Sandra Atzeni

Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis

Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis

Gynecomastia in a male after dasatinib treatment for chronic myeloid leukemia

21: 1532–1544. 6 Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C et al. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood 2008; 111: 1524–1533. 7 Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854. 8 Mayr C, Speicher MR, Kofler DM, Buhmann R, Strehl J, Busch R et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood 2006; 107: 742–751.

Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients.

Several recent reports suggest a possible role for killer immunoglobulin-like receptors (KIR) in the onset of chronic myeloid leukemia (CML) and response to therapy with tyrosine kinase inhibitors (TKIs). To explore this hypothesis, we studied KIRs and their human leukocyte antigen class I ligands in 59 consecutive patients with chronic-phase CML (mean age, 53 years; range, 23-81 years) and a group of 121 healthy control participants belonging to the same ethnic group as the patients. The 2-year cumulative incidence of complete molecular response, obtained after a median of 27 months (range, 4-52 months), was 51.2%. An increased frequency of the activating receptor KIR2DS1 (pm = 0.05) and a reduced frequency of the KIR-ligand combination KIR2DS2/2DL2 absent/C1 present (pm = 0.001) were significantly associated with CML. Moreover, KIR repertoires in patients appeared to influence response to TKI therapy. Homozygosity for KIR haplotype A (pm = 0.01), a decreased frequency of the inhibitory KIR gene KIR2DL2 (pm = 0.02), and low numbers of inhibitory KIR genes (pm = 0.05) were all significantly associated with achievement of complete molecular remission. These data suggest that a decrease in properly stimulated and activated NK cells might contribute to the occurrence of CML and indicate homozygosity for KIR haplotype A as a promising immunogenetic marker of complete molecular response that could help clinicians decide whether to withdraw treatment in patients with CML.

Absence of histological myopathy in chronic myeloid leukemia patients complaining of muscle spasms and myalgia during treatment with nilotinib.

The second-generation tyrosine kinase inhibitor (TKI), Nilotinib Tasigna; Novartis Pharmaceuticals Corporation, East Hanover, ew Jersey, USA), is more selective than imatinib (Gleevec/Glivec; ovartis Pharmaceuticals Corporation, East Hanover, New Jersey, SA) for BCR-ABL. The safety profiles of these drugs are generlly similar with several overlapping non-hematologic adverse vents (AE). Muscle pains or cramps are commonly described uring treatment and sometimes determine the need for dose eduction or dose interruption. In the ENESTnd trial, 16 perent of patients treated with nilotinib 400 mg twice daily [1] eported myalgia or muscle spasms of all grades according to he National Cancer Institute Common Toxicity Criteria, Version (NCI CTC-4); in the GIMEMA trial, 41 percent of patients expeienced bone/muscle/joint pain (combined grouping) [2]. A recent tudy on the health related quality of life (HRQoL) of 448 chronic yeloid leukemia (CML) patients receiving imatinib showed that usculoskeletal pain and muscle cramps were reported by 72% nd 78% of them, respectively [3]. Although some anecdotal eports have described muscle edema or rhabdomyolysis and heir treatment, the pathogenesis and clinical management of yalgia and muscle cramps during TKI therapy remains a chalenge. Additionally, histological studies are completely lacking 4–6]. We discuss the results of muscle biopsy in 2 CML patients who ad to interrupt or reduce therapy with nilotinib because of muscle ain. In April 2005, a 65-year-old man was referred to our center or leukocytosis [white blood cells (WBC) 36.6 × 109/L, hemoglobin Hb) 13.7 g/dL, platelets (PLT) 448 × 109/L] and mild splenomegaly. fter a bone marrow aspirate, he was diagnosed with chronichase CML. The karyotype 46,XY,t(9;22) was found in 100% of the etaphases. In May, treatment was started with 400 mg oral imainib daily. The patient achieved complete hematologic response CHR) after 20 days of therapy, complete cytogenetic response CCyR) after 9 months and major molecular response (MMR) docmented by BCR-ABL p210 < 0.1% on real-time quantitative polyerase chain reaction (RQ-PCR) assay, after 12 months. Five years ater, imatinib had to be discontinued for adverse events [(diarrhea rade 3, increase of ≥7 stools per day over baseline and limited self are in activities of daily living (ADL)]. In May 2010, the patient was tarted on treatment with nilotinib 600 mg, daily. After 1 month, e complained of muscle pain in both thighs and limited walking bility (grade 2 NCI CTC-4). Laboratory analysis revealed normal alues of C-reactive protein (CRP), creatine kinase (CK), lactate ehydrogenase (LDH) and electrolytes (sodium, potassium, calium, phosphate, magnesium, chloride). The drug was discontinued

Essential thrombocytemia following immune thrombocytopenia with JAK2V617F mutation

JAK2V617F mutation is found in about 60% of cases of essential thrombocytemia (ET) and represents a driving mutation. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by a low platelet (PLT) count. So far, only 2 reports described ET following ITP. For the first time we analyzed in a patient the JAK2V617F allele burden at ITP onset occurred 13 years before the ET diagnosis and found the presence of a small clone JAK2V617F positive clone (3%) raised to 27% in the following years. The association of ET and ITP could suggest similar pathogenetic mechanisms that should be further investigated.

Familial occurrence of chronic myeloid leukemia

Although recent years have witnessed a dramatic improvement in our understanding of the pathogenesis of chronic myeloid leukemia (CML), the mechanisms by which the Philadelphia (Ph) chromosome is first formed are unknown and the role of heritable aspects and predisposing environmental factors in the etiology of the disease remains unclear [1]. Observations about CML occurring in families are rare, but a recent population-based study investigating malignancies among first-degree relatives of patients affected by myeloproliferative neoplasms (MPN), assessed a two-fold increased risk of developing CML [2]. Here, we describe the occurrence of CML in a brother and sister and discuss the possible role of heritable aspects in the pathogenesis of the disease. In March 1999, a 45-year-old female was referred to a hematology center for leukocytosis, (white blood cells (WBC) 145.76 10/L, hemoglobin (Hb) 8.5 g/dL, platelets (PLT) 7506 10/L), severe splenomegaly and fever. After a bone marrow aspirate, she was diagnosed with CML in the chronic phase. The karyotype 46,XX,t(9;22)(q34;q11), i(17)(q10) was found in 100% of the metaphases. Molecular analysis showed the b3a2 (p210) BCRABL fusion transcript. Cytoreductive therapy started with hydroxiurea 2.5 g/day. In April, WBC decreased to 15.96 10/L, with Hb1⁄4 8.5 g/dL and PLT1⁄4 7806 10/L. Therapy with interferon a 9 MU/day combined with cycles of subcutaneous Cytarabine 40 mg/day and hydroxiurea 1 g/day was scheduled. After 3 months of treatment, blood tests showed leukocytosis and thrombocytosis (WBC1⁄4 25.76 10/L, Hb1⁄4 8.9 g/dL, PLT1⁄4 4186 10/L); cytogenetic evaluation of bone marrow revealed 85% of metaphases harbouring the t(9;22) translocation. Bone marrow transplantation (BMT) was then considered and HLA typing showed: HLAA*11,*30; B*18,*55; Cw*03,*05; DRB1*03; DQB1*02. Because an HLA-match was not found within the family, BMT was performed from an unrelated donor in September 1999. The patient died 1 month after transplantation without achieving engraftment. In January 2007, her 50-year-old brother was admitted to our center for severe thrombocytosis and leukocytosis (PLT1⁄4 1.5676 10/L, WBC1⁄4 12.66 10/L, Hb1⁄4 14.5 g/dL). Bone marrow aspirate showed 46,XY,t(9;22)(q34;q11) in 90% of the metaphases and molecular analysis revealed the b3a2 (p210) BCR-ABL fusion transcript; JAK2v617f mutation was negative. Treatment was started with Imatinib 400 mg/day. Complete hematologic response was achieved after 27 days of therapy: blood tests showed WBC1⁄4 5.66 10/L, Hb1⁄414.2 g/dl, PLT1⁄4 4076 10/L. Complete cytogenetic and molecular response was achieved after 5 months of treatment with Imatinib and the patient continued to be in remission after 20 months of therapy. Patient HLA typing showed: HLA-A*03,*32; B*07,*64; Cw*07; DRB1*07,*11; DQB1*02,*07. Analysis of HLA haplotype segregation within the family revealed that the two affected siblings had inherited two different haplotypes from their parents and were therefore totally HLA-mismatched.