High Incidences of Invasive Fungal Infections in Acute Myeloid Leukemia Patients Receiving Induction Chemotherapy without Systemic Antifungal Prophylaxis: A Prospective Observational Study in Taiwan

Invasive fungal infections (IFIs) is an important complication for acute myeloid leukemia (AML) patients receiving induction chemotherapy. However, the epidemiological information is not clear in Southeastern Asia, an area of potential high incidences of IFIs. To clarify it, we enrolled 298 non-M3 adult AML patients receiving induction chemotherapy without systemic anti-fungal prophylaxis from Jan 2004 to Dec 2009, when we applied a prospective diagnostic and treatment algorithm for IFIs. Their demographic parameters, IFI characters, and treatment outcome were collected for analysis. The median age of these patients was 51 years. Standard induction chemotherapy was used for 246 (82.6%) patients, and 66.8% of patients achieved complete remission (CR) or partial remission. The incidence of all-category IFIs was 34.6% (5.7% proven IFIs, 5.0% probable IFIs and 23.8% possible IFIs). Candida tropicalis was the leading pathogen among yeast, and lower respiratory tract was the most common site for IFIs (75.4%, 80/106). Standard induction chemotherapy and failure to CR were identified as risk factors for IFIs. The presence of IFI in induction independently predicted worse survival (hazard ratio 1.536 (1.100–2.141), p value = 0.012). Even in those who survived from the initial IFI insults after 3 months, the presence of IFIs in induction still predicted a poor long-term survival. This study confirms high incidences of IFIs in Southeastern Asia, and illustrates potential risk factors; poor short-term and long-term outcomes are also demonstrated. This epidemiological information will provide useful perspectives for anti-fungal prophylaxis and treatment for AML patients during induction, so that best chances of cure and survival can be provided.     

Stem cell transplantation for leukemias following myelodysplastic syndromes or secondary to cytotoxic therapy

Two main forms of therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) have been recognized. The most frequent type, occurring after treatment with alkylating agents, is characterized by abnormalities of chromosomes 5 and/or 7 and t-MDS/AML following treatment with topoisomerase II inhibitors and is associated with molecular aberrations of MLL (11q23) and AML-1 (21q22). Individuals with certain polymorphisms associated with impaired detoxification of cytotoxic agents have an increased risk of developing MDS or AML after treatment of unrelated cancers. Multidrug chemotherapy is less effective for patients with MDS, or AML following MDS, or t-MDS/AML when compared with primary AML, and results in lower complete remission (CR) rates and lower long-term survival. Patients with good risk cytogenetic features, such as t(15; 17), t(8; 21) and inversion 16 are an exception as their treatment outcome is comparable with primary AML patients. Patients who attain a polyclonal and/or a cytogenetic CR may be candidates for autologous stem cell transplantation. For the remaining patients, the only curative option is allogeneic stem cell transplantation with stem cells from a histocompatible sibling or an alternative donor. Reduced intensity conditioning regimens may be considered for patients older than 50 years or patients with comorbidities. The advice is to treat patients early after diagnosis and preferably before progression as these patients have the highest chance of a favorable outcome.     

Early-stage Hodgkin's disease: current approaches to treatment.

Most patients with early-stage Hodgkin''s disease can now be cured by one of several therapeutic approaches. This review highlights the developments in the diagnosis and treatment of the disease that have led to long-term survival rates greater than 90%. Past and present radio-therapy (RT) planning and treatment practices are discussed in the context of both clinical and pathological staging. The role of initial bimodal therapy (RT and chemotherapy [CT]) and the use of CT in patients who suffer relapse after initial treatment with RT alone are reviewed. On the basis of prognostic factors, subgroups of patients for whom bimodal therapy is recommended, including those with a bulky mediastinal mass, have now been identified. Although treatment is highly successful, debilitating consequences of RT and CT, such as infertility, infection and second malignant diseases, remain. Newer treatment regimens may reduce morbidity and have similar or better long-term results with respect to survival and quality of life.     

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin

AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients - predominantly with FLT3 ITD-positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity - the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard “3+7” induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD-positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity – but with a resultant decrease of potential side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD-positive AML.     

Traitement du cancer du testicule

Significant advances have been achieved in testicular cancer treatment for the last 15 years. Almost 100% of the non seminomatous tumors seen at the precocious stages I and II are cured because of the efficacy of chemotherapy in relapses. For clinical stages I, tendancy is to survey after castration without lymphadenectomy. For advanced metastatic stages, platinum has changed chemotherapy performances, allowing to cure 75 to 80% of these patients. The results of a bad pronosis group with large tumor remain to be improved. Seminomas at a localized stage (the most frequent case) are cured by radiotherapy; at an advanced stage, they are as sensitive to chemotherapy as non seminomatous tumors.     

Adjuvant immune stimulation with Corynebacterium parvum during maintenance chemotherapy of acute myeloid leukemia

Summary Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achivement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.     

Adjuvant immune stimulation with Corynebacterium parvum during maintenance chemotherapy of acute myeloid leukemia

Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achievement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.     

High expression of miR-338 is associated with poor prognosis in acute myeloid leukemia undergoing chemotherapy

Acute myeloid leukemia (AML) is a heterogeneous disease with unfavorable outcomes. MicroRNAs (miRNAs) are important regulators and prognostic factors involved in AML. To determine the clinical role of miR-338 in AML, a total of 164 adults with de novo AML were collected. These patients were classified into a chemotherapy group and an allogeneic hematopoietic stem cell transplantation (allo-HSCT) group according to the clinical treatment, and then each group was divided into two subgroups based on the median miR-338 expression values. We found that upregulated miR-338 positively correlates with higher frequencies of complex karyotype, RUNX1 mutation, and poor risk status. In the chemotherapy group, high expression of miR-338 was independently associated with shorter EFS and OS. However, no significant differences were observed between the two subgroups within the allo-HSCT group. We also divided all patients into two groups according to the median miR-338 expression values of the whole cohort. In the miR-338 high expression group, patients receiving allo-HSCT had longer OS and EFS than those receiving chemotherapy only. In contrast, patients receiving different therapies had similar OS and EFS in the miR-338 low expression group. Our study suggests that high expression of miR-338 is an adverse prognostic biomarker in patients with AML undergoing chemotherapy and may guide treatment decisions for AML. Furthermore, allo-HSCT could significantly overcome the negative effect of high miR-338 expression, but it seemed to be unbeneficial and unnecessary for low miR-338 expressions.     

Phage display-based generation of novel internalizing antibody fragments for immunotoxin-based treatment of acute myeloid leukemia

The current standard treatment for acute myeloid leukemia (AML) is chemotherapy based on cytarabine and daunorubicine (7 + 3), but it discriminates poorly between malignant and benign cells. Dose-limiting off?target effects and intrinsic drug resistance result in the inefficient eradication of leukemic blast cells and their survival beyond remission. This minimal residual disease is the major cause of relapse and is responsible for a 5-year survival rate of only 24%. More specific and efficient approaches are therefore required to eradicate malignant cells while leaving healthy cells unaffected. In this study, we generated scFv antibodies that bind specifically to the surface of AML blast cells and AML bone marrow biopsy specimens. We isolated the antibodies by phage display, using subtractive whole-cell panning with AML M2?derived Kasumi?1 cells. By selecting for internalizing scFv antibody fragments, we focused on potentially novel agents for intracellular drug delivery and tumor modulation. Two independent methods showed that 4 binders were internalized by Kasumi-1 cells. Furthermore, we observed the AML?selective inhibition of cell proliferation and the induction of apoptosis by a recombinant immunotoxin comprising one scFv fused to a truncated form of Pseudomonas exotoxin A (ETA'). This method may therefore be useful for the selection of novel disease-specific internalizing antibody fragments, providing a novel immunotherapeutic strategy for the treatment of AML patients.     

What is the best option to cure patients with resistant/relapsing Hodgkin's disease?

Nearly 80% of patients with Hodgkin's disease (HD) are cured with chemotherapy with or without radiotherapy. However, in patients with primary refractory or relapsed disease, high-dose therapy (HDT) and autologous or peripheral-blood stem-cell transplantation (ASCT or PBSCT) represents the best curative option. Several prognostic factors to identify patients at high risk for relapse or progression have been analyzed. However, in almost all analyzed series, disease status before high-dose chemotherapy with PBSC support remains the most important factor predicting the outcome of these patients. Nonetheless, the benefit of cytoreduction before HDT has yet to be fully determined and efforts to identify the best active regimen, combining therapeutic activity and CD34+ stem-cell mobilizing potential, represent a challenging issue for these patients. Furthermore new approaches like myeloablative and non-myeloablative allogeneic transplants have been assessed to improve long-term in such patients. In this review we analyzed the results of the most important salvage chemotherapy combinations as well as allogeneic transplantations to clarify the optimal treatment options for patients with resistant/relapsing HD.     

Assessment of the downstream portion of the mitochondrial pathway of caspase activation in patients with acute myeloid leukemia

Most chemotherapeutic agents used in the treatment of acute myeloid leukemia (AML) induce apoptosis by triggering the mitochondrial pathway of caspase activation. To investigate the downstream portion of the mitochondrial pathway of caspase activation in patients with AML, cytosolic lysates were stimulated with cytochrome c and dATP and hydrolysis of Ac-DEVD-AFC by effector caspases was measured. Defects in the distal mitochondrial pathway were more common in samples from patients with AML that relapsed rapidly after induction chemotherapy compared to samples from treatment naïve patients. The incidence of blocked pathways did not differ based on response to induction chemotherapy, as even nonresponders generally had an intact pathway. When the distal mitochondrial pathway was blocked, defects were usually at the level of the effector caspases. Thus, functional defects in the distal portion of the mitochondrial pathway of caspase activation may help explain the nature of response and relapse after treatment.     

Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks

Histone deacetylase inhibitors (HDACIs) like valproic acid (VPA) display activity in leukemia models and induce tumor-selective cytotoxicity against acute myeloid leukemia (AML) blasts. As there are limited data on HDACIs effects, we aimed to dissect VPA effects in vitro using myeloid cell lines with the idea to integrate findings with in vivo data from AML patients treated with VPA additionally to intensive chemotherapy (n = 12). By gene expression profiling we identified an in vitro VPA response signature enriched for genes/pathways known to be implicated in cell cycle arrest, apoptosis, and DNA repair. Following VPA treatment in vivo, gene expression changes in AML patients showed concordant results with the in vitro VPA response despite concomitant intensive chemotherapy. Comparative miRNA profiling revealed VPA-associated miRNA expression changes likely contributing to a VPA-induced reversion of deregulated gene expression. In addition, we were able to define markers predicting VPA response in vivo such as CXCR4 and LBH. These could be validated in an independent cohort of VPA and intensive chemotherapy treated AML patients (n = 114) in which they were inversely correlated with relapse-free survival. In summary, our data provide new insights into the molecular mechanisms of VPA in myeloid blasts, which might be useful in further advancing HDAC inhibition based treatment approaches in AML.     

Potential CD34 signaling through phosphorylated-BAD in chemotherapy-resistant acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) constitutively express growth factors and cytokines for survival. Chemotherapy alters these signals to induce cell death. However, drug resistance in AML remains a major hindrance to successful treatment and early warning is unavailable. Modulation of signaling pathways during chemotherapy may provide a window to detect response and predict treatment outcome. Blood samples collected from AML patients before and at day-3 of induction therapy were compared for changes in expression of CD117, CD34, pro-inflammatory cytokines and mediators of Akt and MAPK pathways, using multi-color flow cytometry. Nine patients were diagnosed as drug-resistant and seven sensitive to chemotherapy. Twelve were paired. Average percentages of CD34 (66.8?±?11.7% vs. 26.2?±?5.8%, p?=?0.033) and pBAD (66.9?±?8.2% vs. 28.9?±?8.2%, p?=?0.016) were significantly increased in chemo-resistant (N?=?9) compared to chemo-sensitive (N?=?5) samples. Percentages of CD34 were strongly correlated with pBAD (R?=?0.785; p?=?0.001; N?=?14) and pFKHR (R?=?0.755; p?=?0.002; N?=?14) at day-3 induction. Chemo-sensitive cases expressed significantly higher percentages of IL-18Rα (71.9?±?9.6% vs. 29.8?±?5.8%, p?=?0.016). Though not significantly different in the outcome, IL-1β was strongly associated with activated Akt-S473, IL-6 with phosphorylated JNK and FKHR while TNF-α appeared to trigger Bim, in treated samples. These preliminary results suggested AML cells resistant to chemotherapy increased expression of CD34 and may signal through pBAD while cells sensitive to chemotherapy-induced IL18Rα expression. These were observed early during induction therapy. Identifying CD34 is interesting as it is a convenient marker to monitor drug-resistance in AML patients. Inhibition of CD34 and pBAD signaling may be important in treating drug-resistant AML.     

Identification of leukemia stem cells in acute myeloid leukemia and their clinical relevance

Acute myeloid leukemia (AML) is considered to be a disease of stem cells. A rare defective stem cell population is purported to drive tumor growth. Similarly to their normal counterparts, leukemic stem cells (LSC) divide extreme slowly. This may explain the ineffectiveness of conventional chemotherapy in combatting this disease. Novel treatment strategies aimed at disrupting the binding of LSC to stem cell niches within the bone marrow might render the LSC vulnerable to chemotherapy and thus improving treatment outcome. This review focuses on the detection of LSC, our current knowledge about their cellular and molecular biology, and LSC interaction with the niche. Finally, we discuss the clinical relevance of LSC and prospective targeted treatment strategies for patients with AML.     

Resonance in periodic chemotherapy: a case study of acute myelogenous leukemia

The effects of periodic chemotherapy administration are evaluated within the context of a G(0)model of the cell cycle. Parameters are estimated for normal bone marrow cells and malignant cells in acute myelogenous leukemia (AML). This model explicitly includes the resting G(0)phase and the feedback mechanism that recruits the cells back into the cell cycle. Periodic chemotherapy administration can induce resonance within our model under high cell kill rate where the average cell cycle times may change during the course of treatment, and therapeutic benefits from these resonances cannot be solely based on cell cycle times in untreated tissue. The depletion rate under chemotherapy and the regrowth rate may differ between the cell populations, and our analysis suggests that this favors the tumour cells. We were able to distinguish between the effects of cycle-non-specific, S -phase-specific and M -phase-specific drugs, and found that these can show differences in sharpness and location of the resonance phenomenon. We conclude that resonance chemotherapy (chronotherapy) is unlikely to be efficacious in the treatment of AML.     

Design,synthesis and evaluation of anti-CD123 antibody drug conjugates

Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.     

Human mismatch repair, drug-induced DNA damage, and secondary cancer

DNA mismatch repair (MMR) is an important replication error avoidance mechanism that prevents mutation. The association of defective MMR with familial and sporadic gastrointestinal and endometrial cancer has been acknowledged for some years. More recently, it has become apparent that MMR defects are common in acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS) that follows successful chemotherapy for a primary malignancy. Therapy-related haematological malignancies are often associated with treatment with alkylating agents. Their frequency is increasing and they now account for at least 10% of all AML cases. There is also evidence for an association between MMR deficient AML/MDS and immunosuppressive treatment with thiopurine drugs. Here we review how MMR interacts with alkylating agent and thiopurine-induced DNA damage and suggest possible ways in which MMR defects may arise in therapy-related AML/MDS.