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Omacetaxine mepesuccinate (Synribo®) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment. [ABSTRACT FROM AUTHOR]

Omacetaxine mepesuccinate promotes apoptosis by inhibiting the production of short-lived oncoproteins. The efficacy and safety of omacetaxine in patients with advanced chronic myeloid leukemia (CML) previously treated with tyrosine kinase inhibitors were assessed in two phase II trials (CML-202 and CML-203). Fifty-one patients in accelerated phase (AP-CML) and 44 in myeloid blast phase (BP-CML) received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1-14 every 28 days until hematologic response/improvement or any cytogenetic response, then days 1-7 every 28 days until disease progression. The primary endpoint was maintenance or attainment of a major hematologic response (MHR). Cytogenetic responses were also evaluated. MHR was 37% in patients with AP-CML and 9% with BP-CML (22% and 5% in those with a history of T315I). Most grade 3/4 adverse events were related to myelosuppression, and were generally manageable. Omacetaxine demonstrates activity and an acceptable safety profile in pretreated patients with advanced CML, irrespective of mutational status. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the efficacy and safety of lenalidomide monotherapy in pretreated patients with peripheral T-cell lymphoma not otherwise specified (PTCL-nos).

Imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, some patients may experience resistance or intolerance to imatinib over time. For these patients, two excellent therapeutic options are available. Dasatinib, approved in 2006 for the treatment of patients with CML in all phases who experience imatinib resistance or intolerance, has displayed significant efficacy, with a 2-year follow-up showing durable hematologic and cytogenetic responses, as well as prolonged progression-free and overall survival. Nilotinib was approved in 2007 for the treatment of patients with CML in chronic phase or CML in accelerated phase, resistant or intolerant to prior therapy including imatinib, based on strong efficacy as well as a favorable safety profile. Several factors, including mutation status, patient history, and existing comorbidities can impact the decision to use dasatinib or nilotinib, or pursue other options such as allogeneic stem cell transplant. The purpose of this review article is to shed light on a further consideration when deciding which agent to use, based on the efficacy and safety of dasatinib and nilotinib. This consideration involves the differences in both the imatinib-resistant and -intolerant patients enrolled in the pivotal studies for each agent, as well as other trial criteria. [ABSTRACT FROM AUTHOR]

Young patients (aged 18-60 years) with good-prognosis diffuse large B-cell lymphoma (DLBCL) [0 and 1 risk factor according to age-adjusted international prognostic index (aa-IPI)] are distinguished from patients with poor-prognosis. Six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) in combination with rituximab achieved best results in young patients with low-risk DLBCL. We retrospectively analyzed the data of 82 patients (18-60 years) with untreated aa-IPI 0-1 DLBCL, from six Italian institutions, who underwent, between January 2002 and January 2007, rituximab-cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomicin and prednisone (R-MACOP-B) therapy followed, in patients with bulky presentation, by 30-36 Gy involved-field radiation therapy (34 patients). An overall response rate was noted in 77 out of 82 (94%) patients (75 patients had a complete response (91%), 2 patients had a partial response). With a median follow-up of 46 months, 7-year progression-free and overall survival were estimated to be 91% and 94%, respectively. R-MACOP-B regimen followed by involved-field radiation on bulky presentation is safe and very effective in the treatment of young patients with low-risk DLBCL. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the result of the study concerning the association of essential thrombocythemia and non-Hodgkin lymphoma.

The JAK2V617F mutation occurs in 50% of patients with essential thrombocythemia (ET). We investigated the correlation between the JAK2V617F mutation and clinical and laboratory characteristics, thrombohemorrhagic risk and incidence of disease evolution in 275 patients with ET followed for a median follow-up of 7 years. JAK2V617F mutation was detected in 175 patients (64%), of whom 173 were heterozygous. Patients with the mutation were older and displayed higher hemoglobin and hematocrit levels, but lower platelet count. Cytotoxic treatment requirement was similar in the two groups, but patients with the mutation showed better responses. Incidence of thrombosis and disease evolution was comparable. JAK2 mutational status assessment was valuable to distinguish two populations of patients with ET, showing distinctive hematologic and clinical features. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study on the impact of additional cytogenetic abnormalities (ACA) on the response and survival of patients with late chronic phase chronic myeloid leukemia (CML), who were treated with the Bcr-Abl tyrosine kinase imatinib mesylate.

Chronic myeloid leukemia (CML) is the first human malignancy for which the promise of targeted therapy has come true. CML is invariably associated with a specific genetic lesion - the t(9;22) chromosomal translocation. As a consequence of this translocation, a BCR-ABL fusion gene is formed on the 22q- derivative (traditionally known as the Philadelphia chromosome) and the deregulated tyrosine kinase activity of the protein encoded by this gene has been shown to be both necessary and sufficient for initiation and maintenance of the disease. Imatinib mesylate, an orally available tyrosine kinase inhibitor that targets Bcr-Abl, entered clinical evaluation in 1998. Its efficacy surpassed almost everyone's predictions, and the observation of high response rates and favorable toxicity profile associated with imatinib therapy led to its approval as first-line treatment for all newly diagnosed CML patients over an exceptionally short period of time. The 6-year results of the Phase III trial have recently been reported and confirm durability of responses and declining incidence of adverse events over time, although, at present, occurrence of unexpected side effects in the long term cannot be excluded. Although imatinib does 'cure' CML and has to be administered chronically to patients, it has revolutionized both outcome and quality of life CML patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, the majority of patients die after relapse or of complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed, especially for elderly patients. An indispensable prerequisite to investigate tailored approaches for AML is the recent progress in the understanding the molecular features that distinguish leukemia progenitors from normal hematopoietic counterparts and the identification of a variety of dysregulated molecular pathways. This in turn would allow the identification of tumor-specific characteristics that provide a rational basis for the development of more tailored, and hence potentially more effective and less toxic, therapeutic approaches. In this review, we describe some of the signaling pathways that are aberrantly regulated in AML, with a specific focus on their pathogenetic and therapeutic significance, and we examine some recent therapies directed against these targets, used in clinical trial for relapsed patients or unfit for conventional chemotherapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the diagnostic and therapeutic challenges involved in an extramedullary myeloid tumour of the stomach and duodenum without acute myeloblastic leukemia.

The conventional treatment included CHOP and several age-adapted regimens, from first to third generation, designed and tested for their feasibility and efficacy in elderly patients. Recently, some trials demonstrated that CHOP-rituximab was superior to CHOP alone. Between February 2003 and November 2005, 24 untreated patients 60 years and older with DLBCL were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B) plus four rituximab administrations. Nineteen of the 24 patients (80%) obtained a CR, four achieved a PR, and the remaining patient had a disease progression. The overall response rate was 96%. Sixteen of the 19 complete responders remain in continuous CR at a median of 24 months (range 12 - 42). Three CRs relapsed within 12 months from the completion of treatment. Clinical and hematological toxicity was moderate. This regimen was effective in inducing a good remission rate with moderate toxic effects in elderly DLBCL patients. [ABSTRACT FROM AUTHOR]

Options for patients with relapsed/refractory lymphoproliferative disorders and multiple myeloma are currently limited. Troxacitabine has shown promise in preclinical studies in a variety of malignancies; hence, the current study was conducted to evaluate the activity of troxacitabine in relapsed or refractory lymphoid malignancies. This was a phase II, open-label, multinational, multicenter study of patients with relapsed or refractory lymphoproliferative disorders or multiple myeloma. Thirty-four adults were enrolled in the study and received the study drug at either 5.4 mg/m2 (n = 16) or 4.3 mg/m2 (n = 18). The dose was decided in a phase I study, during which dose escalation was carried to reach a maximum tolerated dose with an acceptable toxicity profile. Two separate phase I studies were performed in Europe and the US. Troxacitabine was administered by intravenous infusion over 30 min daily for days 1 – 5 every 4 weeks. Treatment was continued to disease progression or until the subjects met criteria for withdrawal or unacceptable toxicities were evident as outlined in the protocol. Two patients had a partial response (PR) to treatment with troxacitabine to yield an overall response rate of 13%. There were no complete responses seen with the drug. Stable disease was achieved in 15 patients (44%). All patients had at least one treatment related adverse event, which led to six withdrawals from the study. Hematologic toxicity constituted the most common adverse events. Serious adverse effects were seen in 62% of patients. None of the 13 deaths were attributed directly to troxacitabine. As a single agent, troxacitabine has limited benefit in patients with advanced lymphoproliferative disorders or multiple myeloma. Future studies will be needed to address modified dosing according to emerging pharmacokinetic and pharmacodynamic data and combination therapy which may lead to improved clinical benefit for troxacitabine in hematologic malignancies. [ABSTRACT FROM AUTHOR]

The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, is one of the most common translocations in pediatric B-lineage acute lymphoblastic leukemia (ALL). It was assumed to be associated with a poor clinical outcome, although intensive therapy and bone marrow transplantation have been shown to be able to overcome the negative prognostic impact. Only few data are available concerning t(1;19)(q23;p13) in adult ALL. In particular, the prognostic significance of this genetic aberration is not yet clear. We describe three cases of adult ALL carrying the t(1;19)(q23;p13), who were all characterized by an aggressive clinical course and short survival, and discuss the molecular features of the disease as recently identified by gene expression profiling. [ABSTRACT FROM AUTHOR]

Baseline anemia is a relevant prognostic factor in the overall population of non-Hodgkin's lymphoma (NHL) patients, and studies focusing on elderly NHL are awaited. We conducted a pooled analysis of a cohort of comparable patients enrolled (1993 – 2001) in three multicenter clinical trials on use of a MACOP-B-like regimen (VNCOP-B) for front-line treatment of elderly aggressive NHL. Models of Cox's proportional hazards regression analysis of prognostic value of pre-/post-treatment hemoglobin values in terms of 5-year overall survival included age, sex, initial tumor staging and response to treatment. Of the 168 patients screened, 16 were excluded due to missing data or lack of 5-year follow-up. In addition to achievement of complete/partial remission (adjusted relative risk [RR], 0.215; p = 0.0001) and advanced stage (II-IV vs. I – II; adjusted RR, 1.55; p = 0.0023), post-treatment hemoglobin values were an independent predictor of survival (adjusted RR per 1-g/dL increment, 0.76; p = 0.0041). In the present analysis, pretreatment hemoglobin values were associated with only marginal risk reduction (adjusted RR per 1-g/dL increment, 0.985; p = 0.049). Post-treatment hemoglobin values appear to provide a strong independent predictor of 5-year survival in elderly aggressive NHL, supporting the potential role of anemia correction in this group of patients. [ABSTRACT FROM AUTHOR]

In order to assess the efficacy and toxicity profile of oxaliplatin, a third generation platinum derivate active against several solid tumors, we carried out a study in a group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL). Between August 2003 and May 2004, 19 pretreated patients were enrolled in a phase II trial and were treated with oxaliplatin. The drug was administered intravenously on day 1 of a 21-day schedule, at a dose of 130 mg/m 2 for a total of 6 cycles. One (5%) patient achieved complete remission (CR) and 5 patients (27%) had partial response (PR), thus giving an overall response rate of 32%. The patient in CR suffered from an aggressive B NHL. One of the 5 patients in PR had an aggressive B NHL, whereas the remaining 4 had an indolent B NHL. The treatment was well tolerated with minimal hematologic and extrahematologic toxicity. These data suggest and confirm the efficacy and low toxicity of oxaliplatin in the treatment of patients with heavily pretreated NHL. Further trials using oxaliplatin alone or in combination with other conventional drugs are needed. [ABSTRACT FROM AUTHOR]

Antibody-targeted chemotherapy is a promising approach in patients with hematological malignancies. In particular, gemtuzumab ozogamicin (GO, formerly CMA-676), an anti-CD33 antibody linked to calicheamicin, has been approved for the treatment of elderly patients with acute myeloid leukemia (AML) in relapse. Nevertheless, no data are until now available concerning the possible efficacy of GO for myeloid sarcomas (MS). We treated with GO 24 AML patients, in 5 cases presenting with myeloid sarcomas of the skin or bones. The overall complete response rate was 21%. The median duration of response was 6 months. Four out of the 5 patients with myeloid sarcoma showed a regression of the masses, in two cases also obtaining a clearance of marrow blasts. The most common adverse events included thrombocytopenia, neutropenia, infections, elevation of bilirubin and hepatic transaminases. Notably, severe bleeding occurred in 5 cases (21%). VOD was documented in 1 case. We conclude that GO is effective as a single agent in AML and myeloid sarcomas. Further data are required to clarify the possible correlation between GO administration and occurrence of bleeding. [ABSTRACT FROM AUTHOR]

In the last years, fludarabine (FLU) alone or in combination with other drugs has been reported to be effective in the treatment of previously untreated low-grade non-Hodgkin's lymphomas (LG-NHL). We report on the therapeutic efficacy and toxicity of a combination of FLU, idarubicin and cyclophosphamide (FLUIC regimen) in untreated non-follicular LG-NHL. We administered a three-drug combination of FLU (25 mg/m 2 i.v. on days 1 to 3), idarubicin (14 mg/m 2 i.v. on day 1) and cyclophosphamide (200 mg/m 2 i.v. on days 1 to 3) to treat 41 young, previously untreated patients with non-follicular LG-NHL. Chemotherapy was repeated every 4 weeks for a total of 6 cycles. Among 41 patients, 24 (59%) were diagnosed with small lymphocytic, 10 (24%) with immnocytoma, and 7 (17%) with marginal zone subtypes. Nineteen (46%) patients achieved complete response (CR) and 21 (51%) partial response, while the remaining 1 (3%) showed no benefit from the treatment. With respect to histology, we observed CR rates of 38% for the small lymphocytic subtype, 40% for the immunocytoma subtype, and 86% for the marginal zone subtype. Estimated 42-month overall survival and relapse-free survival rates were 64% and 100%, respectively. Hematologic grade 3 - 4 toxicity was seen in 9 (22%) patients; no opportunistic infection or death was associated with administration of the FLUIC regimen. These preliminary data suggest that FLUIC is a very active, well-tolerated regimen for young, untreated patients with advanced non-follicular LG-NHL. [ABSTRACT FROM AUTHOR]

Peripheral blood CD14  +  monocytes from multiple myeloma (MM) patients can be induced to differentiate into fully functional, mature, CD83  +  dendritic cells (DCs) which are highly efficient in priming autologous T lymphocytes in response to the patient-specific tumor idiotype (Id). We have recently scaled up our manufacturing protocol for application in a phase I - II clinical trial of anti-Id vaccination with DCs in MM patients. Elegible patients received a series of by-monthly immunizations consisting of three subcutaneous and two intravenous injections of Id-keyhole limpet hemocyanin (KLH)-pulsed DCs (5 × -, 10 × -, 50 × 10 6 cells and 10 × -, 50 × 10 6 cells, respectively). To generate DCs, monocytes were labeled with clinical grade anti-CD14 conjugates and positively selected by immunomagnetic separation. Cells were then cultured, according to Good Manufacturing Practice guidelines, in FCS-free medium in cell culture bags, and differentiated to DCs with GM-CSF plus IL-4 followed by TNF-α or, more recently, by a cocktail of IL-1β, IL-6, TNF-α and prostaglandin-E 2 . Before maturation, Mo-DCs were pulsed with the autologous Id as whole protein or Id (VDJ)-derived HLA class I restricted peptides. Ten MM patients, who had been treated with two courses of high-dose chemotherapy with peripheral blood stem cell support, entered into the clinical study. CD14  +  monocytes were enriched from 16.1 ± 5.7% to 95.5 ± 3.2% (recovery 67.9 ± 15%, viability > 97%). After cell culture, phenotypic analysis showed that 89.6 ± 6.6% of the cells were mature DCs. We obtained 2.89 ± 1 × 10 8 DCs/leukapheresis which represented 24.5 ± 9% of the initial number of CD14  +  cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (31 ± 10.9 of initial CD14  +  cells) of DCs than TNF-α alone, secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic and autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of pre-loaded DCs. The recovery of thawed, viable DCs, was 78 ± 10%. Thus, positive selection of CD14  +  monocytes allows the generation of a uniform population of mature pre-loaded DCs which can be cryopreserved with no effects on phenotype and function and are suitable for clinical trials. Based on these results, a DCs-based phase II trial of anti-Id vaccination with VDJ-derived HLA class I-restricted peptides and KLH is underway for lymphoma patients. [ABSTRACT FROM AUTHOR]

Rituximab is active in chronic lymphocytic leukemia (CLL) and may interfere with autoantibodies production in some immune diseases. We report the results of rituximab treatment in 7 patients with CLL-associated symptomatic autoimmune diseases refractory to standard immunosuppressive therapies: warm antibody hemolytic anemia (AHA) 4 patients, cold agglutinin disease (CAD) 1, immune thrombocytopenia (IT) 1, axonal degenerating neuropathy (ADN) 1. Rituximab was given at the dose of 375 mg/m 2 per week for 4 weeks. One patient with AHA and one with CAD achieved complete normalization of hemoglobin levels and laboratory signs of haemolysis, with response duration (RD) of 8+ and 38+ months, respectively. In the patient with IT, complete remission was reached after the first week of treatment and RD was 6 months. The patient with ADN achieved a marked neurological improvement after rituximab therapy, with RD of 12 months. Retreatment of both patients with IT and ADN was effective. Rituximab may be an alternative agent for the treatment CLL-associated autoimmune diseases. [ABSTRACT FROM AUTHOR]

The lung is a relatively rare site for mucosa-associated lymphoid tissue (MALT) lymphomas: we report the largest available single-center series of patients with this presentation. From August 1992 to October 2000, 12 patients with untreated primary low-grade MALT lymphoma of the lung were submitted either to chemotherapy alone (n = 8), surgery alone (n = 2) or surgery plus chemotherapy (n = 2). At diagnosis, 6 (50%) were asymptomatic and 6 (50%) had nonspecific pulmonary symptoms. The most common radiologic findings were a pulmonary infiltrate (7 cases) and a mass lesion (5 cases). Histological diagnosis was obtained with transbronchial lung biopsy/bronchoalveolar lavage (BAL) (6 cases), with transthoracic needle biopsy (1 case), or an open thoracotomy (5 cases). All patients had stage IE. All 12 (100%) achieved complete remission; 3 (25%) local recurrences were observed. The global 6-year survival rate was 100% with a relapse-free survival rate of 50%. In conclusion, these data underline the diagnostic utility of BAL and the therapeutic efficacy of a chemotherapeutic strategy based on regimens such as N-CVP in the context of localized MALT lymphoma of the lung. [ABSTRACT FROM AUTHOR]

Documents the effectiveness of combination fludarabine, arabinosyl cytosine and idarubicin (FLAI) regimen in poor-risk acute myeloid leukemia patients. Complete remission rate; Projected 2-year and relapse-free survival; Mean time to hematologic recovery; Mobilization of peripheral blood stem cells.

Evaluates the feasibility of autologous stem cell transplantation in chronic hepatitis B and C virus carriers. Patient characteristics; Hepatic toxicity during first line treatment; Percent of patients who achieved complete remission; Patient survival.

Patients with a monoclonal gammapathy of undertermined significance (MGUS) are usually submitted to a periodical clinical follow-up, but it is not known if this surveillance can ameliorate the prognosis of a plasma cell malignancy that will be eventually detected. We compared the clinical and laboratory characteristics at onset, the response to chemotherapy and the survival, of 21 cases of newly diagnosed multiple myeloma (MM) arising from the malignant transformation of MGUS and 41 cases without a previous history of MGUS, recruited to the same first-line treatments over a 3 years period. The former group showed a significant lower frequency of advanced stages as well as other several prognostic factors of high risk including anemia, renal failure, bone lesions and increase of beta2 microglobulin and C-reactive protein levels. Despite a similar response to treatment of the two groups, MM arising from MGUS showed a significantly longer median survival than MM without prior MGUS. This was particularly true for stage I, while stages II and III behaved similarly. We conclude that the regular clinical monitoring of MGUS patients allowed the identification of earlier malignant transformation, when tumor burden is lower, as indicated by lower beta2 microglobulin levels and marrow plasmacytosis of stage I MM arising from MGUS. Moreover, a slower proliferation rate of myeloma cells, as suggested by lower C-reactive protein levels, may be considered so as to explain the longer survival of these patients. [ABSTRACT FROM AUTHOR]

The article presents a retrospective monocentric analysis of 14 patients with relapsed or refractory aggressive T-cell lymphomas who received allogeneic stem cell transplant (allo-SCT) at the University of Bologna's Institute of Hematology and Medical Oncology in Italy between June 1983 and June 2008. The analysis reveals that all of these patients had a fatal disease progression. These patients were also evaluable for acute graft-versus- host disease (aGVHD) grade assessment.

The article discusses the development of acute myeloid leukemia in patient with ataxia telangiectasia (AT). It is noted that two-thirds of patients with AT experience severe to moderate immunodeficiency while more than 50 percent show compartmental immunoglobulin deficit. The author also highlights the need for more information to determine the appropriate dosages of chemotherapy to reduce toxicities and remission rates in AT patients with myeloid leukemia.

A letter to the editor is presented concerning the unsettled problem of the mechanism of drug resistance in leukemia and cancer therapy.

Presents a letter to the editor discussing the efficacy and safety of oral fludarabine/cyclophosphamide regimen in treating indolent lymphomas.

Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several new agents, the prognosis of acute lymphoid leukemia (ALL) patients relapsing after stem-cell transplantation (SCT) remains poor. Monoclonal-antibodies (moAb) could provide a useful tool in this setting. In particular, anti-CD52 moAb is useful in lymphoid malignancies. We thus treated as compassionate with campath-1H 3 ALL patients relapsed after SCT. In 2 cases we observed a reduction of peripheral blood and/or bone marrow blasts. In 1 case a GVHD grade reduction was observed. Larger trials are required in order to define the role of campath-1H in ALL. [ABSTRACT FROM AUTHOR]

Presents a case study of a 56-year-old man with a diagnosis of stage IIE diffuse large B-cell lymphoma made on right orchiectomy due to right testicular involvement. Description of cutaneous B-cell lymphomas; Relapse shown by the patient ten years after treatment.