Strategy For Acute Myeloid Leukemia Research Articles

Targeted Delivery of Antisense Oligodeoxynucleotide by Transferrin Conjugated pH-Sensitive Lipopolyplex Nanoparticles: A Novel Oligonucleotide-Based Therapeutic Strategy in Acute Myeloid Leukemia

Therapeutic use of oligodeoxynucleotides (ODNs) that hybridize to and downregulate target mRNAs encoding proteins that contribute to malignant transformation has a sound rationale, but has had an overall limited clinical success in cancer due to insufficient intracellular delivery. Here we report a development of formulations capable of promoting targeted delivery and enhanced pharmacologic activity of ODNs in acute myeloid leukemia (AML) cell lines and patient primary cells. In this study, transferrin (Tf) conjugated pH-sensitive lipopolyplex nanoparticles (LPs) were prepared to deliver GTI-2040, an antisense ODN against the R2 subunit of ribonucleotide reductase that has been shown to contribute to chemoresistance in AML. LPs had an average particle size around 110 nm and a moderately positive zeta potential at approximately 10 mV. The ODN encapsulation efficiency of LPs was >90%. These nanoparticles could release ODNs at acidic endosomal pH and facilitate the cytoplasmic delivery of ODNs after endocytosis. In addition, Tf-mediated targeted delivery of GTI-2040 was achieved. R2 downregulation at both mRNA and protein levels was improved by 8-fold in Kasumi-1 cells and 2- to 20-fold in AML patient primary cells treated with GTI-2040-Tf-LPs, compared to free GTI-2040 treatment. Moreover, Tf-LPs were more effective than nontargeted LPs, with 10 to 100% improvement at various concentrations in Kasumi-1 cells and an average of 45% improvement at 3 microM concentration in AML patient primary cells. Treatment with 1 microM GTI-2040-Tf-LPs sensitized AML cells to the chemotherapy agent cytarabine, by decreasing its IC(50) value from 47.69 nM to 9.05 nM. This study suggests that the combination of pH sensitive LP formulation and Tf mediated targeting is a promising strategy for antisense ODN delivery in leukemia therapy.

New Target for Anti-Leukemia Attack

Complementary proteomic and genetic experiments identify a possible therapeutic strategy for acute myeloid leukemia.

Present status and perspectives regarding the therapeutic strategy for acute myeloid leukemia, non‐Hodgkin's lymphoma and multiple myeloma in the elderly

The incidence of cancers increases with advancing age. To improve the quality of life of elderly patients with hematological malignancies, appropriate therapeutic approaches have to be provided under adequate informed consent and with evaluation of the prognostic factors that predict the therapeutic outcome of each disease. Even in elderly patients, combination chemotherapies are effective for obtaining a good outcome for selected populations judged by factors such as performance status, pre-existing comorbid conditions or disease features; however, non-intensive treatment or supportive care might also be considered for patient groups with a poor prognosis. Therefore, the clinical parameters of the relevance for treatment decisions in the elderly are herein addressed. During cancer treatment, attention must be paid to the presence of age-related organ dysfunction, drug resistance, drug-induced side-effects such as end organ-targeted toxicity, or neutropenia due to myelosuppression by cytotoxic drugs. Current therapeutic approaches are therefore expected to have good compliance and better outcome in elderly patients by the introduction of several molecularly targeted therapies, novel nucleoside analogs or non-myeloablative stem cell transplantation.

Bis(1H‐indol‐2‐yl)methanones are effective inhibitors of FLT3‐ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro

Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H-indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of both compounds with chemotherapy revealed synergistic effects in apoptosis assays. The compounds did not show significant toxicity in human bone marrow cells derived from healthy donors. Compound102 overcame resistance to PKC412 within a non-myelotoxic dose-range. Western Blotting experiments of 32D-FLT3-ITD cells showed dose-dependent dephosphorylation of FLT3-ITD and of its downstream targets STAT5, AKT and ERK upon incubation with either compound. In conclusion, bis(1H-indol-2-yl)methanones overcome resistance mediated by FLT3-ITD mutations at position N676 and show strong efficacy in FLT3-ITD-positive cells alone as well as in combination with chemotherapy. We propose that further development of methanone compounds overcoming resistance to currently established FLT3-TKIs is an important step forward to an anticipated need within our future therapeutic algorithm in FLT3-ITD-positive AML.

Development of Mek inhibition (MEK-I)-Based Therapeutic Strategies in Acute Myeloid Leukemia (AML)

In hematologic malignancies, constitutive activation of the Raf/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Indeed, we have recently demonstrated that selective MEK-I potently inhibit the growth of AML cell lines and ex vivo-cultured primary AML blasts (Blood 2006, 108:254). However, these effects are mostly related to the inhibition of cell cycle progression, while apoptosis induction requires higher concentrations of the inhibitors and longer times of exposure. Thus, we investigated MEK-I-induced changes in phospho-protein expression and gene expression profiles, in order to identify relevant downstream targets and to design rational MEK-I-based combination strategies. Analysis of phosphorylation levels of 18 different target proteins performed in OCI-AML3 cells indicated that MEK blockade induces, among other effects, an over-activation of RAF and MEK, suggesting the interruption of a negative feedback loop. Moreover, gene expression profiling indicated that, in the same cellular model, MEK-I induced upregulation of the Flt-3 receptor. Based on these observations, as well as on recent evidence indicating that the Raf inhibitor sorafenib directly inhibits signaling through Flt-3 (JNCI 2008, 100:184), experiments were performed in OCI-AML3 and MOLM-13 (which harbors a Flt3 ITD) cells to test the activity of MEK-I in combination with sorafenib. Simultaneous inhibition of Flt3/Raf and MEK resulted in the synergistic inhibition of cell growth, as measured by isobologram analysis (Chou–Talalay method) in both model systems, with combination indexes (CI) of 0.12 and 0.48 for OCI-AML3 and MOLM-13 cells, respectively. Neither sorafenib nor MEK-I induced apoptosis in either cell line when used alone; however, apoptosis was observed in up to 50% of the cells with the combined treatment. Based on our previous experience, as well as on the ability of MEK-I to modulate the expression, among others, of genes controlling mitochondrial homeostasis (e.g. PPIF, GRPEL1), we next investigated the impact of simultaneous inhibition of the MEK and Bcl-2 pathways in AML cells. Exposure of OCI-AML3 and MOLM-13 cells to a combination of MEK-I and the Bcl-2/Bcl-xL inhibitor, ABT-737 (kindly provided by Abbott Laboratories) synergistically inhibited cell growth, with CI ranging from 0.45 to 0.04 in OCI-AML3 and from 0.75 to 0.14 in MOLM-13, respectively. In both cellular models, ABT-737dose-dependently induced apoptosis, while MEK-I, at the concentrations used in combination experiments, did not appreciably increase apoptotic cell death; however, simultaneous Bcl- 2/Bcl-xL inhibition and MEK blockade resulted in the massive induction of apoptosis (up to 85% and 67% net apoptosis induction in OCI-AML3 and MOLM-13 cells, respectively). Such pro-apoptotic interaction was highly synergistic with CI of 0.18 and 0.16 in OCIAML3 and MOLM-13 cells, respectively. In contrast, combination with MEK-I did not appreciably sensitize the MEK-I-resistant cell line U937 to either sorafenib- or ABT-737- induced growth inhibitory and pro-apoptotic effects. Overall these results support the role of the Raf/MEK/ERK kinase module as a prime target for the molecular therapy of AML and suggest that both “vertical” and “lateral” combination strategies based on MEK inhibition may produce highly synergistic anti-leukemic effects.

RNAi-Based Functional Genomics Screening of the Human Kinome Identifies Major Growth Regulating Kinases in Acute Myeloid Leukemia Cells

In order to improve treatment strategies for Acute Myeloid Leukemia (AML), we adapted a functional genomics approach using RNAi screening to identify molecular targets that are vital to the growth of AML. Herein we report the first large-scale kinome gene silencing screen in AML. A high throughput RNAi screen was developed for the efficient siRNA transfection of AML cell lines. Eight commercially available cationic lipid-based transfection reagents were tested for their ability to transfect several AML cell lines with siRNA. These extensive transfection optimization experiments identified two AML cells lines TF-1 and ML4 with up to 95–100 and 70–75% transfection efficiency respectively. Two independent replicate kinome screens were performed on both cell lines using a siRNA library targeting 572 kinase genes with 2 siRNA/gene. At 96 hours post transfection, cell proliferation was assessed and the B-score method was used to background correct and analyze the screening data. Several siRNA to specific kinases were identified that significantly inhibit cell proliferation of up to ~40–88%. Hits were defined at two thresholds: siRNA having a B-score of <−2 providing a statistically significance of p<0.05 (confidence of > 95%) and a cutoff B-score of <−1.5 providing greater than 87% confidence for each siRNA hit. Two different kinases (2 siRNA/gene/screen) were identified as major growth regulating kinases in TF1 cells with all 4 siRNA/gene having a B-score <−2. For two additional kinases, 3/4 siRNA for each gene had a Bscore <−2. Expanding the cutoff to a B-score <−1.5 three further kinases were targeted by at least 3/4 siRNA/gene. Similar analysis using the same criteria for ML4 cells identified one kinase targeted by 3/4 siRNA at a B-score <−2, seven kinases with 2/4 siRNA <−2 and two kinases with 3/4 siRNA/gene at a B-score of <−1.5. Common hits for both cell lines with at least 6/8 siRNA per gene from 4 screens performing at a B-score <−2 identified two kinases, one of them PLK1. Applying a B-score threshold of <−1.5, we identified five kinases for which at least 5/8 siRNA/gene from 4 screens met these criteria. Kinases/genes will be presented at the meeting.Confirmation of gene silencing and validation of growth response is currently underway for a subset of genes. Among the strongest hits are siRNA targeting PLK1, as well as siRNA targeting three other kinase-genes involved in regulating cell cycle progression and checkpoints and gene ontology (GO) analysis showed enrichment in cell cycle and cell cycle-checkpoint processes. Inhibitors against PLK1 and other kinase hits identified in the screen are in (pre)-clinical development and if confirmed, our experiments provide a strong rational to test these in AML. The application of RNAi based screening is useful in the identification of genes important in AML proliferation, which could serve as targets for therapeutic intervention and guide AML drug development. Furthermore, results from these types of functional genomics approaches hold promise to be rapidly translated into clinical application.

A Phase I Evaluation of Low Dose Decitabine Targeting DNA Hypermethylation in Patients with Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin's Lymphoma (NHL): Dose-Limiting Myelosuppression without Evidence of Hypomethylation

Background: Epigenetic modifications including CpG island promoter methylation that favor transcriptionally repressed chromatin have been identified in a variety of B-cell malignancies, including CLL, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLCL). Recent investigations by our group and others have demonstrated aberrant hypermethylation in a variety of genes critical for cell cycle regulation or apoptosis in NHL and CLL, including p15, p16, DERMO1, DAPK1, FOXE1, GRM7, and TWIST1. Targeting aberrant DNA hypermethylation through inhibition of DNA methyltransferase (DNMT) with low-dose decitabine has provided a new treatment strategy in acute myeloid leukemia (AML), and we postulated that a similar approach may be effective in CLL and B-cell NHL.Methods: Two separate phase I trials were conducted at the Ohio State University to determine the minimum effective pharmacologic dose (MEPD) of the DNMT inhibitor, decitabine, in the treatment of patients (pts) with relapsed or refractory CLL and aggressive NHL. In both trials, the MEPD was defined as the dose of decitabine where evidence of hypomethylation of selected genes (DAPK1, TWIST, and DERMO-1 for CLL; DAPK1, p15, and p16 for NHL) or selected gene re-expression was observed in 5 of 6 pts with ≤ 1 pt at each dose level experiencing dose limiting toxicity (DLT). Eligibility criteria included at least one prior therapy, ECOG performance status 0–2, and normal hepatic and renal function. Absolute neutrophil count ≥ 1500/mm3 and platelets ≥ 75,000/mm3 were required for all NHL pts. Twenty-eight days defined a cycle and hematologic recovery to ≥ 75% of baseline or ≤ grade (gr.) 2 by day 35 was necessary for decitabine retreatment in both trials.Results: Twenty pts (median age 69.5, range 32–82) with relapsed/refractory CLL (n=16) or DLCL (n=4) after a median of 4.5 prior therapies (range, 2–8) were enrolled. Only 1 of 20 pts had previously undergone stem cell transplantation, 2 years prior to study enrollment. Pts received 1–3 cycles of decitabine, and were removed from study due to DLT or disease progression. DLT was observed in 2 of 4 CLL and 2 of 2 DLCL pts receiving decitabine at 15 mg/m2/day over 1 hour for 10 days, consisting of gr. 4 thrombocytopenia (n=3) beyond day 35 and gr. 3 hyperbilirubinemia (n=1). As a result, 6 pts with CLL were treated with decitabine at 10 mg/m2/day for 10 days without DLT; however, sufficient evidence of hypomethylation was not observed. Therefore, due to the failure to obtain MEPD at decitabine doses of 10 mg/m2 over 10 days, a shorter 5-day infusion schedule was examined in both CLL and DLCL in order to permit maximal dose escalation. With decitabine at 15 mg/m2/day on days 1–5, DLT occurred in 2 of 6 CLL and 2 of 2 DLCL pts, consisting of persistent gr. 3–4 neutropenia or thrombocytopenia after day 35, gr. 3 gram positive sepsis, and gr. 4 neutropenic fever. No responses were observed. In 18 pts with circulating CLL cells or lymph nodes accessible to biopsy, LC-MS analysis of global DNA methylation demonstrated no significant changes in genome-wide methylation in samples collected pre-treatment and on days 3, 5, 15, and 22 of cycle 1. Plasma pharmacokinetics (PK) in 11 pts demonstrated a mean Cmax of 1.4 ± 1.0 μM, AUC of 61.2 ± 28.1min*μM, total clearance of 1.5 ± 1.2 ml/min/m2, and beta half-life 25.5 ± 6.9 min, similar to previously published findings in AML (Blum W, JCO 25:3884-3891, 2007). There was a trend of increase in PK parameters with increased dose, but no difference was found between the PK in CLL and NHL patients nor with repeat dosing.Conclusions: Dose-limiting myelosuppression and resultant infectious complications prevents dose escalation of decitabine to dose levels associated with hypomethylation in CLL and DLCL. Alternative agents targeting DNA methylation in B-cell malignancies should be explored.

Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors

Modulation of gene expression through histone deacetylase (HDAC) inhibition is considered a possible therapeutic strategy in acute myeloid leukaemia (AML). In vitro effects and basal gene expression of structurally different HDAC inhibitors were examined. Primary human AML cells were derived from 59 consecutive patients. The HDAC inhibitors valproic acid, PXD101, trichostatin A and sodium butyrate inhibited leukaemic and clonogenic cell proliferation and increased apoptosis in a dose-dependent manner when tested at high concentrations. However, at lower concentrations proliferation increased for a subset of patients. This divergence was also observed in the presence of all-trans retinoic acid, theophylline and decitabine, and in cocultures with bone marrow stromal cells. Levels of IL-1beta, IL-6, GM-CSF and TNFalpha increased. Based on the basal expression of 100 genes the patients with growth enhancement at intermediate HDAC inhibitor concentrations and those without this response were clustered into two mutually exclusive groups. Functional characterization and gene expression analyses identify AML patient subsets that differ in their response to HDAC inhibitors. These observations may explain why HDAC inhibitor therapy affects only a subset of patients.

Sensitivity toward sorafenib and sunitinib varies between different activating and drug-resistant FLT3-ITD mutations

Activating mutations in FLT3 are known to be a frequent transforming event in acute myeloid leukemia. Small molecule-inhibitor therapy targeting the FLT3 kinase is, therefore, an attractive strategy. FLT3 kinase inhibitors, such as PKC412, have already entered clinical trials. Even though results are encouraging, emergence of primary and secondary resistance does occur in the majority of patients. Thus, it will be crucial to carefully characterize the activity of every single compound against different activating and resistance FLT3-internal tandem duplication (ITD) mutations. Here we tested the efficacy of sunitinib and sorafenib to inhibit primary FLT3 activating mutations (ITD and D835Y) and of secondary resistance mutations. Ba/F3 cell lines stably expressing oncogenic FLT3 mutations were used to calculate cellular IC(50) values for sunitinib and sorafenib using cell proliferation assays. Differential IC(50) values for sorafenib toward FLT3-ITD and FLT3-D835Y were confirmed by Western blotting. Cell death was measured by propidium-iodide staining and flow cytometry. Sorafenib inhibits FLT3-ITD more potent than FLT3-D835Y, while sunitinib is equally effective against both mutant forms of FLT3. Importantly, sensitivity toward sorafenib and sunitinib varies between the different secondary FLT3-ITD resistance mutations. These results establish sensitivity profiles for the FLT3 inhibitors sunitinib and sorafenib. This may help to develop rational treatment strategies for acute myeloid leukemia with these compounds.

Insight into the molecular pathogenesis of myeloid malignancies

Molecular mutations play an increasing role for classification, prognostication, and therapeutic strategies in acute myeloid leukemia and myelodysplastic syndrome. Due to the rapid expansion of known molecular markers, this paper aims to outline some of the recent progress to improve understanding of the pathogenesis in these myeloid malignancies. Novel concepts conceive myelodysplastic syndrome and acute myeloid leukemia as endpoints of a continuous process of leukemogenesis, which is characterized by the interaction of mutations interfering with transcription and differentiation with activating mutations enhancing proliferation. The detection of novel molecular mutations such as NPM1 widened the spectrum of molecular markers in acute myeloid leukemia. Finally, attention focusses on detailed subtyping of already known molecular markers. The fast progress in the molecular characterization of acute myeloid leukemia and myelodysplastic syndrome in recent years provides the basis for an optimization of therapeutic concepts. The introduction of new methods such as gene expression profiling catalyzes this process.

C/EBPα and the pathophysiology of acute myeloid leukemia

The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. Conditional mouse models provide direct evidence that loss of C/EBPalpha function leads to the accumulation of myeloid blasts in the bone marrow. Targeted disruption of the wild type C/EBPalpha protein, while conserving the dominant-negative 30 kDa isoform of C/EBPalpha, induces an AML-like disease in mice. In hematopoietic stem cells C/EBPalpha serves to limit cell self-renewal. Finally, C/EBPalpha function is disrupted at different levels in specific subgroups of acute myeloid leukemia patients. There is evidence that impaired C/EBPalpha function contributes directly to the development of acute myeloid leukemia. Normal myeloid development and acute myeloid leukemia are now thought to reflect opposite sides of the same hematopoietic coin. Restoring C/EBPalpha function represents a promising target for novel therapeutic strategies in acute myeloid leukemia.

Inhibition of Bcl-2 Signaling at Nanomolar Concentrations by Small Molecule BH3 Inhibitor, ABT-737 as a Novel Therapeutic Strategy in Acute Myeloid Leukemia (AML).

In this study, we investigated the anti-leukemic activity of a novel small molecule BH3 inhibitor (ABT-737) that binds with high affinity to Bcl-2, Bcl-xL and Bcl-w (Ki < 1nM). ABT-737 inhibited 50% of cell growth of HL-60, NB4 and KG-1 cells at IC50's below 100nM, while its less active enantiomer did not affect cell growth at concentrations of 1μM. The dose-response curve was shifted to the right in cells over-expressing the drug targets, Bcl-2 or Bcl-XL (IC50 for HL-60/neo - 1μM, HL-60/BclXL - 4μM and HL-60/Bcl-2 - 5μM). ABT-737 inhibited Bcl-2/Bax heterodimerization starting at 1 hour as evidenced by IP/Western blot analysis. Furthermore, Bax cleavage (at 3 hours) resulted in pro-apoptotic Bax-p18 and later a change to “death conformation” of Bax. This resulted in mitochondrial depolarization and cleavage of caspases-9, -3 and -8. Bax-knockout Hct116 cells were largely protected from cytolytic activity of ABT-737 demonstrating the critical role of Bax in apoptosis induction. In primary AML samples (n=9), 100 nM ABT-737 induced apoptosis in 70±7% of CD34+ progenitor cells (DMSO-control, 28±4%, p<0.001) at 24 hrs. ABT-737 inhibited clonogenic growth of AML with IC50 of 25nM (n=3) but spared normal progenitors n=3 (no inhibition at 100nM). To investigate the role of Bcl-2 phosphorylation in the sensitivity to BH3 inhibitor, we used IL-3 dependent NSF.N1/H7 mouse myeloid cells modified by site-directed mutagenesis to produce various Bcl-2 phospho-mutants. NSF.N1/H7 cells stably transfected with phosphomimetic T69E/S70E/S87E (EEE) Bcl-2 mutants were resistant to ABT-737 (IC50>500nM) as compared to cells expressing wt-Bcl-2 or the nonphosphorylatable T69A/S70A/S87A (AAA) Bcl2 mutants (IC50s of 50 and 25nM). This suggests that phosphorylation-dependent conformational change of Bcl-2 affects the ability of BH3 inhibitors to disrupt Bcl-2/Bax dimers and induce apoptosis. Since the S70E phosphorylation site of Bcl-2 is a known ERK substrate, we examined combined effects of ABT-737 and MEK inhibitor PD98059 in OCI-AML3 cells resistant to ABT-737 alone. The combined activity of PD98059 and ABT-737, evaluated by isobologram analysis, revealed a striking synergistic interaction between the MEK and BH3 inhibitors, with combination indices (CI) of 0.09 to 0.56. The hypothesis that phosphorylation-dependent conformational change of Bcl-2 affects the ability of BH3 inhibitors to disrupt Bcl-2/Bax dimers and induce apoptosis is presently under investigation. Inhibition of MEK signaling may therefore enhance the efficacy of BH3 inhibitors in AML and possibly other malignancies with phosphorylated Bcl-2. In conclusion, small molecule BH3 inhibitors are potent inducers of apoptosis in myeloid leukemias via disruption of Bcl-2/Bax dimerization and activation of the downstream apoptotic cascade. Differential inhibition of AML but not normal progenitor cells at low nanomolar concentrations advocates further development of BH3 inhibitors as a novel therapeutic strategy for AML.

Is modulation of multidrug resistance a viable strategy for acute myeloid leukemia?

Is modulation of multidrug resistance a viable strategy for acute myeloid leukemia?

Rational approaches to design of therapeutics targeting molecular markers.

This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.

Pathophysiology of cytokines and therapeutic strategies in acute myeloid leukemia

Cytokines regulating normal hematopoiesis as well as contributing to disordered hematopoiesis in hematological neoplasias are attracting increasing interest in view of their growing therapeutic potential. In addition, insights into the pathophysiology of various disease states, including leukemia, allow the design of new therapeutic strategies.

Treatment strategies in acute myeloid leukemia (AML)

The strategy for treatment of relapsed or refractory acute myeloid leukemia must primarily be based on the patient's age and clinical condition as well as on the stage of the disease. Accordingly, the general decision between an intensive approach including high-dose chemotherapy or possibly immediate allogeneic bone marrow transplantation versus less-aggressive palliative treatment will precede the selection of the most appropriate salvage regimen. In patients qualifying for intensive second-line chemotherapy the duration of the first remission and the number of relapses provide the means to discriminate between refractoriness or maintained responsiveness to conventional protocols. More than 50% of patients with first relapses after 6-12 months remission duration will respond to standard therapy again and should therefore not be entered on investigational agents with unproven antileukemic activity. The latter seems deeply warranted, on the other hand, for early relapses, second recurrences and resistant first relapses with a remission rate of less than 30% after conventional regimens. These guidelines not only provide an objective rationale for selecting the most appropriate strategy at relapse in individual patients. Furthermore, they facilitate interstudy comparisons and a better judgement of different treatment protocols.

Treatment strategies in acute myeloid leukemia (AML)

Chemotherapy remains the backbone of treatment in AML. Of all adult patients 65% go into remission and have a chance of longer survival and of even being cured. Among the responders, 25% can be cured by intensive and long-term chemotherapy. Since the effect of chemotherapy appears not to be limited to a special period of time, its antileukemic and curative potential could be further exploited by multiple-step chemotherapy combining double induction, intensified consolidation and long-term maintenance. Improved antimicrobial treatment and the use of hematopoietic growth factors may help making multiple-step chemotherapy practicable, thereby increasing the cure rate in AML.

Treatment strategies in acute myeloid leukemia (AML)

Chemotherapy remains the backbone of treatment in AML. Of all adult patients 65% go into remission and have a chance of longer survival and of even being cured. Among the responders, 25% can be cured by intensive and long-term chemotherapy. Since the effect of chemotherapy appears not to be limited to a special period of time, its antileukemic and curative potential could be further exploited by multiple-step chemotherapy combining double induction, intensified consolidation and long-term maintenance. Improved antimicrobial treatment and the use of hematopoietic growth factors may help making multiple-step chemotherapy practicable, thereby increasing the cure rate in AML.

Blood components in the care of the cancer patient

Human leukocyte antigen-mismatched leukocyte infusions outside of the context of transplantation are a promising strategy for acute myeloid leukemia. Recent studies using such non-engrafting alloreactive cellular therapy (NEACT) revealed that survival of elderly patients increased from 10% to 39% when NEACT was given following chemotherapy, and that durable complete remissions were achieved in about a third of patients with relapsed or chemorefractory disease. We review the clinical reports of different NEACT approaches to date and describe how although T-cell and NK alloreactivity could generate immediate anti-leukemic effects, long-term disease control may be achieved by stimulating recipient-derived T-cell responses against tumor-associated antigens. Other variables likely impacting NEACT such as the release of pro-inflammatory cytokines from donor-host bidirectional alloreactivity and the choice of chemotherapeutics as well as future avenues for improving NEACT, such as optimizing the cell dose and potential synergies with adjuvant pharmacologic immune checkpoint blockade, are discussed.