Kalman Filanovsky

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

Hypomethylating agents have become the standard therapy for patients with high‐risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA‐treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high‐risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29–92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130–134, 2013.

Higher Infection Rate After 7- Compared With 5-Day Cycle of Azacitidine in Patients With Higher-Risk Myelodysplastic Syndrome

INTRODUCTION Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patients age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.

Advantage of MIDAM Protocol in Treatment of Elderly Patients With Refractory and Relapsing Acute Myeloid Leukemia

regarding treatment of refractory and relapsing acute myeloid leuke-mia (AML) with the intermediate-dose cytarabine and mitoxantrone(MIDAM) regimen. As is well known, the complete response rates(CRR) for these patients are low and the remission duration is short.The MIDAM regimen consisting of cytarabine 1g/m

Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients

This multicentre study evaluated 5‐year progression‐free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography‐computed tomography performed after two cycles (PET‐2). Between September 2006 and August 2013, 359 patients aged 18–60 years, were recruited in nine Israeli centres. Early‐HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET‐2‐positive patients received additional ABVD followed by involved‐site radiotherapy (ISRT). Patients with negative PET‐2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced‐HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET‐2‐negative patients further received ABVD ×4; PET‐2‐positive patients received EB ×4 and ISRT to residual masses. With a median follow‐up of 55 (13–119) months, 5‐year PFS was 91% and 69% for PET‐2‐negative and positive early‐HL, respectively; 5‐year OS was 100% and 95%, respectively. For advanced‐HL, the PFS was 81% and 68%, respectively (P = 0·08); 5‐year OS was 98% and 91%, respectively. PET‐2 positivity is associated with inferior prognosis in early‐HL, even with additional ABVD and ISRT. Advanced‐HL patients benefit from therapy escalation following positive PET‐2. EB can be safely de‐escalated to ABVD in PET‐2‐negative patients.

Systemic mastocytosis associated with smoldering multiple myeloma: an unexpected diagnosis in a patient with a rash

Mastocytosis covers a spectrum of heterogeneous disorders, characterized by increased proliferation, accumulation, and survival of abnormal mast cells in various organs and tissues. The classification for systemic mastocytosis was established by Valent et al. [1] and confirmed in the World Health Organization (WHO) 2008 classification. It recognizes seven different groups of mastocytosis: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with associated clonal hematological non-mast-cell disorder (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma. Cutaneous mast cell disease should be differentiated from systemic disorders. Patients lacking skin involvements have a more aggressive disorder, whereas patients with skin involvements show a more indolent course. Systemic mastocytosis (SM) variants of mast cell disease, with multifocal mast cells involving bone marrow, or at least one extracutaneous organ, are often associated with clonal myeloid malignancy. In routine evaluation of bone marrow specimens, systemic mastocytosis consitituted approximately 0.3% of all hematological diagnoses and nearly 1.5% of all myelogenous tumors [2]. Mast cells, unlike other myeloid cells, complete their maturation exclusively in extramedullary organs. SM-AHNMD is the second most frequent (10– 35%) subtype of SM after ISM. More than 90% of SM-AHNMD cases are associated with myeloid neoplasms [3]. Cases of plasma cell dyscrasia have occasionally been found to be associated with systemic mastocytosis [4–6]. A 76-year-old man with a 4-year history of a rash, which was diagnosed clinically by a dermatologist as urticaria pigmentosa, was referred to our hematology institute for a bone marrow biopsy, as part of the work-up. He was asymptomatic, with an unremarkable medical history. Initial physical examination revealed only a light-brown-hued monomorphic maculopapular rash on the shoulders, chest, abdomen, and anterior part of the thigh. Laboratory studies showed a white blood cell (WBC) count of 7.86 10/mL, with normal differential count, a hemoglobin concentration of 11.5 g/dL, and a platelet count of 2326 10/mL. Serum biochemistry tests were all within the normal range. Imaging studies, including a chest X-ray, skeletal survey, and abdominal ultrasound were found to be normal. A bone scan detected diffuse, axial, and appendicular increased uptake. A bone density study revealed mild osteoporosis. Bone marrow aspiration demonstrated prominent focal infiltration of spindleshaped hypogranular mast cells, which stained positive for toluene blue. The c-KIT point mutation D816V was detected by polymerase chain reaction (PCR) analysis in a bone marrow sample. A trephine biopsy revealed a hypercellular bone marrow, with loss of fat and marked nodular infiltrates of mast cells, associated with a dense network of reticulin fibers. The infiltrates were surrounded by small lymphocytes and eosinophils. A significant atypical

Incidence of Profound Hypogammaglobulinemia and Infection Rate in Lymphoma Patients Following the Combination of Chemotherapy and Rituximab

BACKGROUND The Anti-CD20 monoclonal antibody Rituximab suppresses B-lymphocytes and may induce hypogammaglobulinemia in treated patients. The incidence and clinical significance of rituximab induced hypogammaglobulinemia in lymphoma patients is underestimated. METHODS We retrospectively analyzed the rates of hypogammaglobulinemia, infection and infection-related mortality in 136 lymphoma patients who were treated with a combination of chemotherapy and rituximab. RESULTS Rituximab given in more than 8 doses (OR 6.05, 95% CI: 1.24-29.5), relative hypogammaglobulinemia at time of lymphoma diagnosis (OR 4.2, 95% CI: 1.26-14.1) and the combination of fludarabine with rituximab (OR 3.4, 95% CI: 1.24-9.47) were factors significantly associated with prolonged (more than 6 months) hypogammaglobulinemia. The combination of fludarabine and rituximab (OR 6.4, 95% CI: 1.49-27.0) and secondarily prolonged hypogammaglobulinemia (OR 4.5, 95% CI: 1.19-18.5) were found to be predictive factors for severe infections and infection-related mortality. CONCLUSION These data suggest the importance of following serum immunoglobulin levels before and after combination immuno-chemotherapy, particularly in patients with recurrent infections or relapsed/refractory disease.

The May-Hegglin anomaly.

A 24-yr-old woman at 11 weeks gestation was referred to our hematology department, on account of the discovery of severe thrombocytopenia, during a routine complete blood count examination. She was completely asymptomatic, without any prior bleeding tendency. For many years patient had previous unexplained moderate thrombocytopenia. Peripheral blood examination revealed a white cell count of 8.8 K ⁄ lL, a hemoglobin concentration of 12.1 g ⁄dL, and platelet count of 21 K ⁄ lL (normal range 130–400). Mean platelet volume was significantly elevated 19.7 fl (normal 7.2–11.1 fl). A May–Grünvald–Giemsa stained peripheral blood smear showed the presence of spindle-shaped sky-blue inclusion bodies in the cytoplasm periphery most the neutrophils. These inclusions referred to as Döhle like. Some of the platelets were giants and equivalent in size to erythrocytes (see Fig. 1A). Megakaryocytic numbers in bone marrow aspiration specimen were slightly increased. We noticed that in the cytoplasm, most of the megakaryocytes had coarse streaks (see Fig. 1B). Megakaryocytic nuclear remnants were also increased. May-Hegglin anomaly (MHA) is a rare autosomal dominant platelet disorder, characterized by macrothrombocytopenia, and leukocyte inclusion bodies. Majority of affected heterozygotes or asymptomatic, a minority have a tendency to mild bleeding episodes. The MHA, caused by mutations in the MYH9 gene, which encoding a heavy chain of non-muscle myosin IIA (NMMHC-IIA), had been localized on chromosome 22q12.3–13.1. It is important to diagnose MHA early, to be alert during invasive procedures as well as to prevent excessive treatment when these patients are diagnosed as immune thrombocytopenia.

Can bone marrow cellularity help in predicting prognosis in myelodysplastic syndromes

To ascertain the relevance of bone marrow cellularity (BMC) to the interpretation of blast percentage (blast%) in MDS prognostication.

Safety and efficacy of ibrutinib in a patient with severe renal impairment

Ibrutinib (Imbruvica) is a first-in-class oral inhibitor of Bruton’s tyrosine kinase (BTK), an essential enzyme in B-cell receptor signaling pathway. Since recent approval by the U.S. Food and Drug Administration and European Medicines Agency, it has been widely applied in the therapy of patients with lymphoproliferative disorders, such as mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström’s macroglobulinemia.1 Many of these patients are elderly and have comorbidities including impaired renal function.2,3 There are scarce data in the literature regarding safety and efficacy of the drug in this cohort of patients.4 Despite the fact that less than 10% of ibrutinib is excreted by kidneys, increase in creatinine level 1.5 to 3 times the upper limit of normal occurs in up to 9% of patients during treatment4 and occasionally patients were developed serious renal failure.5 Moreover, patients with preexisting renal impairment were generally excluded from clinical trials using this drug.4,6 Herein, we describe a 78year-old male with severe chronic renal failure (creatinine level 4.46 mg/dL (normal, 0.5-0.9) CrCl 13 mL/min and mantle cell lymphoma that relapsed five years after the first complete remission induced by treatment with cyclophosphamide, oncovin, hydroxydoxorubicin, rituximab and prednisone (CHOP-R regimen). Additional biochemical tests such as electrolytes, uric acid and lactate dehydrogenase were within a normal limit. The patient had a transitional cell carcinoma of the ureter four years ago that was successfully treated by partial right ureterectomy followed by bacillus Calmette-Guerin (BCG) vaccine therapy, although creatinine level gradually increased to 2.0 mg/dL. Abdominal ultrasonography demonstrated normal kidney size and structure. Pretreatment positron-emission computer tomography (CT-PET) revealed widespread lymphadenopathy with high 18fluorodeoxyglucose (FDG) uptake in nasopharynx, mediastinal lymph nodes and duodenum. Bone marrow was not involved. Treatment was started with standard ibrutinib dose 560 mg once daily and tumor lysis syndrome prophylaxis by intensive oral hydration and allopurinol. Weekly renal function assessment was performed. During the first three mounts of treatment any adverse event was observed; repeated CTPET showed improvement with no FDG avid disease. Moreover, creatinine level after initiation of the treatment rapidly decreased (Figure 1). This finding suggests that additional renal function deterioration caused by disease progression. In conclusion, our case showed that ibrutinib can be safely used in patients with severe renal failure under close renal function monitoring. Additional clinical post marketing evaluation needs to be performing in order to confirm our observation. References

Thrombotic thrombocytopenic purpura following terbinafine therapy.

To the Editor: Terbinafine is a highly effective antifungal medication, applied mainly in the dermatophyte treatment. The systemic use of terbinafine has been increasing in the past decade. The drug is well tolerated [1] and hematological adverse reactions are very rare [2,3]. Thrombotic thrombocytopenic purpura (TTP) is an uncommon disease, characterized by deficient activity in the von Willebrand (vWF) factor-cleaving protease ADAMTS13, which specifically cleaves the multimeric vWF factor. Deficiency of ADAMTS13 increases the plasma levels of large vWF multimer, which ultimately leads to platelet clumping, consumptive thrombocytopenia, and thrombi formation [4,5]. Development of TTP has been linked occasionally to a certain medication. Herein, we described patient who experienced TTP following treatment with terbinafine. A 34-year-old Jewish man was referred to our hospital with complaints on fever, weakness, and abdominal pain during 3 days before admission. He had a history of schizophrenia and hyperlipidemia and he had received olanzapine, escitalopram, and simvastatin for several years. Two weeks prior to the appearance of the symptoms, treatment with terbinafine in a daily dose of 250 mg was started for onychomycosis. At admission, the physical examination was unremarkable. Laboratory tests revealed WBC 6.8 3 10/l, hemoglobin 8.9 g/dl, reticulocytes count 3.4%, platelet count 15 3 10/l; lactate dehydrogenase (LDH), and creatinine were elevated 2205 IU/l and 1.6 mg/dl, respectively, while the liver enzymes were within the normal range. Urinalysis was unremarkable. The peripheral blood smear showed multiple schistocytes. Coombs test was negative and the coagulation profile was normal. Serologic study for HIV, hepatitis B and C, as well as antinuclear antibodies were negative. Serum ADAMTS-13 activity was markedly decreased <1% and the anti-ADAMTS-13 antibodies performed by the enzyme-linked immunosorbent assay (ELISA) were moderately increased 37 U/ml (normal range, 0–15). Diagnosis of TTP was established. Terbinafine treatment was ceased and daily 1.0 plasma volume therapeutic plasma exchange (TPE) together with prednisone 1 mg/kg was started. The patient’s clinical condition improved rapidly after the first plasma exchange, whereas the platelet count and LDH level normalized 4 days later. However, 10 days after TPE cessation the patient was readmitted due to recurrent anemia and thrombocytopenia; LDH increased again to 570 IU/l and red cell fragments reappeared on the blood smear. The patient underwent daily TPE retreatment with slow tapering in the procedures number during the subsequent month. Repeated tests on ADAMTS-13 during the follow up of 2 years showed gradual normalization of the activity and disappearance of the antibodies. Several drugs such as clopidogrel, oral contraceptives, quinine, cyclosporine, and others have been reported as the causative factors for TTP by predominant immune-mediated mechanism or less often by the direct toxicity [6–8]. Only few cases of TTP associated with terbinafine were reported and only into social medical site, all of them in the first month of treatment URL http://www.ehalthme.com/ds/lamisil/thrombotic1 thrombocytopenic1purpura [accessed on 10 august 2014]. Mechanism of TTP induction has not been determined [9]. In this case, initial treatment with terbinafine had been followed by a rapid onset of microangiopathic anemia and thrombocytopenia with the finding of anti-ADAMTS-13 antibodies and low levels of ADAMTS-13, supporting a hypothesis of immunemediated toxicity. A short time of illness development after the drug administration and absence of other causes strongly suggest that TTP was triggered by