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PubMedDate not supplied

Interferons for the treatment of hematological malignancies.

Interferon (IFN) has diverse activities against the proliferation and function of various tumor cells. Recently, IFN-alpha has been widely used in the treatment of several hematological malignancies including chronic myelogenous leukemia (CML), multiple myeloma, and hairy cell leukemia. IFN-alpha is becoming a first-choice drug in the treatment of CML, because it has been reported to suppress or abolish the Ph1 chromosome in CML patients. IFN-alpha is used in combination with conventional chemotherapeutic regimens in the treatment of multiple myeloma. There are many ongoing trials that include IFN-alpha in their regimens to determine whether or not the prognosis of multiple myeloma can be improved. Although the precise mechanism of the action of IFN has not been fully explained, the clinical applications of IFN for various hematological malignancies are expanding.

Female↗

PubMed1987

Staphylococcus aureus bacteremia in patients with hematological malignancies and/or agranulocytosis.

A total of 6,253 cases of Staphylococcus aureus bacteremia, including 274 (4.4%) endocarditis cases, were registered in Denmark in the period 1975-1984. Patients with hematological malignancies and/or agranulocytosis accounted for 479 of the bacteremia cases. The incidence of endocarditis in this group of patients was only 0.4% as compared to 4.7% in other patients with staphylococcal bacteremia (p less than 0.01). The lower incidence of endocarditis complicating bacteremia in these patients may justify a shorter course of therapy than usually recommended for suspected endocarditis. Patients with hematological malignancies and other patients with agranulocytosis had a higher mortality (49 and 46%, respectively) than other patients with S. aureus bacteremia (33%). The highest mortality was found in patients with multiple myeloma (71%, p less than 0.01), the lowest in patients with acute lymphocytic leukemia (28%, p less than 0.01). The higher mortality in these patients may indicate that empiric antibiotic regimens in granulocytopenic patients should include a specific anti-staphylococcal agent.

Aged↗

PubMed1991

[Infection prophylaxis in patients with hematological malignancies (II)--Successful prophylaxis of tuberculosis with isoniazid].

In a retrospective study to evaluate the efficacy of isoniazid (INH) for the prevention of tuberculosis, we studied 1760 patients with hematological malignancies over a twenty-year period (1970-1989). 759 patients received oral INH, most of all received 400 mg per day. Only one (0.1%) of the patients receiving INH developed tuberculosis, whereas nine (0.9%) of the 1001 patients who did not receive INH developed tuberculosis (p less than 0.05). We found that INH was very effective in the prevention of tuberculosis in patients with hematological malignancies, and was well tolerated.

Adolescent↗

PubMed2002

Interleukin 12 immunotherapy after autologous stem cell transplantation for hematological malignancies.

PURPOSE: To determine the safety, maximum tolerated dose,and biological effects of recombinant human IL-12 after autologous stem cell transplantation for cancer. EXPERIMENTAL DESIGN: Twelve patients with hematological malignancies (8 non-Hodgkin's lymphoma, 2 Hodgkin's disease, and 2 plasma cell myeloma) began interleukin (IL)-12 therapy at a median of 66 days after transplantation. Recombinant human IL-12 was given by bolus i.v. injection in doses of 30, 100, or 250 ng/kg once as an inpatient and then, after a 2-week hiatus, once daily for 5 consecutive days every 3 weeks on an outpatient basis. RESULTS: Common side effects included fever, chills, fatigue, nausea or vomiting, and asymptomatic elevation in serum liver function tests. Transient neutropenia and thrombocytopenia were also common, but no patient required platelet transfusion or had a neutropenic fever. Dose-limiting toxicities (diarrhea and elevated liver function tests) occurred in 2 of 3 patients treated in the 250 ng/kg cohort. Biological effects, including increases in serum IFN-gamma levels and transient lymphopenia involving CD4 T cells, CD8 T cells, B cells, and NK cells, were seen at all three dose levels. CONCLUSIONS: Biologically active doses of IL-12 can be given safely to patients after autologous stem cell transplantation for high-risk hematological malignancies. Further studies are indicated to assess the efficacy of IL-12 in this setting.

Adult↗

PubMed2000

[Cryptococcus neoformans infection in hematologic malignancies].

PURPOSE: Cryptococcus is an opportunistic infection that affects immunodepressed patients and is a classical complication of AIDS-stage HIV infection. The aim of this study was to investigate Cryptococcus neoformans infections in patients with hematological malignancies. METHODS: Six cases have been described of cryptococcosis detected in Nantes, France over the past 10 years in patients with hematological malignancies. RESULTS: This infection has been found particularly in the context of lymphoproliferative disorders (chronic lymphocytic leukemia, Waldenström macroglobulinemia, Hodgkin's disease, and non-Hodgkin's lymphoma), and also following cytotoxic therapy. In four cases, the patients were treated with fludarabine, which rapidly caused long-duration marked lymphocytopenia, notably in CD4 cells. Cell-mediated immunity plays a major role in systemic defense against C. neoformans. It therefore seems that fludarabine favors the spread of cryptococcal infections. CONCLUSION: In the context of lymphoproliferative syndromes treated with cytotoxic drugs, in particular fludarabine, it appears important to take into account the possible presence of cryptococcal infection in the presence of respiratory, neurological or cutaneous disorders, so that a correct diagnosis can be made and the appropriate treatment administered.

Adult↗

PubMed2004

Predictive model for the length of hospital stay of children with hematologic malignancies, neutropenia, and presumed infection.

Few studies have assessed the predictive factors for the length of hospital stay for children with malignancies admitted with a diagnosis of presumed infection. We performed an observational prospective study of children 13 years old or younger with hematologic malignancies and neutropenia admitted for presumed infection to set up a predictive model for the length of stay using variables available at admission. Episodes in which children were on induction chemotherapy were excluded from the study. In a multivariate linear regression model, age 6 years or older, an ill appearance, relapse of the hematologic malignancy, and the presence of a central venous catheter were the factors associated with longer lengths of stay for these children.

Age Factors↗

PubMed1999

A single-center population-based consecutive series of 1500 cytogenetically investigated adult hematological malignancies: karyotypic features in relation to morphology, age and gender.

During the 18-yr period 1976-93, a population-based series of 1586 adults with suspected or confirmed hematological malignancies were successfully cytogenetically investigated at a single center. Eighty-six cases were excluded due to unretrievable medical records or if analyzed only in remission or at relapse. The remaining 1500 medical records were reviewed regarding morphology and clinical parameters in order to investigate possible associations between karyotypic pattern (normal, 1, 2 or complex anomalies; specific abnormalities) and gender, age and morphological subgroups. The impact of time-period, i.e. 1976-87 vs. 1988-93, and referring center on cytogenetic findings was also studied. A total of 372 acute myeloid leukemias (AML), 389 myelodysplastic syndromes (MDS), 64 acute lymphoblastic leukemias (ALL) and 262 chronic myeloid leukemias (CML) were identified, altogether 1087 cases. Patients with other (n=261) or no hematological malignancies (n = 152) were excluded from the present analysis. Cytogenetic abnormalities were detected in 52% AML, 51 % MDS, 68% ALL and 97% CML, frequencies that did not differ significantly between the 2 time periods or referring centers. No significant age- or gender-related differences in karyotypic patterns were discerned in AML, MDS, ALL or CML, whereas the karyotypic patterns varied among the FAB groups in both AML (p= 0.001) and MDS (p < 0.001). The specific abnormalities t(8;21), t(15;17) and inv(16) were more common (p < 0.001) in younger AML patients and 5q- was more frequent in females with MDS (p<0.001). These findings indicate, in contrast to previous series, that neoplasia-associated karyotypic aberrations are not more common among older patients or in males.

Adult↗

PubMed2005

Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies.

PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. PATIENTS AND METHODS: Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. RESULTS: The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily x 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. CONCLUSION: Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.

Adolescent↗

PubMed2002

Molecular monitoring of hematologic malignancies: current and future issues.

Genetic markers associated with hematologic malignancies such as acute promyelocytic leukemia (APL) can be detected with high sensitivity and specificity using the reverse-transcription polymerase chain reaction (RT-PCR). This procedure can be applied to monitor minimal residual disease. In patients with APL, RT-PCR is now being used to detect molecular relapse, and a strong association has been found between outcome and the treatment of molecular as opposed to hematologic relapse. In APL, results from PCR assays are also being used to guide therapy. Prognostic groups can be defined using molecular and clinical characteristics of the disease as well as patient characteristics. In the future, PCR monitoring strategies may be adapted to the risk of relapse of individual patients. Patients at high risk of relapse may be monitored much more rigorously than patients at low risk of relapse. Although RT-PCR is in routine use as a clinical tool, the lack of standardization of techniques in different laboratories has resulted in some difficulties in interpretation of results. There is a real need for an international consensus on standardization of PCR techniques.

Hematologic Neoplasms↗

PubMed2003

Map kinase signaling pathways and hematologic malignancies.

Mitogen-activated protein (Map) kinases are widely expressed serine-threonine kinases that mediate important regulatory signals in the cell. Three major groups of Map kinases exist: the p38 Map kinase family, the extracellular signal-regulated kinase (Erk) family, and the c-Jun NH2-terminal kinase (JNK) family. The members of the different Map kinase groups participate in the generation of various cellular responses, including gene transcription, induction of cell death or maintenance of cell survival, malignant transformation, and regulation of cell-cycle progression. Depending on the specific family isoform involved and the cellular context, Map kinase pathways can mediate signals that either promote or suppress the growth of malignant hematopoietic cells. Over the last few years, extensive work by several groups has established that Map kinase pathways play critical roles in the pathogenesis of various hematologic malignancies, providing new molecular targets for future therapeutic approaches. In this review, the involvement of various Map kinase pathways in the pathophysiology of hematologic malignances is summarized and the clinical implications of the recent advances in the field are discussed.

Cytokines↗

PubMed2004

Expression of CII TA gene in five human malignant hematological cell lines and its significance.

The role of MHC class II transactivator (C II TA) in constitutive or IFN-gamma inducible expression of HLA molecules in human malignant hematological cell lines was investigated. The expression of HLA molecules and C II TA protein was detected by Western blot, immunohistochemistry and flow cytometry. The expression of C II TA gene was determined by RT-PCR. The capability of peripheral blood T cell reaction stimulated by tumor cells was monitored by mixed lymphocyte reaction. It was found that the HLAII-positive tumor cells expressed the C II TA quite well, and the expression of HLA I + II was increased in the tumor cells with constitutive or inducible expression of C II TA after induced by IFN-gamma. The tumor cells which did not express C II TA after induced by IFN-gamma were not response to the expression of HLA II promoted by IFN-gamma. It suggests a correlation between the inability of some malignant hematological cell lines in response to IFN-gamma for HLA expression and the deficiency in the inducible expression of C II TA, indicating C II TA might take part in the regulation of HLA I + II expression in the tumor cells, which might play an important role in tumor immunologic escape.

Animals↗

PubMed2007

Early hospital discharge with oral antimicrobial therapy in patients with hematologic malignancies and low-risk febrile neutropenia.

Although consensus exists relating criteria for the identification of low-risk patients with febrile neutropenia, no clear indication on how to manage these patients has been so far provided particularly in outpatients affected by hematologic malignancies. The feasibility and safety of early discharge was prospectively evaluated in 100 outpatients with hematologic malignancies and febrile neutropenia. A strategy considering the risk-index of the Multinational Association of Supportive Care in Cancer (MASCC) was applied. High-risk patients were entirely managed at hospital. Low-risk patients were early discharged if they were afebrile since 48 h and not on supportive therapy requiring hospitalization. Out of 90 low-risk episodes, in 69 instances (76.7%), patients were discharged after a median of 4 days and continued home therapy with oral cefixime (78%) or other antibiotics. Only five outpatients (7.2%) had fever recurrence. Twenty-one low-risk patients were not early discharged due to worsening conditions (three deaths), need of multiple daily dose therapy, or discharge refuse. No clinical characteristic was able to predict the eligibility for early discharge. The MASCC risk-index is a useful aid in the identification of high-risk febrile neutropenia needing whole in-hospital treatment. As for low-risk patients, hospitalization at least in the first days of fever is required. Cefixime could be included among the oral antibacterial drugs to be used in the outpatient treatment of adult patients with febrile neutropenia.

Administration, Oral↗

PubMed2005

Methylation of the MLH1 gene in hematological malignancies.

Hypermethylation of the MLH1 gene has been described in many kinds of human cancers with microsatellite instability (MSI). However, it is not clear whether the same mechanism occurs in hematological malignancies. Genomic DNA was extracted from 31 patients with adult T-cell leukemia/lymphoma (ATL), 9 patients with acute lymphoblastic leukemia (ALL) who had MSI, and 12 leukemia and lymphoma cell lines with MSI. Aberrant methylation of the MLH1 gene was found in 2/31 (6%) ATL patients, and in 1/12 (8%) cell lines with MSI. MLH1 promoter was not methylated in either of the twelve peripheral blood samples from normal individuals or ALL samples. The MLH1 gene was expressed in the normal peripheral blood samples, but not in the MLH1-methylated cell line KCL22. Demethylation with 5-Azacytidine treatment restored MLH1 expression in the KCL22 cell line. Methylation of the MSH2 gene was not found in any of the samples. Our data show that hypermethylation of the MLH1 gene is occasionally involved in the pathogenesis of hematological malignancies, but is not always associated with MSI.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Expression of p16INK4A and p14ARF in hematological malignancies.

The INK4A/ARF locus yields two tumor suppressors, p16INK4A and p14ARF, and is frequently deleted in human tumors. We studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used a quantitative reverse transcription-PCR assay. Normal peripheral bloods, bone marrow and lymph nodes expressed little or undetectable p16INK4A and p14ARF mRNAs, which were readily detected in 12 and 17 of 41 cell lines, respectively. Patients with hematological malignancies frequently lacked p16INK4A expression (60/137) and lost p14ARF expression less frequently (19/137, 13.9%). Almost all patients without p14ARF expression lacked p16INK4A expression, which may correspond to deletions of the INK4A/ARF locus. Undetectable p16INK4A expression with p14ARF expression in 41 patients may correspond to p16INK4A promoter methylation or to normal expression status of the p16INK4A gene. All patients with follicular lymphoma (FL), myeloma or acute myeloid leukemia (AML) expressed p14ARF while nine of 23 patients with diffuse large B cell lymphoma (DLBCL) lost p14ARF expression. Patients with ALL, AML or blast crisis of chronic myelogenous leukemia expressed abundant p16INK4A mRNAs more frequently than patients with other diseases (12/33 vs 6/104, P < 0.01). Patients with FL and high p14ARF expression had a significantly shorter survival time while survival for patients with DLBCL and increased p14ARF expression tended to be longer. These observations indicate that p16INK4A and p14ARF expression is differentially affected among hemato- logical malignancies and that not only inactivation but also increased expression may have clinical significance.

Adolescent↗

PubMed2006

CD44 and hematologic malignancies.

The expression of CD44 was upregulated in some hematological malignancies and is associated with metastasis and prognosis. The ligation of CD44 with specific monoclonal antibodies can trigger terminal differentiation of leukemic blasts in some subtypes, so it is probable to develop an anti-CD44 based differentiation therapy in leukemia. The effects of CD44 and its monoclonal antibodies are discussed in this review.

Hematologic Neoplasms↗

PubMed2004

Improved laboratory diagnosis of bacterial and fungal infections in patients with hematological malignancies using PCR and ribosomal RNA sequence analysis.

During October 1999 to November 2000, 98 blood culture specimens from the same number of febrile episodes originating from 49 patients with hematological malignancies were examined for the presence of eubacteria and fungi based on 16S rRNA gene and the 5.8, 18 and 28S rRNA combined with in vitro PCR amplification and sequencing, in addition to conventional blood culture laboratory techniques. Nineteen of the samples were associated with positive blood cultures. Eubacterial (16S rRNA) PCR detected bacterial DNA in 26 febrile episodes, i.e. in an additional 7 febrile episodes than blood-culture alone. The species identified by partial 16S rRNA gene sequencing were as follows Staphylococcus spp (n = 6), Staphylococcus epidermidis (n = 5), Acinetobacter spp (n = 5), Escherichia coli (n = 2), Enterobacter agglomerans (n = 2), Campylobacter spp (n = 1), Citrobacter spp (n = 1), Corynebacterium spp (n = 1), Enterobacter faecium (n = 1), Ralstonia spp (n = 1), Acidovorax spp. (n = 1) and Stenotrophomonas maltophilia (n = 1). Gram-positive bacteria were found in 12/27 (44.6%) and gram-negative bacteria were found in 15/27 (55.6%). After optimization of a PCR-based fungal detection method, none of the febrile episodes were shown to be attributable to fungi. The results of this study suggest that fungi are not common causal agents of febrile episodes in patients with a hematological malignancy at this centre and that molecular techniques can augment cultural methods in the diagnosis of causal agents of bacteremia in patients, so that appropriate antibiotic regimens may be commenced in patients with culture-negative episodes of infection.

Adolescent↗

PubMed2001

Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies.

The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults remains unclear. This study reports the results of UD-CBT in 22 adults with hematologic malignancies following conditioning with thiotepa, busulfan, cyclophosphamide, and antithymocyte globulin in 21, with thiotepa, fludarabine, and antithymocyte globulin in 1, and graft-versus-host disease (GVHD) prophylaxis with cyclosporine and prednisone. Median age was 29 years (range, 18-46 years), and median weight was 69.5 kg (range, 41-85 kg). HLA match was 6 of 6 in 1 case, 5 of 6 in 13 cases, and 4 of 6 in 8 cases. Median number of nucleated cells infused was 1.71 x 10(7)/kg (range, 1.01 x 10(7)/kg to 4.96 x 10(7)/kg). All 20 patients surviving more than 30 days had myeloid engraftment, and only 1, who received the lowest cell dose, developed secondary graft failure. Median time to reach an absolute neutrophil count of at least 0.5 x 10(9)/L was 22 days (range, 13-52 days). Median time to platelets numbered at least 20 x 10(9)/L was 69 days (range, 49-153 days). Seven patients (32%) developed acute GVHD above grade II, and 9 of 10 patients at risk developed chronic GVHD, which became extensive in 4 patients. Twelve patients remained alive and disease-free 3 to 45 months after transplantation. Disease-free survival (DFS) at 1 year was 53%. Age strongly influenced DFS (P =.01). For patients aged 30 years or younger, the DFS at 1 year was 73%. These preliminary results suggest that UD-CBT should be considered a reasonable alternative in young adults with hematologic malignancy and no appropriate bone marrow donor.

Adult↗

PubMed1990

The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing.

DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS, K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11, 12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative frequencies of N-RAS gene mutations in these hematologic disorders was as follows: acute myelogenous leukemia (AML), 15%; acute lymphoblastic leukemia (ALL), 14%; myelodysplastic syndromes, 24%; and myeloid and lymphoid blast crisis of chronic myelogenous leukemia (CML), 3%. No correlation was observed between the presence of mutations and cytologic features or immunophenotype of these malignancies. Mutations involving codons 12 or 13 were equally prevalent, with a glycine to aspartic acid substitution being the most frequently encountered change. A single T-ALL case had a codon 11 mutation resulting in substitution of alanine with threonine. We failed to find mutations in exons 1 and 2 of the K-RAS or Ha-RAS genes in any case except a single AML with a mutation in codon 61 of the K-RAS gene. Also, no mutations were identified in chronic phase of CML, chronic lymphocytic leukemia. Ph1 positive ALL, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma. These results indicate that RAS mutations, especially those involving exon 1 of the N-RAS gene, are frequent only in a subset of hematologic malignancies.

Adolescent↗