High-Risk, Advanced-Stage Hodgkin Lymphoma: The Impact of Combined Escalated BEACOPP and ABVD Treatment in Patients Who Rapidly Achieve Metabolic Complete Remission on Interim FDG-PET/CT Scan.

The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG-PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score ≥3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis.

The impact of R-VACOP-B and interim FDG-PET/CT on outcome in primary mediastinal large B cell lymphoma.

The choice of a rituximab-based regimen and the prognostic significance of interim 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in primary mediastinal large B cell lymphoma (PMBCL) are debatable. We evaluated the clinical features and outcomes of 95 consecutive patients with PMBCL who were treated between 1985 and 2009. Forty-three patients received rituximab-based chemotherapy, R-VACOP-B (N = 30) or R-CHOP21 (N = 13), whereas 52 patients were treated with VACOP-B (N = 47) or CHOP21 (N = 5). Radiotherapy was not given. Patients who received rituximab had a 5-year progression-free survival (PFS) of 79 % and overall survival (OS) of 97 % compared with 58 % (p = 0.06) and 88 % (p = 0.2), respectively, without rituximab. Five-year PFS in patients treated with R-VACOP-B, R-CHOP21, VACOP-B, and CHOP21 were 83, 69, 62, and 20 %, respectively (p = 0.039). However, direct comparison showed that the difference between PFS rates in patients receiving R-VACOP-B compared to R-CHOP21 was not statistically significant (p = 0.3). None of the standard clinical risk factors predicted for PFS and OS in patients receiving rituximab (R)-chemotherapy. Mid-interim FDG-PET/CT scans were performed in 30/43 patients who received R-chemotherapy. The negative predictive values of mid-PET activity were high (100 % for R-VACOP-B and 86 % for R-CHOP21) while the positive predictive values (PPV) were relatively low (30 and 75 %, respectively). Despite the low PPV, the 5-year PFS for mid-PET-negative patients (N = 16) was significantly higher (94 %) than that for mid-PET-positive (N = 14) patients (57 %, p = 0.015). This retrospective analysis demonstrates that the superiority of VACOP-B over CHOP21 for treatment of PMBCL disappeared once rituximab was added. The potential benefit of using interim PET activity as a guide for continuing therapy in patients with PMBCL remains unclear due to the relatively low PPV.

Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis.

Second generation tyrosine kinase inhibitors have recently been introduced as first-line treatment for chronic phase chronic myelogenous leukemia. We aimed to evaluate the efficacy and safety of 2(nd) generation tyrosine kinase inhibitors versus imatinib as first-line treatment for these patients. We carried out a systematic review and meta-analysis of randomized controlled trials comparing 2(nd) generation tyrosine kinase inhibitors to imatinib as first-line treatment in chronic phase chronic myelogenous leukemia patients. Outcomes assessed were: complete cytogenetic response and major molecular response at 12, 18 and 24 months, all-cause mortality and progression to accelerated phase/blastic crisis at 12, 18 and 24 months, and chronic myelogenous leukemia related mortality and toxicity at last follow up. Relative risks were estimated and pooled using a fixed effect model. Our search yielded four trials including 2,120 patients. At 12 months, treatment with 2(nd) generation tyrosine kinase inhibitors significantly improved both complete cytogenetic response and major molecular response (relative risk 1.16, 95% CI: 1.09-1.23, and 1.68, 95% CI: 1.48-1.91, respectively). While major molecular response was improved at all time points, complete cytogenetic response improved at 18 months but not at 24 months. Importantly, rate of progression to accelerated phase/blastic crisis was significantly lower with the newer tyrosine kinase inhibitors throughout all time points. Second generation tyrosine kinase inhibitors improved chronic myelogenous leukemia related mortality without a statistically significant difference in all-cause mortality at 12, 18 and 24 months. We conclude that 2(nd) generation tyrosine kinase inhibitors can be added safely to the first-line treatment armamentarium of chronic phase chronic myelogenous leukemia patients. Although an advantage is suggested by surrogate parameters, longer follow up is necessary to see if this translates into superior overall survival.

Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

BACKGROUND: Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony-stimulating factors (CSFs) are frequently administered during and after chemotherapy to reduce complications. However, their safety with regard to disease-related outcomes and survival in AML is unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the impact of CSFs on patient outcomes, including survival. OBJECTIVES: To assess the safety/efficacy of CSFs with regard to disease-related outcomes and survival in patients with AML. SEARCH METHODS: We conducted a comprehensive search strategy. We identified relevant randomized clinical trials by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 7), MEDLINE (January 1966 to July 2010), LILACS (up to December 2009), databases of ongoing trials and relevant conference proceedings. SELECTION CRITERIA: Randomized controlled trials that compared the addition of CSFs during and following chemotherapy to chemotherapy alone in patients with AML. We excluded trials evaluating the role of CSFs administered for the purpose of stem cell collection and/or priming (e.g. before and/or only for the duration of chemotherapy). DATA COLLECTION AND ANALYSIS: Two review authors appraised the quality of trials and extracted data. For each trial, we expressed results as relative risk (RR) with 95% confidence intervals (CI) for dichotomous data. We analyzed time-to-event outcomes as hazard ratios (HRs). MAIN RESULTS: The search yielded 19 trials including 5256 patients. The addition of CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days and at the end of follow up (RR 0.97; 95% CI 0.80 to 1.18 and RR 1.01; 95% CI 0.98 to 1.05, respectively) or in overall survival (HR 1.00; 95% 0.93 to 1.08). There was no difference in complete remission rates (RR 1.03; 95% CI 0.99 to 1.07), relapse rates (RR 0.97; 95% CI 0.89 to 1.05) and disease-free survival (HR 1.00; 95% CI 0.90 to 1.13). CSFs did not decrease the occurrence of bacteremias (RR 0.96; 95% CI 0.82 to 1.12), nor the occurrence of invasive fungal infections (RR 1.40; 95% CI 0.90 to 2.19). CSFs marginally increased adverse events requiring discontinuation of CSFs as compared to the control arm (RR 1.33; 95% CI 1.00 to 1.56). AUTHORS' CONCLUSIONS: In summary, colony-stimulating factors should not be given routinely to acute myelogenous leukemia patients post-chemotherapy since they do not affect overall survival or infectious parameters including the rate of bacteremias and invasive fungal infections.

High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia patients--systematic review and meta-analysis.

Imatinib at a dose of 400 mg daily is considered frontline treatment in chronic phase chronic myeloid leukemia (CP-CML). We conducted a systematic review and meta-analysis of randomized controlled trials comparing frontline treatment with imatinib 400 mg daily versus higher doses (≥600 mg daily) in patients with CP-CML. The search yielded four trials, randomizing 1,673 patients. At 12 months, high dose compared with standard dose imatinib improved complete cytogenetic response (CCyR) (RR 1.17, 95% CI 1.08-1.26, four trials, I(2) = 33%) as well as major molecular response (MMolR) (RR 1.26, 95% CI 1.12-1.42, four trials, I(2) = 0%). There was no difference in all-cause mortality or disease progression at the end of follow up. Adverse events requiring discontinuation were more common in the high-dose arm (RR 1.98, 95% CI 1.20-3.26, three trials, I(2) = 0%), as were Grade III/IV neutropenia and thrombocytopenia: RR 1.56, 95% CI 1.15-2.12 and RR 1.86, 95% CI 1.28-2.70, respectively. There is currently insufficient evidence to support the routine use of higher doses of imatinib as frontline treatment for CP-CML. Extended follow up is needed to evaluate if the superior CCyR and MMolR with higher doses of imatinib will translate to long-term clinical benefit.

Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

BACKGROUND: Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony-stimulating factors (CSFs) are frequently administered during and after chemotherapy to reduce complications. However, their safety with regard to disease-related outcomes and survival in AML is unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the impact of CSFs on patient outcomes, including survival. OBJECTIVES: To assess the safety/efficacy of CSFs with regard to disease-related outcomes and survival in patients with AML. SEARCH STRATEGY: We conducted a comprehensive search strategy. We identified relevant randomized clinical trials by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 7), MEDLINE (January 1966 to July 2010), LILACS (up to December 2009), databases of ongoing trials and relevant conference proceedings. SELECTION CRITERIA: Randomized controlled trials that compared the addition of CSFs during and following chemotherapy to chemotherapy alone in patients with AML. We excluded trials evaluating the role of CSFs administered for the purpose of stem cell collection and/or priming (e.g. before and/or only for the duration of chemotherapy). DATA COLLECTION AND ANALYSIS: Two review authors appraised the quality of trials and extracted data. For each trial, we expressed results as relative risk (RR) with 95% confidence intervals (CI) for dichotomous data. We analyzed time-to-event outcomes as hazard ratios (HRs). MAIN RESULTS: The search yielded 19 trials including 5256 patients. The addition of CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days and at the end of follow up (RR 0.97; 95% CI 0.80 to 1.18 and RR 1.01; 95% CI 0.98 to 1.05, respectively) or in overall survival(HR 1.00; 95% 0.93 to 1.08). There was no difference in complete remission rates(RR 1.03; 95% CI 0.99 to 1.07), relapse rates(RR 0.97; 95% CI 0.89 to 1.05) and disease-free survival(HR 1.00; 95% CI 0.90 to 1.13). CSFs did not decrease the occurrence of bacteremias(RR 0.96; 95% CI 0.82 to 1.12), nor the occurrence of invasive fungal infections(RR 1.40; 95% CI 0.90 to 2.19). CSFs marginally increased adverse events requiring discontinuation of CSFs as compared to the control arm(RR 1.33; 95% CI 1.00 to 1.56). AUTHORS' CONCLUSIONS: The addition of CSFs to chemotherapy does not adversely influence all-cause mortality, complete remission or relapse rates in patients with AML. Although the benefit of CSFs is limited to reduction of neutropenic and febrile days, they can be administered safely when necessary.

Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis.

Immunosuppressive therapy is the treatment for aplastic anemia patients ineligible for transplantation. The role of hematopoietic growth factors as adjunct to treatment in these patients is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials comparing treatment with immunosuppressive therapy and hematopoietic growth factors to immunosuppressive therapy alone in patients with aplastic anemia. Two reviewers appraised the quality of trials and extracted data. For each trial, results were expressed as relative risks with 95% confidence intervals (CI) for dichotomous data. The addition of hematopoietic growth factors yielded no difference in overall mortality at 100 days, one year and five years [relative risks 1.33 (95% CI 0.56-3.18), relative risks 0.90 (95% CI 0.50-1.63) and relative risks 0.89 (95% CI 0.55-1.46), respectively]. There was no difference in overall hematologic response and in the occurrence of infections. HGF significantly decreased the risk for relapse, relative risks 0.45 (95% CI 0.30-0.68, 3 trials). Hematopoietic growth factors were not associated with higher occurrence of myelodysplastic syndrome and acute myeloid leukemia or paroxysmal nocturnal hemoglobinuria. The addition of hematopoietic growth factors does not affect mortality, response rate or infections occurrence. Therefore, it should not be recommended routinely as an adjunct to the immunosuppressive therapy for patients with aplastic anemia.

Rituximab-associated acute thrombocytopenia: an under-diagnosed phenomenon.

Acute infusion reactions are the most common documented adverse reactions reported with rituximab, with overt cytokine release syndrome, and hematological adverse events being much rarer. The clinical course of a patient with mantle cell lymphoma, who developed acute thrombocytopenia and leukopenia following rituximab administration, is described and the literature reviewed. Serum complement and the levels of three cytokines--TNF-alpha, IL-6, and IL-1, were measured 2 days after the infusion of rituximab by using ELISA assay. Drug-dependent antibodies against platelets were evaluated by two procedures as follows: an immunofluorescence test applying flow cytometry and Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA). Serum levels of TNF-a were significantly increased compared with normal, whereas those of IL-6 and IL-1 were not increased significantly. Flow cytometry assay and the MAIPA assay failed to detect rituximab-dependent antibodies against platelets. Complement levels were decreased compared with normal. Literature search yielded 10 publications reporting on another 15 patients. The most common type of lymphoma was mantle cell lymphoma, six patients had bone marrow involvement, and 10 patients had splenomegaly. In 10 patients, acute cytopenia was preceded by cytokine release syndrome or infusion-related symptoms. Usually, thrombocytopenia was not associated with bleeding manifestations. Thrombocytopenia was the most commonly acute cytopenia reported. The postulated pathogenesis is associated with cytokine release syndrome and complement activation. Patients with potential risk factors like splenomegaly and bone marrow involvement, who develop clinical manifestations compatible with cytokine release syndrome, should be closely monitored for rituximab-associated cytopenia.

Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) and those with lymphoproliferative disorders (LPD) have a higher incidence of infections due to secondary hypogammaglobulinemia. One approach is the prophylactic administration of intravenous immunoglobulins (IVIG). Randomized controlled trials (RCTs) showed conflicting results in terms of type, schedule, dose and hematological patients benefiting from IVIG. We therefore performed a systematic review and meta-analysis to evaluate the role of IVIG in these patients. OBJECTIVES: To determine whether prophylaxis with IVIG reduces mortality or affects other outcomes in patients with hematological malignancies. SEARCH STRATEGY: PubMed (January 1966 to December 2007), CENTRAL (The Cochrane Library, up to 2007, issue 1), LILACS and conference proceedings published between 2002-2007 were searched. The terms "immunoglobulins" or "gammaglobulins" or specific gammaglobulins and similar and the terms "hematologic neoplasms" or "hematologic malignancies" or "transplant" or "autotransplant" or "allotransplant" or "bone marrow transplant" or "peripheral stem cell transplant" and similar were selected. References of all included trials and reviews identified were scanned for additional trials. SELECTION CRITERIA: All RCTs comparing prophylaxis of IVIG with placebo, no treatment or another immunoglobulin preparation, different administration schedules or doses for patients with hematological malignancies were included. One author screened all abstracts identified through the search strategy and two reviewers independently inspected each reference identified by the search and applied inclusion criteria. DATA COLLECTION AND ANALYSIS: For each trial, results were expressed as relative risks (RR) with 95% confidence intervals (CI) for dichotomous data and weighted mean differences for continuous data. We conducted meta-analysis, where enough similar trials were available, using the fixed- effects model, unless significant heterogeneity was present. We performed sensitivity analyses to assess the effect of individual methodological quality measures on effect estimates, including allocation generation, concealment and blinding. MAIN RESULTS: Forty trials were included: thirty included HSCT patients and ten included patients LPD. When polyvalent immunoglobulins or hyperimmune cytomegalovirus (CMV)-IVIG was compared to control for HSCT, there was no difference in all-cause mortality. Polyvalent immunoglobulins significantly reduced the risk for interstitial pneumonitis but increased the risk for veno-occlusive disease and adverse events. In LPD, no benefit in terms of mortality IVIG could be demonstrated but there was a decrease in clinically and microbiologically documented infections. AUTHORS' CONCLUSIONS: In patients undergoing HSCT, routine prophylaxis with IVIG is not supported. Its use may be considered in LPD patients with hypogammaglobulinemia and recurrent infections, for reduction of clinically documented infections.

Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma.

OBJECTIVE: To determine the safety and outcome following standard-dose ibritumomab tiuxetan followed by BEAM high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients with chemo-refractory aggressive non-Hodgkin's lymphoma. PATIENTS AND METHODS: The study included 23 patients, median age 55 years (range, 35-66) with chemo-refractory lymphoma, either primary refractory (n = 11) or in refractory relapse (n = 12). Rituximab 250 mg/m(2) followed by ibritumomab tiuxetan 0.4 mCi/kg were given on day -14 and high-dose BEAM chemotherapy started on day -6. RESULTS: All patients engrafted. Twenty-one patients are evaluable for response; 11 achieved CR, 9 achieved PR, 5 of whom converted to CR with additional radiation therapy (overall CR rate 76%). With a median follow-up of 17 months (range, 4-27) 16 patients are alive and 12 are progression-free. The estimated 2-year overall and progression-free survival are 67% (95% CI, 46-87%) and 52% (95% CI, 31-72%), respectively. The day-100 rate of treatment-related mortality was 9% (95% CI, 2-33%) and the 2-year cumulative incidence of relapse was 31% (95% CI, 17-57%). Extensive prior therapy (>3 lines), high LDH and IPI score at ASCT, bulky disease, and progression during last chemotherapy were risk factors for reduced survival. CONCLUSION: Ibritumomab tiuxetan-BEAM and ASCT is relatively safe and may improve outcome in patients with refractory lymphoma. Although excess nonrelapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved outcome. Standard-risk patients with chemo-sensitive disease may also benefit from ibritumomab tiuxetan-BEAM and ASCT. This hypothesis merits further study in larger-scale prospective randomized studies.

Targeted and tailored therapy in hemato-oncology: vision for the 21st century.

Summarizing our vision of hemato-oncology in the 21st century, we believe that with time, and with the expected progress in both medicine and biotechnology, the role of non-specific chemotherapy will decrease, while that of targeted therapies will increase. Unfortunately, for most tumors chemotherapy is still the cornerstone of treatment. We should therefore focus on finding more targeted agents, better tailoring of treatments, and identifying the risk factors for cancer development and the means of prevention of--what is likely to be--the number one killer of this century.

Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells.

Northern blotting confirmed previous results indicating that the mitogen-activated protein kinase (MAPK) phosphatase Pyst2-L was highly expressed in leukocytes obtained from acute myeloid leukemia (AML) patients. High levels of Pyst2-L mRNA were expressed in bone marrow (BM) and peripheral leukocytes from nine AML and acute lymphoblastic leukemia (ALL) patients. BM from healthy individuals expressed very low levels of Pyst2-L. Whereas high levels of Pyst2-L mRNA and protein were detected in several leukemia cell lines, Pyst2-L mRNA was detected neither in 33/34 samples of normal peripheral blood mononuclear cells (PBMC) nor in leukocyte fractions enriched with CD34+ cells. Certain solid tumor and lymphoblastoid cell lines expressed high levels of Pyst2-L mRNA. In view of the association of Pyst2-L to MAPK signaling cascades, we tested if cell activation, a process involving MAPK signaling, influences Pyst2-L expression. Indeed, activation of T cells and endothelial cells increased Pyst2-L in these cells. Furthermore, TPA, a known MAPK activator, induces the expression of both Pyst2-L mRNA as well as the Pyst2-L protein in leukemia cells. This induction was partially inhibited by PD098059, an Mek1/2-specific inhibitor. Based on the results of this and previous studies, we hypothesize that the high levels of Pyst2-L detected in the active state of AML and ALL diseases and in other types of cancer reflect an altered MAPK signaling pathway in such malignant processes. This alteration may be the result of a failed attempt to counter the constitutive activation of MAPK in transformed cells or alternatively, may represent the activated state of such cells.

[Bone marrow transplantation--new developments in the last decade].

The last decade has witnessed very significant developments in the field of bone marrow transplantation (BMT), resulting in the improved safety and availability of this procedure. The expansion of international registries of voluntary, unrelated donors, the establishment of banks of fetal cord blood stem cells, as well as improved technology for transplantation of stem cells derived from partially matched family members, offer this treatment to patients hitherto not eligible for BMT. In addition to better donor availability, there has been a change in the concept regarding the role of BMT in the treatment of cancer: the understanding that the transplanted donor cells are capable of mounting an immunological assault against the host malignant cells. This goal can be achieved without fully destroying the patient's bone marrow stem cells and thus prepare the patient for transplantation with a reduced dose intensity of the myelotoxic drugs. Such nonmyeloablative conditioning increases the safety of the procedure. These developments have resulted in a vast expansion of the patient population eligible for BMT, including patients older than those who could have benefited from conventional allogeneic BMT with its associated high mortality in the older age groups, and those lacking fully matched family donors. This article surveys these developments and reviews the clinical indications for BMT in selected malignancies that are evidence-based. The role of BMT and its timing, in the light of new alternative solutions already in the market, is also discussed. Such critical evaluation is particularly warranted in view of the vastly higher rate of BMT per capita in Israel, as compared to other western countries, and given the late side effects inherent in the procedure.

Intravenous busulfan-based conditioning prior to allogeneic hematopoietic stem cell transplantation: myeloablation with reduced toxicity.

OBJECTIVE: Allogeneic transplantation is a potentially curative treatment for hematologic malignancies but is associated with a high rate of complications. Busulfan is a common component of pretransplant conditioning but has an erratic and unpredictable bioavailability when administered orally. Intravenous (IV) busulfan was recently introduced into clinical practice. Prior studies showed consistent and predictable drug delivery with tight control of busulfan plasma levels, avoiding over- and under-dosing. This study was designed to define the role of IV busulfan in different transplant and disease settings. PATIENTS AND METHODS: The study included 43 patients with various hematologic malignancies conditioned with high-dose IV busulfan-containing regimens prior to allogeneic transplantation. The donors were HLA-matched siblings (n=24), matched unrelated (n=14), or 1-antigen mismatched related donors (n=5). Outcome parameters were recorded. RESULTS: Forty-two patients had initial engraftment. The toxicity profile was favorable. No patient developed veno-occlusive disease of the liver. Acute graft-vs-host disease (GVHD) grades II-IV occurred in 18 patients (42%). Six patients died of treatment-related causes, five of complications related to acute GVHD, and only one died of organ toxicity. Actuarial non-relapse-related mortality risk was 10% at day 100 and 18% at 2 years posttransplant. The actuarial 2-year overall survival and disease-free survival (DFS) rates were 63% and 44%, respectively. Disease status other than refractory relapse, myeloid disease, and no severe GVHD posttransplant predicted for longer DFS in a multivariant model. CONCLUSIONS: IV busulfan-containing regimens allow consistent engraftment of allografts from related and unrelated donors such that myeloablation is administered with a toxicity profile typical of non-myeloablative conditioning. Favorable outcome was seen in patients with myeloid leukemias and in early or intermediately advanced disease; however, this regimen may not be sufficiently cytoreductive in patients with very advanced or active leukemia and in acute lymphoblastic leukemia. IV busulfan merits further study to better define its role as a preferred substitute for oral busulfan in pretransplant conditioning.

cDNA microarray analysis reveals an overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia.

The information contained in the draft sequence of the human genome offers a solid basis to study gene function. The DNA microarray technology is one of the most important tools enabling the performance of such studies. The global expression analysis using microarrays enables the construction of a simultaneous expression pattern of thousands of genes and thus an unprecedented opportunity to obtain molecular signatures of the state of activity of diseased cells. Microarray analysis may thus provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments. Ultimately such analyses may lead to improved early diagnosis and innovative therapeutic approaches. Yet, by employing this advanced technology in order to identify new target molecules for diagnosis or therapy, one is faced with the necessity to focUs on one or several genes and to investigate them further. A huge number of differentially expressed genes are usually identified when 2 cell samples are comparatively analyzed in an individual assay. Several factors, mainly a possible genetic diversity between the samples, minimize the capability of reaching an educated conclusion as to which gene or genes to select for further studies. Gene expression arrays were employed to identify genes whose expression characterizes leukemic leukocytes. Many different genes were differentially expressed by "leukemic-phase leukocytes," derived from three untreated acute myelogenous leukemia (AML) patients and by "remission-phase leukocytes," obtained from the same patients following induction of remission. However, only two of these genes, the dual-specificity MAPK phosphatase PYST2 and the tryptophan 5-hydroxylase, were found to be more highly expressed by the leukemic-phase than by remission-phase leukocytes of all three patients. The microarray results of only the PYST2 gene could be verified by RT-PCR. By focusing on genes that had a similar expression pattern in cells from multiple donors we overcame the problem of genetic diversity and identified, out of 60 differentially expressed genes, a single candidate target gene in AML. Pooling specimens in order to overcome the problem of genetic diversity (e.g., clinical material obtained from treated patients and from untreated ones), is not recommended because it may dilute the treatment effects. Therefore, it is essential to perform each experiment using individual preparations.

Overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia.

In a previous study we used gene expression arrays to identify genes that are more highly expressed by leukemic than by non-leukemic leukocytes from acute myelogenous leukemia patients. One of such genes was Phosphorylates tyrosine serine threonine 2 (PYST2), a dual-specificity Mitogen-activated protein (MAP) kinase (MAPK) phosphatase. In the present study, high levels of PYST2 mRNA were detected by RT-PCR and by Northern blotting in bone marrow (BM) leukocytes and in peripheral blood mononuclear cells from additional eight AML patients. No PYST2 mRNA was detected in nine out of twelve samples of Peripheral blood mononuclear cells (PBMC) from healthy blood bank donors and very low levels were detected by the same techniques in the other three PBMC samples from the healthy donors. Relatively high levels of PYST2 were detected in a variety of myeloid leukemia and other cancer cell lines. In view of the potential role played by PYST2 in MAPK signaling cascades we propose that an over expression of PYST2 in malignant cells may reflect a disrupted or an altered MAPK signaling pathway in malignancy processes.

Meta-analysis of autologous bone marrow transplantation versus chemotherapy in adult patients with acute myeloid leukemia in first remission.

In the present study, we have conducted a meta-analysis comparing autologous bone marrow transplantation (ABMT) and intensive chemotherapy in adult acute myeloid leukemia (AML) patients in first remission. Combined results of the six appropriate randomised controlled studies indicate that ABMT had no advantage over chemotherapy or no further treatment concerning death rate (overall rate ratio (RR)-0.95, 95% CI, 0.81-1.11), while was superior to chemotherapy concerning event rate (overall RR--0.82, 95% CI, 0.71-0.94). In conclusion, ABMT did not improve survival but it improved event-free survival (EFS) when compared with chemotherapy or no further treatment in patients with AML in first complete remission.

Acute myeloid leukemia associated with nephrotic syndrome: case report and literature review.

The hematological malignancies associated with nephrotic syndrome are mainly Hodgkin's and non-Hodgkin's lymphomas and chronic lymphocytic leukemia. Acute myelogenous leukemia (AML) has rarely been described in association with the nephrotic syndrome. The clinical course of a 44-year-old patient with AML who presented with nephrotic syndrome is described and the clinicopathologic features of the other cases reported in the world literature are reviewed. We could not find a consistent pattern regarding the subtype of leukemia, renal pathology, and temporal relationship between the nephrotic syndrome and the leukemia or the response to treatment. The present case was unique in that the clinical course of the renal disorder correlated with the course of the leukemia responding to treatment with anti-leukemic agents. We conclude that nephrotic syndrome can also be associated with AML. In some cases there is a direct causal effect of the leukemic process on the renal pathology while in others it is exerted indirectly via other complications of the malignancy or the treatment.

Is cure of chronic myeloid leukemia in the third millennium a down to earth target (ed) or a castle in the air?

The therapeutic approach in chronic myeloid leukemia (CML) has undergone a revolutionary change during the last 2 decades with the introduction of the tyrosine kinase inhibitors. The use of these agents has changed overall survival as well as the quality of life of CML patients. Since the introduction of imatinib, newer agents have been developed and their role as first line treatment was examined. The use of genomics and proteomics as a means to tailor treatment of CML patients is underway. Meanwhile, clinical parameters as disease phase and response to treatment are used to guide a personalized approach. In this review, we will discuss the various aspects of personalized medicine in CML, including the use of the different scoring systems to guide treatment, disease phase as a means to choose the proper approach and the value of early response evaluation in decision-making. The approach towards patients resistant to tyrosine kinase inhibitors (TKIs), individual strategies for discontinuation of TKIs and "operational" cure in CML will also be discussed and finally the personalized treatment for CML patients in the near future based on present outcomes.