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PubMed2006

Nonmyeloablative allogeneic hematopoietic stem cell transplantation in 26 cases of hematological malignancies.

The purpose of this study was to investigate the efficacy of non-myeloablative allogeneic stem cell transplantation (allo-NST) and its related technologies in hematological malignancies. 26 patients with hematological malignancies (acute leukemia 10, chronic myeloid leukemia 14, multiple myeloma 2) received allo-NST following conditioning regimens with fludarabine/cyclophosphamide/ATG in 14 cases or busulfan or melphalan/cyclophosphamide/ATG in 12 cases prior to infusion of 2 or 3 collections of G-CSF (600 microg/d) or G-CSF (300 microg/d) plus GM-CSF (300 microg/d) mobilized blood stem cell on the fifth day. A combination of cyclosporine A (CsA) and methotrexate (MTX) was administered for GVHD prophylaxis. Patients were eligible for donor lymphocyte infusion (DLI) (or donor stem cell infusion (DSI)) given in graded increments according to the chimeric formation and clinical feature. Generally, the dose of the first infusion was 1 x 10(7)/kg in 4th week post-transplantation. The engraftment analyses 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 out of 26 patients, 22 (84.62%) were engrafted, 18/22 were full donor chimerism (FDC) up to now. Acute GVHD occurred in 3/26 (11.54%), while chronic GVHD was diagnosed in 6 out of 26 (23.07%) patients. The incidence and degree of infection and hemorrhage were low and slight. It is concluded that NST is a safe and effective therapy for hematological malignancies, whereas related technologies such as adaptation selected, conditioning regimen and transplantation immunotherapy should be studied further.

Adult↗

PubMed2000

Potential diagnostic, prognostic and therapeutic implications of some new regulatory proteins in hematologic malignancies.

Multiple cell surface receptors play an important role in the biology of hematological malignant cells. Like already clustered monoclonal antibodies, the use of new markers of differentiation provide some new information about their structure and function. Here we consider the role of few selected regulatory proteins that are most frequently involved in the processes of activation, cell differentiation and proliferation of human hematological malignant cells. These molecules, being either lineage-restricted or multi-lineage cell activation ones, are involved in cell-cell and cell-matrix communications. They are involved in various leukocyte functions such as mobility, interaction with endothelium, and homing. Since physiologic cell growth involves not only cell division, but also programmed-cell death, we considered some apoptosis-regulatory molecules implicated in the clinical heterogeneity of hematological malignancies. The presence or absence of staining for these molecules is not only an important discriminatory immunophenotypic feature, but it appears useful also for prognosis and particularly in an experimental therapeutical setting. The prognostic significance of cell-expression of these molecules has not yet been clearly established, but it might be helpful in the evaluation of stability and progression of the disease.

Antigens, CD↗

PubMed2003

Donor lymphocyte infusion. An adaptive cellular immunotherapy for treatment of hematological malignancies.

The application of immunotherapy in the treatment of hematological malignancies is relatively new. Donor lymphocyte infusion (DLI) is a form of adaptive cellular therapy where the transfer of cells from immunocompetent donor to patient with cancer who relapsed after bone marrow transplantation results in destruction of the malignant cells. Hereby, we review the concepts, mechanisms, and results of the application of DLI in treatment of some hematological malignancies.

Bone Marrow Transplantation↗

PubMedDate not supplied

A protocol for the evaluation and treatment of oral mucositis in patients with hematological malignancies.

A study is made to determine the true incidence of oral lesions attributable to hematological malignancies and their therapies, with the purpose of preventing, diagnosing and treating the oral manifestations of the hematological disorder and the situations of mucositis produced by the different chemo or radiotherapeutic regimens administered. A review was made of patients with hematological malignancies undergoing treatment or programmed for hematopoietic transplantation, with clinical assessment and microbiological culture or histological study where required. A protocol is developed in these patients for the prophylaxis, control and management of their oral lesions, thus contributing to improve the knowledge and treatment of patients with hematological malignancies.

Clinical Protocols↗

PubMed2005

[DNA diagnosis in hematologic malignancies].

Genetic microarrays applied to hematologic malignancies identified a number of subgroups with a defined gene expression pattern, which were not identified by morphology, cytogenetics or molecular genetics. In many cases, these expression patterns links tumor cells to the normal developmental counterpart, and represent distinct disease subgroups with different clinical presentations and outcomes. Furthermore, genetic microarrays will be useful in predicting prognosis and identifying novel target of therapy.

Hematologic Neoplasms↗

PubMed1984

The hematologic malignancies. Leukemia, lymphoma, and myeloma.

Many of the conceptual advances in the treatment of advanced cancer have resulted from studies of the hematologic malignancies: The signal importance of complete remission, the complete disappearance of evident disease, as the major contributor to significant palliation; the first studies of adjuvant therapy, that is chemotherapy given to patients free of disease, which demonstrated prolongation of disease-free periods; the first studies of intensification, including early, intermittent, and late; combination chemotherapy; and finally, the important observation that advanced metastatic malignancies can be cured were made in studies of these important diseases. Because of treatment advances that have occurred over the last 10 to 20 years, the majority of patients with adult hematologic malignancies that were once considered universally fatal can be either cured or have substantial palliation. Treatment for adult acute leukemia has advanced such that 15% to 20% of patients have prolonged disease and treatment-free survivorship; in Hodgkin's disease, over 70% of patients can be cured; and for the lymphomas, the majority or 50% to 60% of patients can be cured with available treatments. Major treatment advances in supportive treatment such as allogeneic transfusion and allogeneic and autologous bone marrow transplantation improve the perspective for control of the hematologic malignancies. In addition, the potential for biologic response modifiers or the biologic products of normal cells that are normally involved in the regulation of both proliferation and differentiation show enormous potential for the treatment of advanced disease. Studies of interferon have shown promising early results in chronic granulocytic leukemia and in hairy cell leukemia. A new class of drugs, the acridine analogs, of which AMSA (4'-[9-acridinylamino]methanesulfon-M-anisidide) is a member, has been introduced and has established activity against acute leukemia. VP-16 (etoposide) has just become commercially available and is an important drug both in leukemia and lymphoma. Finally, the discovery of new knowledge about the biochemical pharmacology of drugs such as arabinosyl cytosine has offered a major advance in salvage treatment and the potential for substantial further improvement in the frontline management of these diseases. The rapid advances in both palliative and curative treatment for the hematologic malignancies have generally found broad application to the management of advanced cancer arising from other organ systems.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Apoptosis induced by molecular targeting therapy in hematological malignancies.

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.

Antibodies, Monoclonal↗

PubMed1996

Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy.

Sixteen patients with advanced hematologic malignancies were transplanted with HLA-identical allogeneic peripheral blood stem cells (PBSCs) that were selected for CD34+ cells by an avidin-biotin immunoadsorption technique. The median age of patients was 48 years (range, 37 to 67). Patients received 12.0 or 13.2 Gy of total body irradiation followed by 120 mg/kg of cyclophosphamide. Normal donors received 16 mg/kg of granulocyte-colony stimulating factor on days 1 to 6 followed by PBSC harvests on days 4 to 7. PBSC harvests were processed each day on a single avidin-blotin column containing an antibody to the CD34 antigen and processed cells were infused without cryopreservation daily for 4 consecutive days. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine alone for 5 patients and CSA plus methotrexate for 11 patients. A median of 18.64 (6.74 to 34.97) x 10(8) CD34+ cells/kg patient body weight were collected from each donor. A median of 8.96 (2.62 to 17.34) x 10(8) CD34+ cells/kg patient body weight were recovered after avidin-biotin adsorption which represented a median CD34+ cell yield of 53% (18% to 77%) with a median purity of 62% (34% to 82%). There was a reduction in CD3+ cells from a median of 557.26 (227.73 to 677.77) x 106/kg to 0.73 x 10(4)/kg (0.40 to 3.65), in CD4+ cells from 351.72 (194.47 to 520.11) x 10(6)/kg to 0.40 (0.15 to 1.03) x 10(4)/kg and in CD8+ cells from 169.74 (53.34 to 325.83) x 10(6)/ kg to 0.32 (0.12 to 2.71) x 10(4)/kg representing a median 2.8 (2.19 to 3.14) log reduction in T cells. One patient died of infection on day 3 posttransplant and was unevaluable for recovery of neutrophils. The median day to recovery of 500 neutrophils/mL was 15 (8 to 26) in the remaining 15 patients. Six of 16 patients falled to achieve a platelet count of 20,000/mL before death on days 3 to 97 of transplant-related complications. The median day to achieving platelets of 20,000 mL in the remaining 10 patients was 11 (7 to 31). Eight of 16 patients (50%) died between 3 and 97 days posttransplant, 7 of transplant-related causes, and 1 of progressive disease. Grade 2-4 acute GVHD occurred in 12 out of 14 (86%) and grades 3-4 in 6 out of 14 (43%) evaluable patients. Six of 8 evaluable patients developed clinical chronic GVHD and 1 developed subclinical chronic GVHD. Bone marrow and/or peripheral blood chimerism studies in 12 evaluable patients showed 97% to 100% donor type in 11 patients with 1 patient in relapse showing 40% donor cells 60 to 90 days posttransplant. Four of 16 patients (25%) are alive and disease-free 312 to 576 days after transplant. There were no episodes of graft failure or rejection. This study shows that allogeneic transplantation using CD34+ selected PBSC results in prompt and sustained engraftment. CD34+ selection, as employed in this preliminary study, however, resulted in an apparently higher rate of acute and chronic GVHD. However, The sample size is quite small and precludes a more definitive conclusion regarding GVHD.

Adult↗

PubMed2000

[New combination therapies in hematological malignancies].

New combination therapies against hematological malignancies have recently been reported. Anti-CD20 chimeric antibody adds a therapeutic benefit to standard-dose CHOP therapy without causing significant additional toxicity in the treatment of indolent B cell lymphoma. Multidrug resistant modifiers such as PSC833 and MS209 in combination with chemotherapy are useful for treating poor risk AML patients, whose leukemia/lymphoma cells express P-glycoprotein. Fludarabine containing FL and FLAG therapy were effective in patients with AML in relapse. The early addition of chemotherapy to ATRA, and maintenance therapy with chemotherapy and intermittent ATRA, can reduce the incidence of relapse in cases of acute promyelocytic leukemia.

Antibodies, Monoclonal↗

PubMed1991

[Clinical investigation on acute respiratory failure in patients with severe hematologic malignancy].

Ten patients with severe hematologic malignancies (four with acute leukemia, three with multiple myeloma, one with prolymphocytic leukemia, one with malignant lymphoma and one with blastic crisis of chronic myelogenous leukemia) developed respiratory failure during the period between April 1986 and May 1990. Clinically, the patients manifested high-fever, dyspnea refractory to oxygen therapy, diffuse pulmonary rales and severe hypoxemia without evidence of cardiogenic pulmonary edema. Chest roentgenograms displayed diffuse alveolar infiltrates. Respiratory failure occurred as early as 48 hours and as late as 66 days after the administration of intensive anti-neoplastic chemotherapy. At that time leukocyte count was between 100/microliters and 54,900/microliters. Marked leukocytosis was observed in two patients with AML and PLL. Respiratory failure was preceded by sepsis in one patient with AML and by pneumonia in nine patients. DIC was diagnosed in four patients. All patients treated with high dose methyl prednisolone (mPSL) within 12 hours after the onset of respiratory failure. Only one patient required assisted ventilation. High dose mPSL had significant effect on seven of ten patients. But three patients died from progressive respiratory failure, sepsis, pneumonia and multi-organ failure.

Acute Disease↗

PubMed1988

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy.

Nine patients with advanced hematological malignancy were entered into a phase I study to determine the maximum tolerated doses of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) combined with a standard dose of total body irradiation (TBI). Ara-C was administered continuously over 36 h and two doses of CY were given at 24-h intervals during Ara-C administration. TBI was given as 2.0 Gy fractions on each of 6 consecutive days followed by bone marrow transplantation. The initial three patients received a total dose of 6048 mg/m2 of Ara-C and 84 mg/kg of CY, with two of three patients experiencing fatal toxicity. The next two patients received a total dose of 5040 mg/m2 of Ara-C and 70 mg/kg of CY and both experienced fatal toxicity. The next four patients received a total dose of 3024 mg/m2 of Ara-C, 56 mg/kg of CY; two patients had no toxicity but two had grade 4 (fatal) toxicity. Four of the six patients with fatal toxicity did not complete the TBI regimen and two of these did not receive marrow infusion. One patient is alive (greater than 547 days post-transplant) but has relapsed (day 305). It is concluded that phase I trials of regimens containing concurrent administration of Ara-C and CY may not be appropriate due to severe dose-independent toxicity as demonstrated in this study.

Adolescent↗

PubMed1987

[Phase II study of chlorambucil in patients with hematological malignancies].

Eight patients with various hematological malignancies were treated with chlorambucil, an analogue of nitrogen mustard. Five patients with CLL, 2 patients with malignant lymphoma, and one each with pseudolymphoma of the lung and primary macroglobulinemia were given 4-6 mg of chlorambucil per day for 1-2 weeks at 2-4 week intervals or a daily dose of 6 mg continuously. Two cases of CLL and one each of follicular lymphoma and pseudolymphoma achieved partial remission. Side effects included myelosuppression, especially leukopenia. Chlorambucil can be used orally without severe toxicity for longer periods and the major indication for this drug seems to be CLL and favorable type of malignant lymphoma.

Administration, Oral↗

PubMedDate not supplied

Laparoscopic splenectomy in the management of benign and malignant hematologic diseases.

OBJECTIVES: The use of laparoscopy to treat malignant hematological diseases is not completely accepted. Our aim was to analyze operative and postoperative results of laparoscopic splenectomy performed for benign versus malignant hematological disorders. METHODS: Between 1994 and 2003, 76 consecutive patients underwent laparoscopic splenectomy. The first 38 cases were performed by using an anterior approach, whereas in the remaining 38 cases a semilateral position was used. RESULTS: Baseline characteristics showed that patients with malignant diseases were significantly older (56.9 vs 32.6 years, P < 0.001). Seventy-two (94.7%) procedures were completed laparoscopically. Conversion was required in 4 cases (5.2%). Mean operative time was 138.5 minutes for benign and 151.0 minutes for malignant diseases, (P > 0.05, ns). The hand-assisted technique was used in 3 patients with massive splenomegaly. Pathologic features showed that spleen volume was higher in patients with malignant diseases (mean interpole diameter 18.1 cm vs 13.7 cm, P < 0.001). Massive splenomegaly (interpole diameter over 20 cm, weight over 1000 g) was present in 13 patients (17.1%); 9 had malignant diseases. Overall perioperative mortality was 1.3% and major postoperative complications occurred in 6 patients (7.8%). Postoperative splenoportal partial thrombosis was identified in 9.7% of patients. CONCLUSIONS: Laparoscopic splenectomy is a well-accepted, less-invasive procedure for hematological disorders. Neoplastic diseases or splenomegaly, or both, do not seem to limit the indications for a minimally invasive approach after the learning curve.

Adolescent↗

PubMed2005

Appendicitis in childhood hematologic malignancies: analysis and comparison with typhilitis.

BACKGROUND/PURPOSE: Recognition of appendicitis in the child with hematologic malignancy may be difficult particularly in the setting of neutropenia and multiple medications causing an altered inflammatory response. Typhilitis may produce a similar constellation of clinical findings causing further diagnostic confusion. This review compares the relative frequency of these two conditions in children with hematologic malignancy with a focus on the clinical presentation, distinguishing features, surgical management, and outcome for patients with appendicitis. METHODS: This institutional review board-approved retrospective study evaluated 464 pediatric patients treated for hematologic malignancy at our institution from 1997 to 2003. From this cohort, we identified all children with a diagnosis of appendicitis or typhilitis. Data include demographics, clinical presentation, laboratory studies, and computed tomography (CT) scan findings. Groups were compared using the Fisher exact test. Significance was defined as P < .05. RESULTS: Eight (1.7%) of 464 children were diagnosed with typhilitis and 7 (1.5%) with appendicitis. There were no demographic differences between patients with appendicitis and typhilitis. Distinguishing clinical features in children with typhilitis included presence of fever and diarrhea. Clinical presentation in children with appendicitis was atypical in 5 of 7 cases yielding an incorrect preoperative diagnosis in all 5. Radiographic evaluation by CT scan accurately defined typhilitis, but not appendicitis. An operation was performed on all 7 children with appendicitis with no operative morbidity or mortality. CONCLUSIONS: Appendicitis and typhilitis occur with similar frequency in children with leukemia and lymphoma. Typhilitis is accurately diagnosed with clinical findings of fever, diarrhea, abdominal pain, and typical CT scan findings. Appendicitis tends to present with atypical findings, but can be successfully managed with standard surgical care.

Adolescent↗

PubMed1996

[Double cancer in elderly patients with hematologic malignancies].

The occurrence of multiple malignancy was studied in 674 patients with hematologic malignancies who were admitted to this department during the past 10 years. Of the 674 patients, 205 were aged 65 years or older, and 56 (8.3%) had another cancer. The frequency of multiple malignancy was significantly higher in older patients than in younger patients: 44 (21.5%) vs. 12 (2.6%). The major hematologic conditions in patients with multiple malignancy were multiple myeloma, myelodysplastic syndromes, non-Hodgkin's lymphoma, and chronic myelogenous leukemia. The major sites of cancers other than hematological malignancies were the stomach, colon, breast, and esophagus. Many of the older patients had gastric cancer or colon cancer, and gastric cancer was common in the younger patients. The multiple malignant neoplasms were synchronous in as many as 20 of the 44 older patients. There was only one such case among the younger patients. Of the 56 patients, nine had received alkylating agents, and one has received etoposide. In brief, elderly patients with hematologic malignancies are likely to have multiple malignant neoplasms. If they are synchronous, the patient's prognosis may be adversely affected, because simultaneous management of multiple malignant neoplasms is not easy.

Aged↗

PubMed2001

Impact of open lung biopsy for undiagnosed pulmonary infiltrates in patients with hematological malignancies.

Pulmonary complications are frequently encountered in patients with hematological malignancy. The optimal therapeutic decision including open lung biopsy (OLB) for such patients is uncertain. We herein examine the clinical impact of OLB on these patients. Seven patients with progressively diffuse pulmonary infiltrates despite aggressive medical treatment were examined. The underlying diseases, prior treatment for presumptive pneumonia, the change in therapeutic approach after operation, and clinical outcome were reviewed retrospectively. Diffuse pulmonary infiltrates were caused by infection in two patients and by noninfectious etiology such as alveolar proteinosis, idiopathic interstitial pneumonitis, leukemic involvement, and drug-induced alveolar damage in the others. Four patients who had serious underlying hematologic diseases such as myelodysplastic syndrome, acute and chronic myeloid leukemia, and T cell lymphoma died. Three patients with acute lymphoid leukemia survived. In two of these three, change of therapeutic strategies after OLB was created for the survival. OLB in patients with hematological malignancy may be useful in selected patients with a treatable hematologic disease who have treatable underlying causes of the pulmonary infiltrate.

Adolescent↗

PubMed2002

Fungal infections in nontransplant patients with hematologic malignancies.

Fungal infections are a major cause of morbidity and mortality in patients with hematologic malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Dimorphic fungi can cause serious infection in immunocompetent persons, but infection is more likely to be disseminated in patients with compromised cell-mediated immunity. Cryptococcus neoformans and Pneumosystis carinii typically cause infections in persons with severe T-cell suppression. The frequency of rare pathogenic fungi commonly resistant to amphotericin B has significantly increased over the past 20 years among patients with hematologic malignancies. Examples of such emerging pathogens include Trichosporon, Fusarium, and Scedosporium species, and dark-walled molds. This article reviews the epidemiology, clinical manifestations, diagnostic evaluation, and treatment of the major fungal pathogens in nontransplant patients with hematologic malignancies.

Antifungal Agents↗

PubMed2005

Brief report: practicability and safety of amphotericin B deoxycholate as continuous infusion in neutropenic patients with hematological malignancies.

Fungal infections are a major cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Amphotericin B is the treatment of choice, but its administration is often hampered by severe side-effects, which may be reduced by continuous infusion of this drug. We describe 17 consecutive patients with hematological malignancies, suffering from fever of unknown origin with possible fungal infections, treated with amphotericin B as continuous infusion compared with a control group of 10 patients treated with conventional rapid infusion of amphotericin B over 2 - 6 h. No acute side-effects or severe nephrotoxicity were observed during continuous infusion of amphotericin B. Target doses were reached faster in patients with continuous infusion of amphotericin B than in patients with rapid infusion. We conclude that continuous infusion of amphotericin B is safe in neutropenic patients with hematological malignancies.

Adult↗