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Current prognostication in myelofibrosis (MF) is based on clinicopathological features and mutations in a limited number of driver genes. The impact of other genetic mutations remains unclear. We evaluated for mutations in a myeloid panel of 54 genes using next-generation sequencing. Multivariate Cox regression analysis was used to determine prognostic factors for overall survival (OS) and leukaemia-free survival (LFS), based on mutations of these genes and relevant clinical and haematological features. One hundred and one patients (primary MF, N = 70; secondary MF, N = 31) with a median follow-up of 49 (1–256) months were studied. For the entire cohort, inferior OS was associated with male gender (P = 0.04), age > 65 years (P = 0.04), haemoglobin

Dear Editor, Lucena-Araujo et al. recently reported that internal tandem duplication (ITD) of the FLT3 gene in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy led to inferior overall survival, although there was apparently no significant effect on disease-free survival (DFS) [1]. A 55-year-old man was diagnosed with APL in July 2009. Karyotyping showed t(15;17)(q22;q12), and molecular analysis showed PML-RARA of the BCR3 isoform. Induction treatment with ATRA and idarubicin resulted in first complete remission (CR1). This was followed by consolidation with idarubicin, mitoxantrone and ATRA; and maintenance with ATRA, oral methotrexate and 6-mercaptopurine. First relapse (R1) developed 1 year afterwards. Karyotype showed t(15;17)(q22;q12) without additional aberrations. Reinduction with oral arsenic trioxide (As2O3, 10 mg daily), ATRA (45 mg/m/day), and ascorbic acid (1 g daily) for 6 weeks led to CR2, which was consolidated with two monthly cycles of daunorubicin (50 mg/m/day×2) and cytarabine (100 mg/m/day×5). Four doses of intrathecal methotrexate (12 mg) and cytarabine (50 mg) were given as central nervous system (CNS) prophylaxis. That was followed by maintenance with oral-As2O3, ATRA, and ascorbic acid, given 2 weeks every 2 months for 2 years [2]. Molecular monitoring of peripheral blood for PML-RARA had been persistently negative. Three months after completion of maintenance, progressive headache developed. Cerebrospinal fluid (CSF) showed a pleocytosis of 220×10/L, consisting almost exclusively of abnormal promyelocytes (Fig. 1a), indicating frank CNS infiltration and therefore second relapse (R2). However, bone marrow examination only showed 6 % blasts (Fig. 1b), indicating minimal leukemia infiltration. He was treated with intrathecal methotrexate and cytarabine; and re-induced with oral-As2O3, ATRA, and ascorbic acid. On confirmation of CR3 and negativity for PML-RARA, he received craniospinal irradiation and then an autologous hematopoietic stem cell transplantation (HSCT), as he was judged unsuitable for allogeneic HSCT in view of his age and advanced leukemia. Polymerase chain reaction (PCR) [3] showed wild type FLT3 in the peripheral blood and marrow at R2. However, FLT3 ITD was detectable in the R2 CSF blasts (Fig. 1c). To increase the sensitivity for detecting the FLT3 ITD subclone, the FLT3 ITD band was gel purified and sequenced (Fig. 1c). Based on the FLT3 ITD sequence, a clonospecific PCR primer was designed. With the more sensitive clonospecific PCR, FLT3 ITD was still undetectable in the peripheral blood and bone marrow, indicating that at R2, the subclone causing CNS relapse was distinct from the subclone causing marrow relapse. To trace the origin of the FLT3-ITD subclone, the marrow and peripheral blood blasts at R1 were studied. Interestingly, FLT3 ITD was found in the R1 marrow blasts but not in the R1 peripheral blood blasts. On DNA sequencing, this ITD was identical to that in the R2 CSF blasts, showing that the FLT3-ITD subclone in the R1 marrow was related to the FLT3-ITD subclone leading to the CNS infiltration at R2. With clonospecific PCR, R1 peripheral blood blasts was still negative for FLT3 ITD. Therefore, the FLT3-ITD subclone at R1 was a minor subclone that was present only in the marrow. Materials on initial presentation were not available for analysis. In APL, mutations of FLT3, most frequently ITD, are associated with high-presenting WBC count, microgranular variant and the BCR3 isoform of PML-RARA [4, 5]. The impact of FLT3 ITD on outcome has been contentious. H. Gill :A.W. K. Pang : J. Sum :A. Y. H. leung :Y.

The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n = 66; splenic MZL, n = 11; nodal MZL, n = 4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions. © 2011 The Author(s)., published_or_final_version, Springer Open Choice, 21 Feb 2012

Cytomegalovirus (CMV) retinitis is exceptionally rare outside the clinical context of acquired immunodeficiency syndrome and organ allografting. In a population where seropositivity for past CMV infection exceeded 90 %, CMV retinitis was observed in five of 138 patients (3.6 %) receiving fludarabine-containing regimens together with rituximab, which was significantly more frequent than in 141 patients receiving fludarabine-containing regimens alone, where no case was observed (P = 0.029). Treatment of CMV retinitis comprised both intravitreal and systemic ganciclovir/foscarnet. Upon recovery, secondary retinal atrophy occurred in all patients, leading to blindness in 86 % of affected eyes. CMV retinitis is an important complication in patients receiving concomitant rituximab and fludarabine-containing regimens.

The frequency of breakthrough invasive fungal diseases (IFDs) during echinocandin therapy is unclear. We retrospectively analyzed 534 hematologic patients treated with echinocandin (caspofungin, N = 55; micafungin, N = 306; anidulafungin, N = 173). Four proven IFDs were found, caused by Candida parapsilosis (N = 2), C. parapsilosis and Candida glabrata (N = 1), and Fusarium species (N = 1). Four cases of possible IFDs were observed, all showing pulmonary infection. One case showed features suggestive of hepatosplenic candidiasis. Six of these eight cases had previously received the purine analog clofarabine. Breakthrough IFD during echinocandin treatment occurred infrequently (1.5 %), caused predominantly by Candida species. Clofarabine usage was an important risk factor.

published_or_final_version, Springer Open Choice, 21 Feb 2012