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PubMed2005

[Progress of studies on multidrug resistance in hematological malignancies--review].

Chemotherapy remains a major route of intervention in hematological malignancies. However, a key issue in the treatment of hematological malignancies is the development of multidrug resistance (MDR) to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including biochemical mechanisms, such as the overexpression of resistance-conferring proteins and physiological mechanisms involving the hematopoietic microenvironment. In this article the pathomechanism, diagnostic approach, interpretation of results from clinical samples and correlations with hemopoietic microenvironment were briefly reviewed. The aspects of development and problems in MDR study as well as detection methods for MDR were also discussed.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2001

Application of Resistance Reversal Agents in Hematologic Malignancies; Malignancy; Current Clinical Practice.

The clinical application of resistance reversal drugs for patients with hematologic malignancies is reviewed. The phenomenon of multidrug resistance versus other mechanisms are discussed. The pump-like mechanisms of P-glycoprotein, multidrug resistance associated protein, lung resistance protein and of other ATP binding cassette transporter proteins are reviewed briefly, as well as the important substrate drugs and pump-blocking compounds. The problems associated with resistance protein assays in clinical samples and the concept of prognostic versus therapeutic clinical relevance are described, within the context of selected hematologic malignancies. Toxicities and treatment outcomes of phase II and III trials of reversal agents in lymphoma, multiple myeloma, myelodysplastic syndromes, acute myeloid leukemia and blast phase of chronic myeloid leukemia are reviewed. Finally, current options for on-study management of relapsed or refractory hematologic malignancy patients are discussed.

Journal Article↗

PubMed2006

Angiogenesis and antiangiogenic therapy in hematologic malignancies.

Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Although many of the initial studies were performed on solid tumors, increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies. Overexpression of angiogenic factors in particular VEGF and bFGF in most hematologic malignancies may explain the increased angiogenesis found in these malignancies and correlate with poor prognosis as well as decreased overall survival. In this review, we focus on the current literature of angiogenesis and antiangiogenic therapy in hematologic malignancies, and finally describe advances and potential challenges in antiangiogenic treatment in hematologic malignancies.

Angiogenesis Inhibitors↗

PubMed2026

Prolonged SARS-CoV-2 infection in hematologic malignancies: clinical impact, risk factors and intra-host viral evolution.

INTRODUCTION: Prolonged SARS-CoV-2 infection in hematologic patients may go unrecognized. The aim of the study is to describe the incidence, risk factors, viral evolution and clinical outcomes of prolonged SARS-CoV-2 infection in patients with hematologic malignancies. METHODS: This is a prospective, observational study. We performed a longitudinal follow-up rRT-PCR with cycle threshold (Ct) assessment until negativization to 500 patients diagnosed with hematologic malignancies who suffered SARS-CoV-2 infection between March 2020 and August 2023. We considered prolonged COVID-19 to a positive rRT-PCR with a Ct <35 beyond 30 days after microbiological diagnosis with the same viral variant. RESULTS: Prolonged SARS-CoV-2 infection is a complication in 44.8% (156/348) of patients diagnosed with hematologic malignancies with a median time of rRT-PCR positivity of 58 days (IQR 43-88). Active treatment with bispecific antibodies, anti-CD20 antibodies, BTK inhibitors and immunosuppressive drugs for GvHD are significantly associated with prolonged viral shedding; as well as lack of vaccination, lesser booster vaccine doses, absence of anti-S seroconversion after immunization, severe acute infection and delayed antiviral treatment. A 56.4% (88/156) of patients exhibit a pattern of remitting and relapsing symptoms and fluctuant viral load. During those exacerbations, 70.5% of patients experienced an increase in the severity of the acute infection and 34% developed pneumopathy, particularly organizing pneumonia. Persistent COVID-19 caused 54.5% (85/156) of patients to interrupt and 19.9% (31/156) to suspend indefinitely their hematologic treatments. Viral intra-host mutations across the entire viral genome, predominantly within the spike were detected in most patients with prolonged COVID-19, especially in those who received anti-SARS-CoV-2 mAb as sotrovimab (E340, R346, K356) and tixagevimab/cilgavimab (R346, K444 and G446). These substitutions are associated with reduced viral susceptibility. DISCUSSION: Prolonged SARS-CoV-2 infection in hematologic patients is frequent and leads to persistent viral replication, significant morbidity and the emergence of intra-host viral mutations. Optimizing treatments and monitoring viral clearance are medical needs for high-risk patients.

Humans↗

PubMed2002

Challenges in treating hematologic malignancies.

During the past 40 years substantial progress has been made in the treatment of hematologic malignancies, particularly in some subgroups of patients. Today, cure is attainable for patients with Hodgkin's disease and a considerable proportion of patients with high-grade non-Hodgkin's lymphoma. Prognosis is improving in patients with acute promyelocytic leukemia and, to some extent, those with acute lymphoblastic and myeloid leukemias. However, the majority of patients who suffer from a hematologic malignancy live with incurable disease. In CLL, outside the setting of a clinical trial, it is advisable to postpone treatment until the manifestation of clinical symptoms. It is yet to be determined whether treatment strategies based on new prognostic parameters such as cytogenetics can change the course of disease. In indolent lymphomas, cure is not attainable for the vast majority of patients; the median survival of 9 to 10 years has remained unchanged for several decades. Nevertheless, there has been a dramatic change in therapeutic paradigms in the past few years. For the first time, with the use of new cytostatic drugs and recombinant monoclonal antibodies, it is possible to achieve molecular remissions. Whether this will translate into cure or prolonged survival is still to be determined. In Hodgkin's disease, which is curable when treated with radiotherapy, chemotherapy, or combined therapy, depending on the stage of disease, the focus of future studies must be on prevention of early relapse and on primary resistant disease, both of which present a very poor prognosis. Finally, regardless of underlying malignancy and prognosis, the preservation of quality of life is of major consideration in the setting of hematologic malignancies.

Anemia↗

PubMed1989

[Second primary cancer in hematological malignancy experience in VGH-Taipei].

Seven patients of hematological malignancy with second primary cancer had been found at Veteran General Hospital from 1983 to 1988. The second primary cancers either developed subsequently or concurrently with the hematological malignancies. Four patients were diagnosed to be non-Hodgkin's lymphoma and three of them developed squamous cell carcinoma of lung(2) and hepatocellular carcinoma (1) at 44, 20 and 45 months after the initial diagnosis of on-Hodgkin's lymphoma. All three had received chemotherapy and/or radiotherapy. Another one was found to have liposarcoma in the retroperitoneum concurrently. Three patients had chronic lymphocytic leukemia (CLL). Two of them were found to have skin squamous cell carcinoma at the same time. Another one developed cervical squamous cell cancer ten months after treatment with oral leukeran and prednisolone. Literature about synchronous and metachronous neoplasms was reviewed.

Adult↗

PubMed2001

Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation.

The use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancy after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We evaluated the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in 13 patients (median age, 38 years) with relapsed hematologic malignancies (Hodgkin's disease, n = 4; Hodgkin's disease and advanced myelodysplastic syndrome, n = 1; non-Hodgkin's lymphoma, n = 6; multiple myeloma, n = 2) after initial autoSCT. Median time from autoSCT to alloSCT was 12 months (range, 3-24 months); 6 patients had chemotherapy-refractory disease following autoSCT, 6 were in untreated relapse, and 1 had a partial response from salvage chemotherapy. Preparative therapy consisted of cyclophosphamide, 150-200 mg/kg; peritransplantation anti-thymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal irradiation); and a very short course of cyclosporine as GVHD prophylaxis. All patients achieved initial mixed chimerism as defined by greater than 1% donor peripheral white blood cells. Seven patients, who had no evidence of GVHD, received prophylactic DLI beginning 5 to 6 weeks after transplantation for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-tumor effect. Six patients showed conversion to full donor chimerism and 1 lost the graft. Grade II or greater acute GVHD occurred in 9 patients. Seven patients achieved a complete response; 6 had no response. The median survival time of the 13 patients is currently 10 months (range, 3-39 months), with an overall survival probability at 2 years of 45% (95% confidence interval [CI], 19%-73%) and a disease-free survival probability at 2 years of 37.5% (95% CI, 12%-65%). Thus, this novel nonmyeloablative alloSCT strategy followed by prophylactic DLI was well tolerated and can result in durable disease-free survival among patients with advanced hematologic malignancies after a failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in the treatment of hematologic malignancies after an autologous transplantation.

Adult↗

PubMed1994

[Three cases of hematologic malignancies with jumping translocation].

We treated three cases of hematologic malignancies (Burkitt's lymphoma, ALL (L3), AML (M0)) with jumping translocations. Tumor formation was easily occurred in all three cases. The location of the jumping translocation was 1q21 in all three cases. Hematologic malignancies with jumping translocation tend to be B-cell lineage and have poor prognosis. The significance of jumping translocation is unknown yet, but it seems that jumping translocation is related to the tumor progression, rather than tumorigenesis. So that the intensive therapy including bone marrow transplantation must be considered.

Adolescent↗

PubMed1997

Elevated incidence of hematologic malignancies in patients with Sjögren's syndrome compared with patients with rheumatoid arthritis (Finland).

The risk of hematologic malignancies was studied in Finnish patients with rheumatoid arthritis or Sjögren's syndrome, and the difference in the risk between those diseases was evaluated. The study cohorts comprised 676 patients with primary Sjögren's syndrome, 709 with secondary Sjögren's syndrome, and 9,469 with rheumatoid arthritis identified from the Finnish hospitals' national discharge register. The follow-up times were 5,336, 4,254 and 65,391 person-years, respectively. Data on the incidence of malignancies were collected from the files of the Finnish Cancer Registry. The incidence of hematologic malignancies was elevated in the study cohorts. The standardized incidence ratio (SIR) of non-Hodgkin's lymphoma was: 2.2 (95 percent confidence interval [CI] 1.5-3.1) for rheumatoid arthritis; 4.5 (CI = 1.5-11) for secondary Sjögren's syndrome; and 8.7 (CI = 4.3-16) for primary Sjögren's syndrome. The ratio of the SIR of primary Sjögren's syndrome cf rheumatoid arthritis alone was 3.9 (CI = 1.8-8.0) in non-Hodgkin's lymphoma, and 3.4 (CI = 1.2-8.1) in other hematologic cancers. The incidence of hematologic malignancies, especially that of non-Hodgkin's lymphoma, is elevated in patients with rheumatoid arthritis. It is higher in patients with secondary Sjögren's syndrome and highest in patients with primary Sjögren's syndrome. Differences in the immunologic aberration influence oncogenesis.

Arthritis, Rheumatoid↗

PubMed2006

Plasma levels of tumor M2-pyruvate kinase should not be used as a tumor marker for hematological malignancies and solid tumors.

It has been reported that the dimeric isoform of the enzyme pyruvate kinase M2 was overexpressed in various solid tumor cells. Hence, it was suggested that circulating levels of the so-called tumor M2-pyruvate kinase (Tu M2-PK) could be used as a tumor marker for monitoring systemic therapies of various solid tumors. We analyzed its validity as a tumor marker by comparing plasma levels of Tu M2-PK in patients with different non-malignant diseases to levels in healthy individuals and in patients with hematological diseases. Plasma levels of Tu M2-PK were measured using an ELISA assay in a total of 284 patients. The mean Tu M2-PK concentration of 32 U/mL was significantly higher in the group of patients with hematological malignancies (n = 121) (p < 0.001). However, 37% of healthy individuals (n = 63) and 44% of patients with non-malignant diseases (n = 100), especially patients with an acute inflammatory reaction (67%), were found to have elevated levels of Tu M2-PK using a cutoff level of 15 U/mL. The specificity was 59% and the sensitivity was 51%. There was no significant correlation between the prevalence of a hematological malignancy and positive Tu M2-PK result. Thus, our data imply that Tu M2-PK is not a useful tumor marker for hematological malignancies and solid tumors, as a significant number of false positive results were detected in healthy individuals and patients with non-malignant diseases.

Biomarkers, Tumor↗

PubMed1997

Reinterpretation of G-banded complex karyotypes by fluorescence in situ hybridization with chromosome-specific DNA painting probes and alpha-satellite centromere-specific DNA probes in malignant hematological disorders.

In this study, we have performed fluorescence in situ hybridization (FISH) with chromosome-specific DNA painting probes 1, 2, 3, 4, 6, 8, and 12 and centromere-specific DNA probes 7,10,12,17,18, and X after G-banding on the same metaphase spreads from four patients with malignant hematological disorders to more precisely interpret their complex karyotypes. The findings demonstrated that the application of combined G-banding and FISH can more accurately explain complex karyotypes of hematological malignancies. FISH can detect not only the origin of marker chromosomes, but also the complex rearrangements that cannot be identified by routine banding techniques. This approach is very important to complement the cytogenetic analysis of malignant disorders and to evaluate the role of chromosome change in the development, progression, and prognosis of tumors.

Chromosome Banding↗

PubMed2001

11q deletions in hematological malignancies.

Structural aberrations involving 11q are among the most common aberrations in a number of hematological malignancies. Most of the aberrations, such as translocations and deletions, often harbor a breakpoint at 11q23, which suggests that this region might contain a tumor suppressor gene important for the genesis of lymphoproliferative disorders. Interestingly, deletions are concentrated only in some subtypes of hematological malignancies, where they are detected at a relatively high frequency. In B-cell chronic lymphocytic leukemia (B-CLL), deletions have been detected in 20-30% of the cases, whereas almost half of the mantle cell lymphomas (MCL) show deletion at 11q23 in fluorescence in situ hybridization analysis. In T-cell prolymphocytic leukemia (T-PLL), deletions involving the region 11q23.3-23.1 have also been detected to be frequent. In B-cell chronic lymphocytic leukemia, 11q deletion is associated with more rapid disease progression and poor survival in a younger subgroup of patients. The putative tumor suppressor genes have remained unrevealed until recently, when the ATM gene was found to carry mutations in cases with deletion in B-CLL, MCL and T-PLL. These data suggest that 11q deletions and dysfunction of the ATM gene might have significance in the tumorigenesis of certain subsets of hematological malignancies. Importance of 11q deletion as a diagnostic marker needs to be further studied in a larger series of patients. Another issue that remains to be investigated is the involvement of other target genes in the deletion.

Chromosome Aberrations↗

PubMed2003

The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies.

Important insights into the cellular and molecular biology of cancer in general and of hematologic malignancies in particular have been gained in the past two decades. The genes, and their protein products, involved in the transformation of cells from normal to neoplastic, as well as in the progression of neoplastic cells to a more aggressive, therapy-resistant phenotype, are being elucidated in great detail. However, most hematologic malignancies, particularly adult acute leukemias, remain associated with high mortality rates and new therapeutic approaches are urgently needed. The challenge is therefore to carefully and efficiently translate the information gained into effective therapeutic strategies. The clinical success achieved by tyrosine kinase inhibitors, such as ST1571 in chronic myelogenous leukemia, has stimulated interest for kinase-based signaling pathways as therapeutic targets in hematologic malignancies. The mitogen-activated protein kinase (MAPK) pathway is a common point of convergence of many different mitogenic and anti-apoptotic signal transduction pathways in hematopoietic, as well as epithelial, cancer cells and can now be clinically targeted by highly selective small molecule inhibitors. The mounting preclinical evidence of anti-leukemic activity of MAPK inhibitors, alone or in combination with pro-apoptotic small molecules or with conventional chemotherapeutic agents provides rationale that MAPK inhibition-based treatment strategies could soon enrich our therapeutic armamentarium against human leukemias.

Antineoplastic Agents↗

PubMed2004

Thiotepa and fractionated TBI conditioning prior to allogeneic stem cell transplantation for advanced hematologic malignancies: a phase II single institution trial.

Relapse of hematologic malignancies after allogeneic stem cell transplantation remains a common problem, in particular for patients who have advanced disease at the time of transplantation. Thiotepa has excellent antileukemic and immunosuppressive activity, and could therefore be a useful drug in the conditioning regimen for patients with advanced hematologic neoplasms. We retrospectively analyzed toxicity, engraftment and survival data of 41 patients who received a conditioning regimen of thiotepa (600 mg/m2) and hyperfractionated TBI (10 Gy) prior to matched related (n = 25) or matched unrelated (n = 16) allogeneic stem cell transplantation. The mean age at transplantation was 37.8 years (range 20-59), all but five patients had advanced hematologic malignancies at the time of transplantation. GVHD prophylaxis was with standard cyclosporine and methotrexate. Engraftment was excellent, but the regimen was associated with a high incidence of grade III renal (41%) and hepatic (15%) toxicity, and high transplant-related mortality (44% at day +90). The 3-year event-free survival was 13% and overall survival 14%. We conclude that this regimen requires modification to reduce toxicity.

Acute Disease↗

PubMed1996

Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with hematologic malignancies.

OBJECTIVE: This study evaluates the cost-effectiveness of vancomycin serum concentration monitoring in patients with hematologic malignancies. METHODS: The study was designed as a prospective randomized study. Seventy immunocompromised febrile patients with hematologic malignancies were randomly assigned to either a vancomycin therapeutic drug monitoring group (TDM group; n = 37) or to a control group (n = 33). Intervention in the TDM group involved patient follow-up by a clinical pharmacist to obtain and pharmacokinetically interpret serum vancomycin concentrations for dosage individualization. RESULTS: Evaluation of all patients included global clinical response and nephrotoxicity, as well as the economic costs and effectiveness derived from the vancomycin monitoring program. There were no significant differences between the TDM and control groups in the outcome measures, except for the incidence of nephrotoxicity: the rates of minor nephrotoxicity were 33.3% and 13.5% in the control and TDM groups, respectively. The corresponding figures for moderate nephrotoxicity were 9.1% and 0%. Logistic regression analysis confirmed that TDM independently reduced the incidence of nephrotoxicity in this patient population. On the basis of this reduced nephrotoxicity, a incremental cost of $435 per case of nephrotoxicity prevented was found for vancomycin serum concentration monitoring. CONCLUSIONS: A decreased incidence of nephrotoxicity provides evidence of a real clinical benefit to patient management in patients with hematologic malignancies. The TDM for vancomycin therapy in this high-risk population has been shown to be a cost-effective procedure.

Adult↗

PubMed2001

Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero.

To evaluate the risk of acute and late side effects in children whose mothers received chemotherapy during pregnancy for hematological malignancies, we performed an analysis of 84 children with a long-term follow-up. The 84 children in our study were born to mothers with hematological malignancies (29 acute leukemia, 26 Hodgkin's disease, and 29 malignant lymphoma) who received chemotherapy during pregnancy, including 38 during the first trimester. These children were examined for physical health; growth; development; and hematological, cytogenetic, neurological, psychological, and learning disorders. The occurrence of cancer or acute leukemia in these children was also considered. Some of these patients have become parents, and their children were also considered in this analysis. In all of the children studied, including the 12 second-generation children, the birth weight was normal; learning and educational performance were normal; and no congenital, neurological, or psychological abnormalities were observed. With a median follow-up of 18.7 years (range, 6-29 years), no cancer or acute leukemia has been observed. These results confirm our previous reports, suggesting that if a pregnant patient has an aggressive hematological malignancy, chemotherapy at full doses can be safely administered, even during the first trimester, if cure of the hematological malignancy is considered reasonable.

Acute Disease↗

PubMed2004

[Non-myeloablative allogeneic stem cell transplantation in patients with hematologic malignancies].

In order to investigate the clinical efficacy of non-myeloablative allogeneic stem cell transplantation (allo-NST) and related technology in patients with hematologic malignancies, twenty-six cases of hematological malignancies (10 AL, 14 CML, 2 MM patients) received NST following conditioning regimens with fludara + cyclophosphamide + ATG (14 cases) and busulfan or melphalan + cyclophosphamide + ATG (12 cases), G-CSF (600 micro g/d) or G-CSF (300 micro g/d) + GM-CSF (300 micro g/d) were used for mobilizing peripheral blood stem cell. A combination of cyclosporine A (CsA) and methotrexate (MTX) was administered for GVHD prophylaxis. Patients will be eligible for donor lymphocyte infusion (DLI) or donor stem cell infusion (DSI) given in graded increments according to the chimeric formation and clinical reaction. Generally the dose of the first infusion was 1 x 10(7)/kg at 4th week post-transplantation. The engraftment analysis included the detection of microsatellite short tandem repeats (STRs), Bcr/Abl fusion gene, Philadelphia chromosome, HLA-locus analysis, sex chromosome and ABO blood type or blood subtype. The results showed that 22 patients (84.62%) were engrafted, among which 18 patients were full donor chimerism (FDC) up to now. Acute GVHD occurred in 3/26 cases (11.54%). Chronic GVHD was diagnosed in 6 of 26 (23.07%) evaluable patients. The incidence of infection and hemorrhage was low and slight. It is concluded that allo-NST is a safe and effective therapeutic method for hematologic malignancies, but the related technology such as selection of indication, conditioning regimen and transplantation immunotherapy should be studied further.

Adult↗

PubMed2006

Leptin and resistin levels in serum of patients with hematologic malignancies: correlation with clinical characteristics.

AIM: To evaluate leptin and resistin levels in patients with various hematologic malignancies. METHODS: We included 21 patients with lymphoma, 14 with multiple myeloma (MM), 14 with acute leukemia, 13 with chronic lymphocytic leukemia (CLL), and 25 healthy control subjects into our study. The subjects' body mass indexes (BMI) were calculated; hematological and acute phase response parameters, serum lipid were determined; serum leptin and resistin levels were determined by ELISA. RESULTS: Serum leptin level was significantly increased in CLL and MM groups when compared to the control group (p less, similar 0.01). Resistin level was significantly higher in lymphoma patients than in CLL, acute leukemia and control groups (p less, similar 0.01). In the control group, leptin level was negatively correlated with hemoglobin level (r = -0.44, p = 0.047); and in all patients with hematologic malignancies, leptin level was correlated with BMI (r = 0.32, p = 0.02). Leptin in lymphoma subjects correlated with hemoglobin level (r = 0.64, p = 0.005), resistin level correlated with the platelet count in patients with hematologic malignancies (r = 0.26, p = 0.044). In addition, leptin level had negative correlations with international prognostic score (IPS) in Hodgkin lymphoma (r = -0.9, p = 0.002) and with international prognostic index (IPI) in non-Hodgkin lymphoma (r = -0.77, p = 0.03). In CLL patients, leptin level had a correlation with the poor prognostic marker - CD38 level (r = 0.68, p = 0.03). CONCLUSION: We found higher leptin levels in MM and CLL patients, and higher resistin levels in lymphoma patients: this fact demonstrates that changes in adipose tissue and metabolism occur in these disease states.

Adipose Tissue↗