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M Konopleva,
M Milella,
P Ruvolo,
J C Watts,
M R Ricciardi,
B Korchin,
T McQueen,
W Bornmann,
T Tsao,
P Bergamo,
D H Mak,
W Chen,
J McCubrey, A Tafuri,
M Andreeff
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ABSTRACT: Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-X(L), ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2011; 26(4):778-87. · 8.30 Impact Factor
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N Misaghian,
G Ligresti,
L S Steelman,
F E Bertrand,
J Bäsecke,
M Libra,
F Nicoletti,
F Stivala,
M Milella, A Tafuri,
M Cervello,
A M Martelli,
J A McCubrey
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ABSTRACT: Since the discovery of leukemic stem cells (LSCs) over a decade ago, many of their critical biological properties have been elucidated, including their distinct replicative properties, cell surface phenotypes, their increased resistance to chemotherapeutic drugs and the involvement of growth-promoting chromosomal translocations. Of particular importance is their ability to transfer malignancy to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, numerous studies demonstrate that acute myeloid leukemia arises from mutations at the level of stem cell, and chronic myeloid leukemia is also a stem cell disease. In this review, we will evaluate the main characteristics of LSCs elucidated in several well-documented leukemias. In addition, we will discuss points of therapeutic intervention. Promising therapeutic approaches include the targeting of key signal transduction pathways (for example, PI3K, Rac and Wnt) with small-molecule inhibitors and specific cell surface molecules (for example, CD33, CD44 and CD123), with effective cytotoxic antibodies. Also, statins, which are already widely therapeutically used for a variety of diseases, show potential in targeting LSCs. In addition, drugs that inhibit ATP-binding cassette transporter proteins are being extensively studied, as they are important in drug resistance-a frequent characteristic of LSCs. Although the specific targeting of LSCs is a relatively new field, it is a highly promising battleground that may reveal the Holy Grail of cancer therapy.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 23(1):25-42. · 8.30 Impact Factor
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L S Steelman,
S L Abrams,
J Whelan,
F E Bertrand,
D E Ludwig,
J Bäsecke,
M Libra,
F Stivala,
M Milella, A Tafuri,
P Lunghi,
A Bonati,
A M Martelli,
J A McCubrey
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ABSTRACT: Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2008; 22(4):686-707. · 8.30 Impact Factor
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J A McCubrey,
L S Steelman,
S L Abrams,
F E Bertrand,
D E Ludwig,
J Bäsecke,
M Libra,
F Stivala,
M Milella, A Tafuri,
P Lunghi,
A Bonati,
A M Martelli
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ABSTRACT: The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2008; 22(4):708-22. · 8.30 Impact Factor
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ABSTRACT: The MEK/MAPK signaling module is a key integration point along signal transduction cascades that regulate cell growth, survival, and differentiation, and is aberrantly activated in many human tumors. In tumor cells, constitutive MAPK activation affords increased proliferation and resistance to apoptotic stimuli, including classical cytotoxic drugs. In most instances, however, MAPK inhibition has cytostatic rather than cytotoxic effects, which may explain the lack of objective responses observed in early clinical trials of MEK inhibitors. Nevertheless, amenability of the MAPK pathway to pharmacodynamic evaluation and negligible clinical toxicity make MEK inhibitors an ideal platform to build pharmacological combinations with synergistic antitumor activity. In AML, the MEK/MAPK pathway is constitutively activated in the majority of cases (75%), conferring a uniformly poor prognosis; in preclinical models of AML, MEK blockade profoundly inhibits cell growth and proliferation and downregulates the expression of several anti-apoptotic players, thereby lowering the apoptotic threshold. Apoptosis induction, however, requires concentrations of MEK inhibitors much higher than those required to inhibit proliferation. Nevertheless, MEK blockade efficiently and selectively sensitizes leukemic cells to sub-optimal doses of other apoptotic stimuli, including classical cytotoxics (nucleoside analogs, microtubule-targeted drugs, gamma-irradiation), biologicals (retinoids, interferons, arsenic trioxide), and, most interestingly, other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists). In most instances, these MEK inhibition-based combinations result in a striking pro-apoptotic synergism in preclinical models. Here we briefly discuss evidence suggesting that MAPK pathway inhibition could play a prominent role in the development of integrated therapeutic strategies aimed at synergistic anti-leukemic effects.
Current Pharmaceutical Design 02/2005; 11(21):2779-95. · 3.87 Impact Factor
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M C Petti, A Tafuri,
R Latagliata,
M A Aloe Spiriti,
E Montefusco,
M Mancini,
G Meloni,
M T Petrucci,
A Spadea,
R Redi,
G Alimena,
F Mandelli
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ABSTRACT: The aim of the study was to evaluate the antileukemic effectiveness and toxicity of high-dose hydroxyurea (HHY) and to assess its acute toxicity. Between August 1997 and October 1998, 12 consecutive adult patients (>18 years) with high-risk acute myeloid leukemia (AML) (four patients in first early relapse, seven patients with secondary AML, and one patient with de novo AML concomitant to a lymphoproliferative disorder) were enrolled to receive a single course of HY (100 mg/kg per day) until bone marrow aplasia or for a maximum of 30 days. Of the 12 patients, 5 (41.6%) achieved complete remission (CR), 1 achieved partial remission (PR), 4 were resistant to treatment, and 2 died during induction from infection. No patient with relapsed AML achieved CR, while it was achieved by five of eight patients with secondary AML at diagnosis; five of six MDR1+ patients achieved CR. As concerns follow-up of the CR patients, one did not receive any further treatment and died in CR from pulmonary aspergillosis, and one with a concomitant chronic lymphocytic leukemia (CLL) received two courses of FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor) regimen with disappearance of the clonal Ig rearrangement, but relapsed after 11 months and died from pneumonia. The remaining three patients were consolidated with two courses of high-dose cytosine arabinoside (AraC), followed by peripheral blood stem cell transplantation (PBSCT) in one patient. One of them relapsed after 3 months, while the other two are still in continuous complete remission (CCR) after 16 and 28 months, respectively. This study has demonstrated the safety and efficacy of HHY in inducing CR in AML patients with unfavorable prognosis. Despite the small number of patients, these encouraging results warrant further studies.
Annals of Hematology 08/2003; 82(8):476-80. · 2.62 Impact Factor
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M Mancini,
M L Vegna,
G L Castoldi,
C Mecucci,
F Spirito,
L Elia, A Tafuri,
L Annino,
F Pane,
G Rege-Cambrin, [......],
G Specchia,
G Torelli,
M Sborgia,
A Gabbas,
A Tedeschi,
I Della Starza,
N Cascavilla,
F Di Raimondo,
F Mandelli,
R Foà
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ABSTRACT: Within 285 adult acute lymphoblastic leukemias (ALL) included in the multicenter GIMEMA 0496 trial and prospectively studied by conventional cytogenetics, 18 cases (6%) with long arm deletion of chromosome 6 (6q) were identified. These cases were divided into: (i) del(6q) only (n = 6); (ii) del(6q) plus other numerical and/or structural abnormalities (n = 8); (iii) del(6q) and other 'specific' translocations (n = 4). The biologic and clinical features of the patients carrying this anomaly, as well as their outcome, were compared with those of 267 patients without del(6q). A T cell phenotype was more frequently associated with del(6q) cases in general (P = 0.001) and particularly with cases presenting del(6q) as the isolated abnormality (P = 0.0027). No significant difference with respect to multidrug resistance (MDR)/P glycoprotein expression was observed between the two groups of patients (21% vs 28% of MDR-positive cases, respectively). A BCR-ABL fusion transcript was less frequently detected in cases with del(6q) (11%) compared with those without the anomaly (29%). p15 and p16 deletions were identified by Southern blot analysis in 21% of cases with del(6q) and in 26% of cases without del(6q). In this latter group, a T cell phenotype was less frequently associated with p15 and/or p16 deletion than in the group carrying del(6q) (36% vs 100% of cases, P = 0.011). Overall, patients with ALL and del(6q) had a high complete remission (CR) rate (83%); however, they had a lower 18 month event-free survival (31% vs 41%) and a higher relapse rate (70% vs 37%, P = 0.02) compared with patients without del(6q). To date, this is the largest series of adult ALL cases reported with del(6q) homogeneously treated, which have also been prospectively studied for MDR expression and for the detection of known fusion genes. This anomaly, as an isolated change, identifies a subset of cases with hyperleukocytosis (median WBC count 52 x 10(9)/l) and a strict correlation with a T cell phenotype. Overall, del(6q) seems to be associated with an unfavorable clinical outcome, although this finding will need to be confirmed by extended FISH analysis.
Leukemia 11/2002; 16(10):2055-61. · 9.56 Impact Factor
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ABSTRACT: We report a patient with acute promyelocytic leukaemia (APL) who received two doses of gemtuzumab ozogamicin for advanced disease. Previous treatments included front-line all-trans retinoic acid and anthracyclines, polychemotherapy consolidation, salvage chemotherapy for the first relapse followed by autologous stem cell transplantation (ASCT), arsenic trioxide for the second relapse followed by a second ASCT and then high-dose methotrexate for more advanced systemic disease with central nervous system involvement. The patient achieved prolonged haematological and molecular remission after monotherapy with gemtuzumab ozogamicin given at the time of the third relapse.
British Journal of Haematology 11/2001; 115(1):63-5. · 4.94 Impact Factor
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ABSTRACT: Acute colonic pseudo-obstruction, the so-called Ogilvie's syndrome, is a rare and life-threatening digestive complication usually observed in critically ill patients. It is characterized by signs of large-bowel obstruction, without a mechanical cause, and has been reported in various settings, including acute leukemias as a complication of neutropenic enterocolitis after intensive chemotherapy. We describe the case of a young woman who, during the neutropenic phase following autologous bone marrow transplantation for relapsed acute myeloid leukemia, developed neutropenic enterocolitis complicated by an acute pseudo-obstruction of descendent colon and sigma. This process was associated with sepsis and resolved with conservative therapy of the underlying condition, using granulocyte colony-stimulating factor and intravenous neostigmine. We discuss the management of this rare syndrome.
Annals of Hematology 11/2001; 80(10):614-6. · 2.62 Impact Factor
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M R Ricciardi,
M T Petrucci,
C Gregorj,
C Ariola,
R M Lemoli,
M Fogli,
F R Mauro,
R Cerretti,
R Foà,
F Mandelli, A Tafuri
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ABSTRACT: The role of apoptosis and cell kinetics in the mechanisms of disease progression of chronic lymphocytic leukaemia (CLL) is still unclear. In the present study, we investigated the susceptibility of leukaemic cells taken from 75 CLL patients with either stable (STD) or progressive disease (PRD) to enter apoptosis. Particular attention was paid to the relationship between cell cycle status and autologous serum (AS). The susceptibility to enter apoptosis was significantly greater in STD than in PRD, both in standard medium (mean = 23.62% +/- 14.7 versus 14.23% +/- 7.2; P = 0.02) and in the presence of AS (mean = 23.03% +/- 17.9 versus 11.27% +/- 7.6; P = 0.01). Furthermore, cell kinetics studies revealed a higher quiescence in PRD than in STD cases, both in terms of a lower RNA content (P = 0.04) and of higher expression of the negative cell cycle regulator p27kip1 (P = 0.03). These kinetic differences were confirmed by short-term in vitro culture both in fetal calf serum and in AS. The results of this study indicate that CLL cells from PRD cases are characterized by a higher degree quiescence and much lower susceptibility to apoptosis when compared with STD ones. In this context, AS does not appear to play a specific role. The association between these kinetic characteristics and disease progression in CLL prompts further studies to establish whether higher quiescence may be responsible for the decreased susceptibility of PRD cells to enter apoptosis.
British Journal of Haematology 06/2001; 113(2):391-9. · 4.94 Impact Factor
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J Serrano,
F Lo Coco,
T Sprovieri,
L Elia,
A Vitale,
C Gregorj, A Tafuri,
J Sánchez,
J Román,
A Torres,
G Cimino
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ABSTRACT: In this study, we examined myeloperoxidase (MPO) gene expression in a series of 31 non-infant pro-B acute lymphoblastic leukaemia (ALL) patients that included 16 cases with the t(4;11) translocation and/or the resultant ALL1/AF4 chimaeric gene. Sixteen out of 31 cases (51%) were MPO mRNA positive/enzyme negative. MPO mRNA was detected in nine out of 16 (56%) and seven out of 15 (47%) patients with and without the ALL1/AF4 fusion transcript respectively. The comparative study between MPO mRNA positive and negative cases showed statistically significant differences with regard to age and white blood cell (WBC) count, and was 39.5 years vs. 26.3 years (P = 0.016) and 71.4 x 10(9)/l vs. 157.8 x 10(9)/l (P = 0.046) in the MPO mRNA positive and negative groups respectively. The correlation analysis between MPO mRNA expression, age, WBC count and leukaemic relapse according to the presence/absence of the ALL1/AF4 fusion showed that the statistically significant differences observed in the whole group were related mostly to the ALL1/AF4-positive ALL patients. In fact, in this latter group, the mean WBC count and patients' age were 85 +/- 79 x 10(9)/l vs. 289.8 +/- 102 x 10(9)/l (P = 0.0005) and 44.8 +/- 15.3 years vs. 26.7 +/- 13.7 years (P = 0.01) in patients with and without MPO mRNA expression respectively. It appears, therefore, that the assessment of MPO mRNA expression enables a further dissection of leukaemia heterogeneity in apparently homogeneous genetic/immunophenotypic ALL subsets.
British Journal of Haematology 01/2001; 111(4):1065-70. · 4.94 Impact Factor
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ABSTRACT: In this study we report our data on effects of early-acting megakaryocyte growth factors, particularly the c-mpl ligand also known as thrombopoietin (TPO) and interleukin-11 (IL-11), on cell proliferation and apoptosis (Apo) of primary acute myeloid leukemia (AML) cells. A proliferative response to TPO was noticed in the majority of AML samples (17/19) with an average increase of S-phase cells from 7.8% +/- 1.5 to 14.5% +/- 2.1 (p=0.0006). Resulting cell cycle activation did not always correlate with expression of the c-mpl receptor, although it was coupled, in the majority of samples, by an average decrease of apoptotic cells from 13% +/- 0.7 to 8.8% +/- 1.8 (p=0.05). Clonogenic cell growth (CFU-L) was confirmed in 5/17 of the samples with a mean colony number of 21.4 +/- 9.6 x 10(5) cells plated. Conversely, effects of IL-11 on AML cells demonstrated that cell cycle changes (recruitment from G0 to S phase) were promoted only in a minority of samples (2/14) and there was little, if any, effect on CFU-L growth (mean colony number=17.5 +/- 9.5) or Apo (from 13% +/- 0.7 to 13.3 +/- 1.9). Combination of TPO with IL-11 induced a slight increase of clonogenic cell growth, while the addition of IL-3 or SCF to the c-mpl ligand significantly raised the mean colony numbers up to 119.2 +/- 68.3 and 52.9 +/- 22.1 x 10(5) cells plated, respectively. In summary, TPO shows activity on AML cells by stimulating their proliferation in a significant proportion of cases and generally protecting the majority of AML blast cells from induction of Apo. Conversely, IL-11 exerts little effect on the cell cycle activation and Apo. These data help to understand regulation of myeloid leukemia cell growth and should be considered in the clinical use of early-acting megakaryocyte growth factors in acute leukemia.
Leukemia and Lymphoma 01/2001; 40(1-2):179-90. · 2.58 Impact Factor
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ABSTRACT: Despite considerable progress in recent years in the understanding of the biology of multiple myeloma (MM), this disease remains incurable, although many new therapeutic approaches are under evaluation. The rapid development of recombinant technologies has permitted the production of large amounts of cytokines and growth factors, favoring the use of biotherapies also in this disease. Among these products, the interferons have been the most extensively used in clinical trials, giving the most promising results especially in the setting of minimal residual disease, as maintenance therapy after response to conventional therapies, or to high dose chemotherapies followed by bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation. However, more recently, a large number of cytokines and growth factors have been introduced in the clinical practice. Data of the use of erythropoietin have consistently demonstrated the role of this growth factor in ameliorating the grade of anemia as well as the quality of life of those MM patients whose disease is complicated by the presence of a severe or moderate anemia. Using hematopoietic growth factor in the mobilization of PBSC, the quantity of progenitor cells in the peripheral blood increased and the hematological toxicity of chemotherapy could be reduced. Despite the large amount of experimental data indicating a role for interleukins, as IL-2 and IL-6, in controlling tumor growth, there are only few clinical studies dealing with their use in MM. Results show that they arrest tumor progression rather than aid tumor regression, for this reason it appears that IL-2 and anti IL-6 antibodies should be investigated as maintenance therapy, in MM patients responding to chemotherapy. In the future it will be necessary to clarify for MM patients the role of other cytokines such as IL-1 beta and TNF alpha. A possible strategy to improve the clinical outcome of MM patients is to prevent the regrowth of residual tumor cells by establishing adoptive immunity at the stages of minimal residual disease previous obtained using chemotherapy. To this end a possible strategy is to induce an immune response against residual tumor cells by passive (using monoclonal antibodies) or active (using the idiotype expressed by malignant cells) immunotherapy.
Recenti progressi in medicina 11/2000; 91(10):488-93.
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C Mecucci,
R La Starza,
M Negrini,
S Sabbioni,
B Crescenzi,
P Leoni,
F Di Raimondo,
M Krampera,
G Cimino, A Tafuri,
A Cuneo,
A Vitale,
R Foà
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ABSTRACT: Two cases of T acute lymphoblastic leukaemia (T-ALL) with an identical t(4;11)(q21;p15) translocation were identified within a prospective study on the biological and clinical features of adult ALL patients enrolled into the therapeutic protocol ALL0496 of the GIMEMA Italian Group. In both cases, the molecular characterization showed an involvement of the NUP98 gene on 11p15 which rearranges with the RAP1GDS1 gene on 4q21. The morphological and immunological features of the leukaemic cells, as well as the clinical behaviour and response to induction therapy, were the same in both patients. Based on the available data, the t(4;11)(q21;p15) translocation involving the NUP98-RAP1GDS1 fusion gene emerges as a new highly specific genetic abnormality that characterizes a subset of T-ALL.
British Journal of Haematology 07/2000; 109(4):788-93. · 4.94 Impact Factor
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A Tafuri,
R M Lemoli,
M T Petrucci,
M R Ricciardi,
M Fogli,
L Bonsi,
C Ariola,
P Strippoli,
C Gregorj,
M C Petti,
S Tura,
F Mandelli,
G P Bagnara
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ABSTRACT: The c-mpl ligand, thrombopoietin (TPO), is a physiologic regulator of platelet and megakaryocytic production, acting synergistically on thrombopoiesis with the growth factors interleukin 11 (IL-11), stem cell factor, interleukin 3 (IL-3), interleukin 6 (IL-6), and granulocyte-macrophage colony-stimulating factor. Because some of these growth factors, especially TPO and IL-11, are now being evaluated clinically to reduce chemotherapy-associated thrombocytopenia in cancer patients, we evaluated 25 acute myeloid leukemia (AML) samples to test whether TPO, IL-11, and other early-acting megakaryocyte growth factors can affect leukemic cell proliferation, cell cycle activation, and programmed cell death (PCD) protection. TPO induced proliferation in the majority of AML samples from an overall mean proportion of S-phase cells of 7.8% +/-1.5% to 14.5% +/- 2.1% (p = 0.0006). Concurrent G0 cell depletion was found in 47.3% of AML samples. TPO-supported leukemic cell precursor (CFU-L) proliferation was reported in 5 of 17 (29.4%) of the samples with a mean colony number of 21.4 +/- 9.6 x 10(5) cells plated. In 13 of 19 samples, a significant protection from PCD (from an overall mean value of 13% +/-0.7% to 8.8% +/- 1.8%;p = 0.05) was detected after TPO exposure. Conversely, IL-11-induced cell cycle changes (recruitment from G0 to S phase) were detected in only 2 of 14 samples (14.2%). In addition, IL-11 showed little, if any, effect on CFU-L growth (mean colony number = 17.5 9.5) or apoptosis. Combination of TPO with IL-11 resulted in only a slight increase in the number of CFU-L, whereas IL-3 and stem cell factor significantly raised the mean colony numbers up to 119.2 +/- 68.3 and 52.9 +/- 22.1 x 10(5) cells plated, respectively. We conclude that TPO induces cell cycle activation in a significant proportion of cases and generally protects the majority of AML blast cells from PCD. On the other hand, IL-11 has little effect on the cell cycle or PCD. Combination of both TPO and IL-11 is rarely synergistic in stimulating AML clonogenic growth. These findings may be useful for designing clinical studies aimed at reducing chemotherapy-associated thrombocytopenia in AML patients.
Experimental Hematology 09/1999; 27(8):1255-63. · 2.90 Impact Factor
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C Girmenia,
G Alimena,
R Latagliata,
S G Morano,
F Celesti,
L Coppola,
A Spadea,
S Tosti,
S Mecarocci,
G M D'Elia, A Tafuri,
G Cimino,
F Mandelli
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ABSTRACT: Increasing attention to quality of life and to health care costs has recently induced several cancer centers to change in-patient management into an out-patient setting even during high risk phases of disease. The aim of this prospective study was to evaluate feasibility and safety, as well as clinical characteristics, of out-hospital management of AML patients during their post-consolidation phase.
All patients who were treated over a three year period by the three following protocols were included in the study: AML10 EORTC/GIMEMA for patients with AML, except for APL, aged </= 60 years; AML 13 EORTC/GIMEMA, for patients with AML, except for APL, aged >60 years; AIDA GIMEMA for APL patients. All patients submitted to the AML10 and AML13 protocols and those patients submitted to the AIDA protocol with difficult peripheral vein access had a central venous catheter (CVC) sited. Patients treated as in-patients were discharged at the end of consolidation chemotherapy provided they were in a good clinical condition. They were routinely evaluated on an out-patient basis twice weekly. In the event of any complication they were referred to the Emergency Unit of our Department dedicated to out-patients with hematologic diseases.
One hundred and eleven patients with AML were eligible for intensive chemotherapy. After achievement of complete remission they received a total of 133 consolidation courses and in 127 instances they were followed on an out-patient basis during the aplastic phase. There were 69 cases (54%) of rehospitalization, 68 because of fever and only one because of severe anemia. Rehospitalization occurred in 90%,70% and 38% of courses in AML10, AML13 and AIDA protocols, respectively. Only one patient died: the cause of death was a brain hemorrhage. Coagulase negative staphylococci and viridans streptococci were the organisms most frequently isolated from blood. Most coagulase negative staphylococci were isolated in patients submitted to AML10 and AML13 protocols, who had an indwelling CVC. Empiric once-a-day antibacterial therapy with ceftriaxone and amikacin was effective in 75% of the cases and made early discharge possible in 28% of the cases with antibiotic therapy continued in an out-patient setting. Overall, patients were managed out of the hospital for 66% of the period of post-consolidation neutropenia (77%, 48% and 50% of the post-consolidation neutropenia period in patients treated with AIDA, AML10 and AML13 protocols, respectively).
Thanks to the availability of an emergency unit specifically dedicated to out-patients with hematologic diseases, selected out-hospital management of AML patients during post-consolidation cytopenia is a feasible, well accepted and cost-saving option, and can contribute to lower the risk of developing severe nosocomial infections. The empiric therapy with once-a-day ceftriaxone plus amikacin was effective, with the exception of staphylococcal infections, and made it possible to discharge patients early to continue treatment in an out-patient setting.
Haematologica 09/1999; 84(9):814-9. · 6.42 Impact Factor
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L De Felice,
T Di Pucchio,
M G Mascolo,
F Agostini,
M Breccia,
C Guglielmi,
M R Ricciardi, A Tafuri,
M Screnci,
F Mandelli,
W Arcese
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ABSTRACT: Umbilical cord blood (UCB) has been successfully used for haemopoietic stem cell transplantation, although its use has been cautiously limited to paediatric patients because of the reduced volume produced. The clinical results have confirmed that either engraftment or survival significantly correlate with cell dose infused. We have standardized a culture method providing in a short time a significant amplification of both committed progenitors and primitive stem cells for clinical use. Eight-day culture of UCB cells with flt3L/SCF/PIXY 321 induced a 10-fold amplification of CD34+ cells and the expansion of multipotent (CFU-GEMM) and committed (CFU-GM, BFU-E) progenitors respectively of 5-, 7- and 9-fold over input cells. As to the early stem cell pool, the primitive CD34+Thy-1+ cell fraction increased 6-fold and the LTC-IC were amplified 17-fold. Furthermore, the in vitro proliferation was detected by the gradual loss of fluorescence of the CD34+ cells tracked at day 0 with the dye PKH26. After 8 d of amplification >6% of the CD34+ cells remained intensely fluorescent. This subpopulation represents a deeply quiescent cell fraction unresponsive to cytokines and very enriched of primitive stem cells. These cells are most likely to be responsible for long-term reconstitution after transplant.
British Journal of Haematology 08/1999; 106(1):133-41. · 4.94 Impact Factor
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C Girmenia,
R Latagliata,
S Tosti,
S G Morano,
F Celesti,
L Coppola,
A Spadea,
M Breccia,
R Battistini, A Tafuri,
G Cimino,
F Mandelli,
G Alimena
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ABSTRACT: The feasibility and safety of outpatient management of acute promyelocytic leukemia (APL) during the aplastic phase after intensive consolidation chemotherapy, the incidence and types of complications requiring readmission to hospital, and the number of hospital days spared by this policy have been prospectively evaluated. After chemotherapy administration, patients were evaluated on an ambulatory basis. In the event of any complication they referred to the Emergency Unit (EU) of our Department dedicated to outpatients with hematologic diseases. Forty patients with APL observed over a 4 year period were eligible for intensive chemotherapy. After the achievement of complete remission they received a total of 104 consolidation courses and in 98 instances they were followed on an ambulatory basis. There were 41 cases (42%) of rehospitalization for fever (40 cases) or severe anemia (one case). Only one patient died due to a brain hemorrhage. Streptococcus viridans was the organism most frequently isolated from blood. Empiric once-a-day antibacterial therapy with ceftriaxone and amikacin was effective in 87% of the cases and made possible early discharge in 28% of the cases to continue the antibiotic therapy on an outpatient setting. Patients were managed out of the hospital for 76% of the post-consolidation neutropenia period. Thanks to the availability of an EU specifically dedicated to outpatients with hematologic diseases, out-hospital management of APL patients after consolidation therapy appeared to be safe, well accepted, potentially cost-saving, and contributed to saving the risk of developing severe nosocomial infections.
Leukemia 05/1999; 13(4):514-7. · 9.56 Impact Factor
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ABSTRACT: Interleukin-6 (IL-6) serum levels and the proliferative activity of bone marrow plasma cells have been described as important prognostic factors for survival duration in multiple myeloma (MM) patients. Since growth of neoplastic plasma cells is frequently promoted by IL-6, inhibition of its activity has been considered for the management of MM patients. With a similar rationale, IL-6 variants characterized by wild-type or increased affinity for the ligand-specific IL-6 alpha receptor chain and reduced ability to bind and/or dimerize the gp 130 chain have recently been generated. In the present study, the antiproliferative effects of the variants Sant1, Sant5, and Sant7, characterized by increasing antagonistic activity, were investigated by means of a detailed cell kinetic and apoptotic analysis of the IL-6-dependent MM XG-1 cell line. A significant reduction in the mean percent of XG-1 cells in active S-phase (DNA/bromodeoxyuridine incorporation) from 41% to 28.1% (p=0.04), 25.8% (p=0.04), and 15.3% (p=0.02), respectively, was observed using Sant1, Sant5, and Sant7. These effects were confirmed using the acridine-orange (AO) flow-cytometric technique, which showed a similar reduction of S-phase (34.2% of baseline value) in the presence of Sant1, Sant5, and Sant7, as well as a significant G1b arrest (from 44.5% to 47.6%, 48%, and 64.9%). Furthermore, IL-6 variants were capable of down-regulating the G1 cell cycle regulatory protein cyclin D1 expression. Cell cycle effects were coupled with a significant increase of apoptosis, measured by the AO and the terminal deoxynucleotidyl transferase assays, from 12.9% (control culture with IL-6) to 21.2% (Sant1), 29.1% (Sant5), and 23.5% (Sant7). These results were comparable to those obtained by depriving XG-1 of recombinant IL-6. Our study documents the antiproliferative activity exerted by IL-6 mutants on the XG-1 cell line, thus supporting the investigation of these molecules on primary MM cells.
Annals of Hematology 02/1999; 78(1):13-8. · 2.62 Impact Factor
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ABSTRACT: We review here the functional and kinetic characteristics of highly purified hematopoietic CD34+ mobilized into peripheral blood (PB) by granulocyte colony-stimulating factor (G-CSF) with or without chemotherapy for autologous or allogeneic transplantation. Circulating CD34+ cells were evaluated for their colony-forming capacity and trilineage proliferative response to selected recombinant human (rh) CSF in vitro, and the content of very primitive long-term culture initiating cells (LTC-IC). In addition, the cycling status of PB CD34+ cells, including committed clonogenic progenitor cells and the more immature LTC-IC, was determined by the cytosine arabinoside (Ara-C) suicide test and the acridine orange (AO) flow cytometric technique. By comparison, bone marrow (BM) CD34+ cells from the same individuals were studied under steady-state conditions and during G-CSF administration. Clonogenic assays in methylcellulose showed the same frequency of colony-forming unit cells (CFU-C) when PB primed-CD34+ cells and BM cells were stimulated with phytohemagglutinin-lymphocyte-conditioned medium (PHA-LCM). However, mobilized CD34+ cells were significantly more responsive than their steady-state BM counterparts to interleukin-3 (IL-3) and stem cell factor (SCF) combined with G-CSF or IL-3 in the presence of erythropoietin (Epo). Conversely, circulating and BM megakaryocyte precursors (CFU-MK) showed the same clonogenic efficiency in response to IL-3, GM-CSF and IL-3, IL-6 and Epo. Interestingly, very few CD34+ cells expressed the Mpl receptor and this finding resulted in the lower proliferative response of mobilized CFU-MK to the Mpl-ligand (megakaryocyte growth and development factor; MGDF), as compared to BM cells. After 5 weeks of liquid culture supported by the engineered murine stromal cell line M2-10B4 to produce G-CSF and IL-3, we reported a similar frequency of LTC-IC in PB and steady-state BM. Kinetic studies on PB and BM CD34+ cells, including LTC-IC, showed the low number of circulating progenitor cells in S and G2M phase whereas simultaneous DNA/RNA analysis and the Ara-C suicide assay demonstrated that the majority of PB CD34+ cells and LTC-IC are not quiescent (ie in G0 phase) being in G1 phase. Moreover, G-CSF administration prevented apoptosis in a small but significant proportion of mobilized CD34+ cells. Thus, our results indicate that mobilized and BM CD34+ cells can be considered equivalent for the frequency of both committed and more immature hematopoietic progenitor cells, although they show different kinetic and functional profiles. A further set of experiments indicated that G-CSF treatment did not alter the alloantigen presenting function of CD34+ cells which was mainly mediated by the upregulation of costimulatory molecules upon coincubation with allogeneic T cells. Taken together, these findings should allow a better understanding of PBSC transplantation.
Bone Marrow Transplantation 01/1999; 22 Suppl 5:S47-50. · 3.75 Impact Factor
