening corneal perforation. We hesitated from increasing systemic immunosupression due to severity of previous HSV reactivation. Therefore we decided to perform AMT which led to complete corneal healing and full clinical recovery. Moreover, there was no recurrence of severe oGVHD and the patient resumed her daily activities In conclusion, this case report serves as a foundation for further research of AMT possibilities. This procedure could become beneficial in the treatment of severe oGVHD, especially in patients at high risk for infectious complications and contraindication for systemic immunosuppression

An Unusual Presentation of Gaucher’s Disease: Aortic Valve Fibrosis in a Patient Homozygous for a Rare G377S Mutation

Gaucher’s disease (GD) has variable presentations, but cardiac involvement is a generally uncommon clinical manifestation of the disease. In the past 25 years, the underlying genetic disorder in GD has been well characterized, with almost 300 mutations identified in the glucocerebrosidase gene (GBA). Nevertheless, clear genotype-phenotype correlations have been confirmed only for the most frequent mutations. We present a female patient, who was known to have aortic valve pathology from the age of 30. Despite medical follow up, at the age of 60 she presented with heart failure (NYHA III). At that time echocardiography showed severe fibrosed aortic valve stenosis. Valvuloplasty was planned, when thrombocytopenia, previously considered to be autoimmune, became severe. Anemia and leukopenia were also noted. Moderate splenomegaly and severe bone marrow infiltration were found on MRI. Bone marrow aspiration revealed typical Gaucher cells and the enzyme activity assay confirmed the diagnosis. DNA investigation showed that the patient is homozygous for the G377S mutation. To our knowledge, of all mutations identified so far, only homozygosity for the D409H mutation has been associated with cardiovascular valvular disease in patients with a rare type 3c GD. G377S, found in our patient, is a rare mutation, previously reported as a \u27mild’ mutation, because of the finding that homoallelic patients were essentialy asymptomatic or had mild disease. Our patient, also homozygous for G377S mutation, had a severe form of type 1 GD, with rare cardiac valve involvement, which is a previously unreported clinical presentation for this mutation. This case further proves that patients with the same genotypes can have different phenotypes, emphasizing the influence of other genetic and/or environmental factors

Post-thaw Viability of Cryopreserved Hematopoietic Progenitor Cell Grafts: Does It Matter?

Cell viability in peripheral blood progenitor cell (PBPC) grafts and its influence on the clinical course following transplantation was evaluated in 81 consecutive transplantations (72 autologous, 9 allogeneic) performed in patients with hematological diseases. Viability of cells in PBPC grafts immediately upon collection was 98.6±3.5%, after addition of dimethyl sulfoxide (DMSO) 73.3±21.8%, and post-thaw 65.2±16.1%. It did not differ significantly between patients with different diagnoses, gender, age, type of priming used, dose of G-CSF administered or number of CD34+ cells collected. However, grafts stored for more than 60 days showed lower post-thaw viability compared to the ones thawed in the 60 days following cryopreservation (56.6±15.2% vs. 67.6±15.5%, p=0.04). Post-thaw graft viability did not influence engraftment time, but there was a predisposition towards infectious complications in the post-transplant period in patients receiving grafts with lower percentage of viable cells. They developed febrile neutropenia more often (72.2% vs. 50% of patients, p=0.05) and had more febrile days (2.4±2.6 vs. 1.5±2.3, p=0.05) following transplantation. We have demonstrated that PBPC grafts are capable of long term engraftment regardless of the graft storage time or percentage of viable cells post-thaw, which confirms the robustness of CD34+ cells during the freeze/thaw procedures carried out in daily clinical practice. Granulocyte concentration in PBPC grafts could have an influence on infectious complications following transplantation and needs to be further investigated on a larger number of patients

Amniotic membrane transplantation for severe ocular graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Allogeneic stem cell transplantation (allo-SCT) offers cure to otherwise incurable hematologic malignancies, but can also lead to many infectious and immune complications, most importantly graft-versus-host disease (GVHD). Ocular GVHD (oGVHD) occurs in 40-60% of allo-SCT patients and can result in severe ocular surface disease causing vision impairment and deterioration of quality of life. Amniotic membrane transplantation (AMT) is an established technique in the treatment of various diseases of the ocular surface. This method could provide new options in the management of otherwise disabling severe oGVHD We describe a young female patient with myeloproliferative neoplasm who underwent allo-SCT from an unrelated donor and suffered from numerous post-transplant complications. In the early post-transplant period she developed acute skin and liver GVHD, requiring introduction of immunosupressive treatment with steroids. Steroid treatment was then complicated with miopathy, iatrogenic diabetes and many infections. She developed serious herpes virus (HSV) ophtalmitis followed by severe GVHD of the eye. Despite multiagent local therapy, oGVHD progressed to ocular ulcers with threatening corneal perforation. We hesitated from increasing systemic immunosupression due to severity of previous HSV reactivation. Therefore we decided to perform AMT which led to complete corneal healing and full clinical recovery. Moreover, there was no recurrence of severe oGVHD and the patient resumed her daily activities In conclusion, this case report serves as a foundation for further research of AMT possibilities. This procedure could become beneficial in the treatment of severe oGVHD, especially in patients at high risk for infectious complications and contraindication for systemic immunosuppression

Primary Gastrointestinal non-Hodgkin Lymphoma in Adults: Clinicopathologic and Survival Characteristics

Primary non-Hodgkin lymphomas of gastrointestinal tract (PGI-NHL) are the most common extranodal lymphomas with an increasing incidence. The incidence, clinicopathologic characteristics, treatment and survival were assessed in 39 successive, newly diagnosed PGI-NHL patients (23 male and 16 female) treated at »Merkur« University Hospital. The aim of the study was to precisely evaluate their characteristics and compare them with the results reported from other similar studies. The most common site of PGI-NHL was stomach (n=29, 74%), followed by small intestine (n=5, 13%), and colon and rectosigmoid (n=5, 13%). According to the Ann Arbor classification, 34 (87%) patients had stage IE and IIE, and five patients (12%) stage IIIE and IVE. According to World Health Organization (WHO) classification, 29 (87%) patients had diffuse large B-cell lymphoma (DLCBL), two had mantle cell lymphoma, and seven (18%) had marginal zone B-cell lymphoma-mucosa associated tissue (MALT). Twenty-six (66%) patients underwent surgical resection followed by chemotherapy, ten (26%) were treated with chemotherapy alone, and three (8%) were treated surgically. Complete remission was achieved in 28 (72%) and partial remission in seven (18%) patients. Four (10%) patients had progressive disease. In our patients, the major prognostic factor for outcome was the stage of disease. Patients with localized lymphoma (stage IE and IIE) had a significantly longer overall survival: 85% at five years and 65% at ten years. Patients with extended disease (stage IIIE and IVE) had overall survival less than 33%. The prognostic power of erythrocyte sedimentation rate (ESR), total protein, serum albumin, LDH concentration and activity was analyzed. Of these parameters, only LDH had a statistically significant effect on overall survival. In conclusion, our patient group was comparable to other literature reports on PGI-NHL patients according to clinicopathologic characteristics. Disease stage and LDH were the only parameters that had a statistically significant effect patient survival