The random recombination of immunoglobulin V(D)J gene segments produces unique IgM antibodies that serve as the antigen receptor for each developing B cell. Hence, the newly formed B cell repertoire ...is comprised of a variety of specificities that display a range of reactivity with self‐antigens. Newly generated IgM+ immature B cells that are non‐autoreactive or that bind self‐antigen with low avidity are licensed to leave the bone marrow with their intact antigen receptor and to travel via the blood to the peripheral lymphoid tissue for further selection and maturation. In contrast, clones with medium to high avidity for self‐antigen remain within the marrow and undergo central tolerance, a process that revises their antigen receptor or eliminates the autoreactive B cell altogether. Thus, central B cell tolerance is critical for reducing the autoreactive capacity and avidity for self‐antigen of our circulating B cell repertoire. Bone marrow cultures and mouse models have been instrumental for understanding the mechanisms that regulate the selection of bone marrow B cells. Here, we review recent studies that have shed new light on the contribution of the ERK, PI3K, and CXCR4 signaling pathways in the selection of mouse and human immature B cells that either bind or do not bind self‐antigen.
Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective ...randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).
Background and aims
Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1‐negative myeloproliferative neoplasms. The aim of this study was to evaluate ...the real‐life use of anagrelide in patients with ET followed over 25 years at the Haematological Institutes belonging to “Ph1‐negative Myeloproliferative Neoplasms Latium Group.”
Patients and methods
Eligibility criteria were diagnosis of ET and treatment with anagrelide. Data were collected through an ad hoc case report form.
Results
One hundred and fifty patients received anagrelide for a median time of 7.4 years (0.1‐23.2). Anagrelide was administered as first‐line therapy in 34.7% of patients, as second‐line in 52% and as third‐line in 13.3%: 85.4% responded to therapy. Sixty‐eight/136 evaluable patients reported side effects: palpitations, peripheral vasodilation, anaemia, diarrhoea and gastric distress. Fourteen thrombotic (arterial 10, venous 4) and 51 bleeding events (minor 48, major 3) occurred. Sixteen/150 (10.6%) patients developed secondary myelofibrosis and 3/150 (2%) an acute myeloid leukaemia.
Conclusions
In our experience, anagrelide is an effective drug in reducing platelet levels in a high percentage of patients with ET. It is especially addressed to younger people. A careful assessment of the thrombotic risk and monitoring of cardiac function, at diagnosis and during follow‐up, is mandatory.
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy.
BACKGROUND AND OBJECTIVES: The tumor necrosis factor-related ...apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, many cancer cells are resistant to apoptosis induction by TRAIL. The present study was designed to evaluate the sensitivity to TRAIL-induced apoptosis in acute myeloblastic leukemias (AML). DESIGN AND METHODS: TRAIL/TRAIL receptor (TRAIL-R) expression and sensitivity to TRAIL-mediated apoptosis were explored in 79 AML patients, including 17 patients with acute promyelocytic leukemia (APL). RESULTS: In non-APL AML we observed frequent expression of TRAIL decoy receptors (TRAIL-R3 and TRAIL-R4), while TRAIL-R1 and TRAIL-R2 expression was restricted to AML exhibiting monocytic features. Total leukemic blasts, as well as AML colony-forming units (AML-CFU), were invariably resistant to TRAIL-mediated apoptosis. APL express membrane-bound TRAIL on their surface and exhibit a pattern of TRAIL-R expression similar to that observed in the other types of AML. Before, during and after retinoic acid treatment APL cells are TRAIL-resistant. The induction of granulocytic maturation of APL cells by retinoic acid was associated with a marked decline of TRAIL expression. INTERPRETATION AND CONCLUSIONS: The analysis of experimental APL models (i.e., U937 cells engineered to express PML/RAR-Eo and NB4 cells) provided evidence that PML/RAR-Eo expression was associated with downmodulation of TRAIL-R1 and with resistance to TRAIL-mediated apoptosis. We suggest that AML blasts, including APL blasts, are resistant to TRAIL-mediated apoptosis, a phenomenon seemingly related to the expression of TRAIL decoy receptors on these cells. Finally, APL blasts express membrane-bound TRAIL that could confer an immunologic privilege to these cells.
The value of dual-color fluorescence in situ hybridization (FISH) for the detection of inv(16), using two contigs of cosmid probes mapping on both sides of the chromosome 16p breakpoint region, was ...evaluated in 23 acute myeloid leukemias (AML) in different phases of the disease. At diagnosis interphase FISH detected inv(16) in 19/19 (100%) cases with conventional cytogenetics (CC) evident aberration and excluded the rearrangement in two patients with CC suspected inv(16). Moreover, it also identified an associated del(16p) in two patients. At relapse, it revealed the inv(16) in 8/8 (100%) studied cases. These results were concordant with those of reverse transcriptase-polymerase chain reaction (RT-PCR). From 13 patients who obtained at least one complete remission (CR), 31 follow-up samples were analyzed using interphase FISH. Twenty-nine specimens scored negative for inv(16) and two were positive. RT-PCR detected CBFbeta/MYH11 transcripts in four of the nine CR samples analyzed, being more sensitive than interphase FISH. Eight of the 13 patients relapsed at a median time of 6.5 months (range 1-15) from the last negative FISH analysis. Of the two patients with positive FISH in CR, one relapsed soon after. At diagnosis and relapse, interphase-FISH proved to be an effective technique for detecting inv(16) appearing more sensitive than CC. Prospective studies with more frequent controls and possibly additional FISH probes are needed to assess the value of interphase FISH for minimal residual disease (MRD) and relapse prediction.
A home care service has been implemented at our center with the aim of offering domiciliary assistance to patients with hematologic malignancies in advanced phase. We report our experience concerning ...the home management of these patients in the setting of infective complications. Of 151 patients in home care, 70 (46%) developed a total of 109 febrile episodes, performance status and neutrophil count significantly affecting the incidence of infections. Fever was of unknown origin in 51% of cases and microbiologically and clinically documented infections accounted for 26 and 23% of the cases, respectively. Oral ciprofloxacin in patients not neutropenic and intravenous ceftriaxone plus amikacin in neutropenic patients was shown to be effective and suitable for empiric home antibacterial treatment; in fact, 65% of febrile episodes responded to the initial antibacterial therapy with a further 16% after modification. Overall, 19.3% of the infective episodes were fatal, the prognosis appearing to be similar to that usually observed in the same category of patients in an inpatient setting. Our experience appears to show that a home care program could be the option of choice for patients with advanced cancer even in the setting of infective complications. It could improve the quality of life of patients and of their families, and it could save these subjects the risk of developing infections by resistant nosocomial isolates.
Adult Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph1-positive ALL) represents about 30% of all adult ALL, and is considered a poor prognosis disease, since complete remission ...(CR), which can be achieved in 50-70% of cases, is usually short in patients treated with conventional chemotherapy. Presently bone marrow transplantation, performed early in first CR is becoming the treatment of choice, as it has shown to be able to cure some cases. In a ten-year period, at our department, among 108 adult ALL patients, in which cytogenetics was successfully carried out at diagnosis, 24 (22%) resulted Ph1-positive. Molecular biology was performed in 13 out of these 24 patients: 10 patients showed a p210 rearrangement and three p190. All patients have been treated at induction with conventional drugs, with a CR rate of 96%. As post-remission therapy, the first 17 cases (group 1) followed a chemotherapeutic program, like the other adult ALL; while the remaining six patients (group 2) have been enrolled in a pilot study including early BM transplantation. In group 1, the median overall duration of first CR is 7 months; 50% of relapses were recorded within the first 6 months, although in this group five patients exhibited a first CR prolonged more than 30 months. In group 2, among the six patients, three were submitted to allogeneic bone marrow transplantation (BMT), and three to autologous bone marrow transplantation (ABMT). Overall median duration of first CR is 13 months. Three patients relapsed, three are in continuous CR for 11, 31 and 32 months.
We report a case of therapy-related acute myeloid leukemia (t-AML), M4 FAB subtype, with t(10;11)(p14;q21) chromosome abnormality developed in a patient treated for acute promyelocytic leukemia (APL) ...after 4 years of continuous complete remission (CCR). Two distinct forms of t-AML have been described: the classical type and the second type. Our case has many characteristics in common with the second type of t-AML such as: exposure to topoisomerase II active agents (idarubicin (IDA), mitoxantrone (MITOX), etoposide (VP16)), M4 FAB subtype, a latency period of 39 months and absence of a preleukemic phase. However, it differs in the chromosome 11 breakpoint (band q21 instead of q23) and absence of ALL-1 (Hrx, MLL, Htrx) gene involvement. This can represent the second observation of t-AML occurring after treatment for APL.
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