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PubMed1990

[Effect of combination therapy with carumonam and clindamycin on severe infections in patients with hematologic malignancies].

We evaluated the efficacy of a combination therapy with carumonam (CRMN) and clindamycin (CLDM) on severe infections in patients with hematologic malignancies. Fifty three patients were included in this study. The efficacy of the combination therapy was evaluated according to the criteria by TAKAKU et al. Fourteen cases were evaluated as excellent, and 24 cases were as good, with a total rate of effectiveness of 71.7% (38/53). It should be noted that the rate of effectiveness in patients having less than 100/microliters neutrophils was 77.3% (17/22). Adverse effects were observed in 2 patients (3.7%). One case was hepatotoxicity and the other was nephrotoxicity. Both were mild and transient, however. These observations suggested that the combination therapy with CRMN and CLDM was effective and safe for the treatment of severe infections in patients with hematologic malignancies.

Adult↗

PubMed1998

Common and emerging infectious causes of hematological malignancies in the young.

Comparative epidemiological studies have for a long time suggested a link (or links) between infectious agents and hematological malignancies in the young. Identification of Epstein-Barr virus (EBV) as the major cause of specific subtypes of Burkitt's lymphoma and Hodgkin's disease 20 and 10 years ago, respectively, and the recent involvement of human T-cell leukemia virus in non-Hodgkin's lymphomas of the T-cell lineage in young adults in Jamaica have given further credit to early presumptions that these diseases have an infectious etiology. The spectrum of possibly involved viruses: old, EBV, and new, herpesviruses 6, 7 and 8, and unknown retroviruses - as well as the list of partially or totally unresolved disease entities: Hodgkin's disease in adolescents, non-Hodgkin's lymphomas in the immunocompromised, and acute lymphocytic leukemia - is rapidly expanding. Both direct and indirect transforming effects of the above-mentioned viruses are being rapidly disclosed. However, the complex interaction between the different viruses and other causes of hematological malignancies in the young guarantees that many things remain to be discovered also in the future.

Adolescent↗

PubMed2001

Rapid mutational analysis of N-ras proto-oncogene in hematologic malignancies: study of 77 Greek patient.

BACKGROUND AND OBJECTIVES: N-ras mutations are the most commonly detected molecular abnormalities in hematologic malignancies, especially in those of myeloid origin. Different techniques have been used to detect N-ras mutations; however, most of them are either labor intensive or provide sequence data for only a limited number of codons. Consequently, study of the N-ras oncogene has not been convenient in every day clinical practice being restricted, as a rule, to retrospective analysis of patients. DESIGN AND METHODS: In this study we used a recently developed method that enables rapid and reliable detection of mutations at the cDNA level, namely, the non-isotopic RNase cleavage assay (NIRCA). Using this method we were able to screen the N-ras oncogene rapidly and determine the incidence and prognostic significance of N-ras mutations in 77 Greek patients with acute leukemia, myelodysplastic syndromes and chronic myeloproliferative disorders, both at the presentation and during relapse or progression of the disease. RESULTS: Activating N-ras mutations were detected in 7 patients and our results were confirmed by direct sequencing. Interestingly, two novel alterations were identified, a mutation at codon 8 (characterized by a substitution of valine by leucine) in a patient with chronic myeloid leukemia during hematologic relapse of the disease and a polymorphism at codon 92 (1002T-->C, without amino acid substitution) in a patient with chronic myelomonocytic leukemia. INTERPRETATION AND CONCLUSIONS: A rapid and easy protocol that allows the analyses of N-ras sequences has been developed. This reverse transcription-polymerase chain reaction (RT-PCR)/NIRCA protocol can allow the study of this proto-oncogene in every day clinical practice, rapidly facilitating the validation of the diagnostic and prognostic value of N-ras mutational analyses in patients with hematologic malignancies.

Adolescent↗

PubMed2004

Immunotherapeutic approaches for hematologic malignancies.

The immune system has two complementary arms: one is older and seemingly more primitive, called the innate immune system, found in both plants and animals. The second (already many millions of years old!) is the adaptive or antigen-specific immune system, limited to vertebrate animals. The human innate immune system has many cellular elements that include granulocytes, monocytes, macrophages, natural killer (NK) cells, mast cells, eosinophils, and basophils. Receptors for these cells are non-clonal, fixed in the genome, requiring no rearrangement, and recognize conserved molecular patterns that are specific to pathogens. The adaptive immune system (B cells and T cells) have receptors with great variation, able to recognize an almost an unlimited number of highly specific pathogens through rearrangement of receptor gene segments, and can also provide immunological memory so critical for vaccination. As the immune system has evolved to recognize non-self, malignant transformation of self can likely escape immune surveillance with relative ease. Contributors to this chapter are utilizing distinct components of either the innate or adaptive immune system that recognize non-self, in combination with what we know about differences between malignant and normal self, in an effort to develop novel and effective immunologic approaches against hematologic malignancies. In Section I, Dr. Andrea Velardi reviews the benefits of NK cell alloreactivity in mismatched hematopoietic transplantation, provides updates on current clinical trials, and discusses further therapeutic perspectives emerging from murine bone marrow transplant models. In Section II, Dr. David Scheinberg reviews novel leukemic antigens being targeted by humanized monoclonal antibodies as well as mechanisms by which antibody-mediated cytotoxicity occurs in vivo. In Section III, Dr. Ivan Borrello reviews vaccine and adoptive T cell immunotherapy in the treatment of hematologic malignancies. Specifically, he discusses the various vaccine approaches used as well as strategies aimed at augmenting the tumor specificity of T cell therapies.

Animals↗

PubMed1988

Marrow transplantation for hematologic malignancies: a brief review of current status and future prospects.

The ability to transplant bone marrow makes it possible to treat patients with hematologic malignancies with doses of systemic radiotherapy or chemotherapy that would ordinarily result in fatal myelosuppression. With this approach, some otherwise incurable patients can be treated successfully. For most hematologic malignancies (acute nonlymphocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and malignant lymphoma), if transplantation is delayed until patients have end-stage disease (drug-resistant relapse) or blast crisis, approximately 10 to 20% of patients can be saved. If transplantation is carried out earlier in the course of disease, the outcome improves considerably. Some of the major limitations of marrow transplantation are the need for an appropriate source of marrow, the severe myelosuppression seen in the immediate posttransplant period, the complications of graft-v-host disease (GVHD), and disease recurrence. The use of autologous marrow and the formation of a national donor registry may make transplantation more widely applicable. The availability of growth factors can hasten hematopoietic recovery, making the immediate posttransplant period safer. New immunosuppressive regimens and T-cell depletion of donor marrow can diminish the impact of GVHD. The need for better preparative regimens persists and has emerged as the major requirement for continued progress in marrow transplantation.

Bone Marrow Transplantation↗

PubMed1996

[Management of hematologic malignancies during pregnancy].

Hodgkin's disease, non-Hodgkin lymphoma or leukemia occurring in a pregnant patient is a rare event. Diagnosis of hematologic malignancies in a pregnant woman usually poses a quandrum of psychological, ethical and medical considerations. All of these situations require a multidisciplinary team. Adequate staging and treatment of hematologic malignancies are complicated by the pregnancy. In the first trimester, termination of the pregnancy should be considered in order to provide the best outcome for the woman and fetus. In this review we have focused on the use of chemotherapy for the pregnant patient. This review reveals that the use of chemotherapy resulted in both objective disease remissions and the subsequent delivery of normal infant.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

[High dose chemotherapy with autologous bone marrow transplantation and G-CSF for hematologic malignancies].

High dose chemotherapy (HDCT) followed by autologous bone marrow transplantation (ABMT) is one of the cure-oriented therapies for hematologic malignancies. Colony stimulating factors (CSFs) are currently used to stimulate hematopoiesis in various cytopenic conditions including post BMT. Granulocyte CSF (G-CSF) significantly accelerates granulocyte recovery after ABMT. Earlier recovery of neutrophils is associated with lower incidence of severe infections and shorter duration of reverse barrier nursing and hospitalization. Widespread use of G-CSF in ABMT may contribute to managing this treatment safely in multi-centers. Further prospective clinical study to define the optimal application and timing of HDCT with ABMT in hematologic malignancies is required.

Acute Disease↗

PubMed1998

Monoclonal antibody-based therapies for hematologic malignancies.

PURPOSE: To review recent advances in the development and clinical roles of monoclonal antibody (MoAb)-based therapies in the treatment of hematologic malignancies. DESIGN: A search of MEDLINE and CANCERLIT was conducted to identify relevant publications. The bibliographies of these references also were used to identify articles and abstracts. These references were then reviewed. RESULTS: In the two decades since the first patient was treated with MoAb therapy, there have been significant advances in the biology, pharmacology, and clinical application of MoAb-based therapies. Three distinct fields of research have emerged: unconjugated MoAbs, immunotoxin-conjugated MoAbs (ITs), and radionuclide-conjugated MoAbs (RICs). The unconjugated MoAbs are less toxic but depend on host mechanisms to mediate cytotoxicity. The ITs carry a potent toxin, although at the cost of a narrow therapeutic index that may limit clinical use. The RICs offer significant potency, even in refractory disease, but their complexity may limit their use to large cancer centers. The current challenges in the development of MoAb-based therapies are to identify the proper target antigens, contend with bulk disease in which penetration may be limited, and choose the optimal clinical settings for their use, such as the minimal residual disease state or in combination with conventional chemotherapy. CONCLUSION: Although significant research is still needed, MoAb-based therapies promise to offer new options for the treatment of patients with hematologic malignancies.

Animals↗

PubMed2005

Kinases as drug discovery targets in hematologic malignancies.

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.

Cyclin-Dependent Kinases↗

PubMed2002

[Rearrangements of 11q in patients with hematologic malignancies].

BACKGROUND: The aim of this study was to investigate the rearrangement of MLL gene in bone marrow cells of patients with hematological malignancies with various types of 11q aberrations. These aberrations have been observed in acute lymphoblastic and acute myeloid leukemias as well as in myelodysplasias and lymphomas. METHODS AND RESULTS: Correlations of clinical characteristics, type of aberrations, diagnoses and survival of patients were evaluated. Using classical cytogenetic techniques we found 11q aberration in 17 patients with different hematological malignancies. FISH with dual color locus specific probe for MLL gene was used to confirm or exclude the rearrangement of this gene. Whole chromosome painting probes and multicolor FISH were performed for identification of chromosomes involved in complex translocations. Balanced rearrangements of 11q were found in 3 patients, in 14 patients unbalanced aberrations were found with rearrangement (4), deletion (4) and amplification (2) of MLL gene. In 7 patients no rearrangement of MLL gene was found. CONCLUSIONS: Correlation between clinical characteristics, type of aberrations, diagnoses and survival of patients was not significant, therefore further studies of larger cohort of patients are necessary to evaluate the prognostic value of 11q rearrangement.

Adult↗

PubMed1987

Mixed hematopoietic chimerism following bone marrow transplantation for hematologic malignancies.

Twenty-nine of 172 patients (17%) who received an allogeneic bone marrow transplant (BMT) from histocompatible sibling donors for hematologic malignancies were mixed hematopoietic chimeras; ie, they had a mixture of donor and host hematopoietic or lymphohematopoietic cells at greater than or equal to 14 days after transplantation. Twenty-four of the 29 mixed chimeras (83%) have remained in continuous complete remission for up to 116 months (greater than 9 years) following BMT. Four of the 29 patients (14%) have had recurrent leukemia, and 7 of the 29 (24%) have had moderate or severe graft-v-host disease (GVHD). Twelve of these 29 patients have persisted as stable mixed chimeras for greater than or equal to 2 years after BMT, whereas other patients converted to all donor-type hematopoiesis. The incidence of mixed chimerism was independent of the pretransplant regimen, the donor or recipient age (less than 20 v greater than 20 years), remission status (first complete remission of acute leukemia and first chronic phase of chronic myelocytic leukemia v later stages of disease), and type of leukemia. Our data indicate that mixed hematopoietic chimerism is not rare after BMT for hematologic malignancies and that its presence is compatible with long-term disease-free survival. Prospective studies of mixed chimerism after BMT are warranted to achieve better understanding of its biologic importance.

Acute Disease↗

PubMed1999

Biphenotypic hematological malignancy with T-lymphoid and myeloid differentiation: association with t(3;12)(p25;q24.3). Case report and review of the literature.

Biphenotypic hematological malignancies of T-lymphoid and myeloid differentiation are relatively rare and have most commonly been associated with t(8;13). However, this entity is invariably associated with eosinophilia and generally progresses to acute leukemia within a year of diagnosis. We describe a case of a biphenotypic hematological malignancy with T-lymphoid and myeloid differentiation without associated eosinophilia; however, there was an association with t(3;12)(p25;q24.3) as a sole abnormality and progression to acute leukemia within 10 months of presentation. This association with such a malignancy has not previously been described. Additional cases need to be accrued to determine the prognostic significance and clinical implications of such an association.

Biomarkers, Tumor↗

PubMed1996

Parathyroid-hormone-related peptide in hematologic malignancies.

PURPOSE: To determine whether parathyroid-hormone-related peptide (PTHRP) is an important pathogenetic mediator of hypercalcemia in patients with hematologic malignancies. PATIENTS AND METHODS: We conducted a cohort analytic study in 76 consecutive patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease, multiple myeloma, and Waldenstrom's macroglobulinemia, 14 of which were hypercalcemic. Thirty normal subjects served as a control group. RESULTS: Using the NH2 -terminal radioimmunoassay, PTHRP concentrations in heavy controls were undetectable (<7.5 pmol equivalents of PTHRP [fragment 1-34] per liter). The majority of hypercalcemic patients (8/14) had non-Hodgkin's lymphoma, and 62.5% of these (5/8) had significant elevations of circulating PTHRP concentrations (mean 70.5 +/- 38.5 pmol equivalents of PTHRP per liter) (P <0.01). In non-Hodgkin's lymphoma, 11 of 30 patients with advanced disease (stage IV) had elevated PTHRP concentrations, and of these, 8 of 11 had high-grade pathology. In contrast, only 3 or 21 patients with less advanced disease (stage I to III) had elevated PTHRP concentrations. In 4 NHL patients with less advance PTHRP concentrations sampled prior to cytotoxic chemotherapy, tumor response was associated with a decrease in PTHRP. Concomitant suppression of 1,25(OH)2D3 concentrations was observed in 66% of hypercalcemic patients with non-Hodgkin's lymphoma. CONCLUSIONS: These results suggest that PTHRP may be an important pathogenetic factor in the development of hypercalcemia in hematologic malignancies, notably in non-Hodgkin's lymphoma.

Antineoplastic Agents↗

PubMedDate not supplied

Impact of cytogenetic and molecular cytogenetic studies on hematologic malignancies.

Conventional cytogenetic analysis of chromosome abnormalities in hematologic malignancies is hampered by the low mitotic index and poor quality of metaphases. A range of techniques based on fluorescence in situ hybridization (FISH) has greatly enhanced the identification of non-random translocations and deletions, pinpointing regions which contain genes involved in leukemogenesis. One of the main advantages of FISH is its ability to use non-dividing interphase cells as DNA targets, enabling the screening of large numbers of cells and providing access to a variety of cells with different hematopoetic activity. Furthermore, multicolor FISH (SKY, M-FISH and CGH microarrays) combines the screening potential of cytogenetics with the accuracy of molecular genetics, allowing the visualization of the entire human genome in 24 different colors.

Chromosome Aberrations↗

PubMed2005

Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders.

Allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning regimens has been an effective treatment for many patients with hematologic malignancies or inherited blood disorders. Unfortunately, such regimens have been associated with significant toxicity, limiting their use to otherwise healthy, relatively young patients. In an attempt to extend treatment by allogeneic HCT to older patients and those with comorbid conditions, several groups of investigators have developed reduced-intensity or truly nonmyeloablative conditioning regimens, lacking such toxicity. Analogous to conventional regimens, reduced-intensity regimens both eliminated host-versus-graft (rejection) reactions and produced major anti-tumor effects. In contrast, nonmyeloablative regimens have relied on optimizing both pre-and posttransplant immunosuppression to overcome host-versus-graft reactions, while anti-tumor responses have depended mainly on immune-mediated graft-versus-tumor effects. In this review, we define reduced-intensity and truly nonmyeloablative regimens, describe the preclinical development and clinical application of a very low intensity nonmyeloablative regimen, and review results with reduced-intensity regimens in patients with hematologic malignancies or inherited blood disorders.

Animals↗

PubMed2003

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies.

A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies.

The ETV6 (also known as TEL) gene on chromosome 12p13 is the target of a number of translocations associated with various hematologic malignancies. The contribution of ETV6 to leukemogenesis occurs through different mechanisms that involve either its helix-loop-helix dimerization domain or its E26 transformation-specific (ETS) DNA-binding domain. Using fluorescence in situ hybridization we characterized seven new ETV6 rearrangements in chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma. These aberrations, not always discernible at the cytogenetic level, include a t(5;12)(q31;p13), t(6;12;17)(p21;p13;q25), t(7;12)(p15;p13), t(7;12)(p12;p13), t(7;12)(q36;p13), t(12;13)(p13;q12), and a not completely defined t(12;?)(p13;?). Loss or disruption of the second ETV6 allele by a del(12)(p12p13) or by an intragenic ETV6 deletion was detected in two cases. In six cases the 12p13 breakpoint occurred in the 5' end of ETV6, upstream to exons encoding the HLH domain, whereas the remaining case had a breakpoint between the exons coding for the HLH domain and the exons coding for the ETS domain of ETV6. These observations provide further evidence for the multiple contributions of ETV6 in the pathogenesis of a wide range of hematologic malignancies.

Adolescent↗

PubMed1983

Precedents for meaningful recovery during treatment in a medical intensive care unit. Outcome in patients with hematologic malignancy.

The medical records of 77 patients with hematologic malignancy who were admitted to a medical intensive care unit over a 21-month period were reviewed. The overall hospital mortality rate was 80 percent. Sixteen patients (21 percent) were discharged from the intensive care unit but eventually died in the hospital. The cause of death was the result of a new problem in only three of these 16 patients. Hypotension (shock) and acute respiratory failure were the reasons prompting admission to the intensive care unit in 75 percent, but death in the intensive care unit was almost always the result of intractable hypotension rather than refractory hypoxemia. Only four of 52 patients who required mechanical ventilation left the hospital. In all four, the duration of ventilatory support was less than five days and the cause of respiratory failure was noninfectious in nature. Factors such as congestive heart failure, leukopenia, and abnormalities in mental status modified the hospital course, but did not alter outcome once prolonged mechanical ventilation became necessary. The data suggest that once acute respiratory failure develops in patients with lymphoma or leukemia, presumably as a result of infection, and mechanical ventilation for more than a relatively brief period is required, the prognosis is uniformly grim. Decisions to limit aggressive therapies is subsets of intensive care patients such as these should be aided by data that show a lack of precedent for meaningful recovery.

Critical Care↗