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PubMedDate not supplied

Risk of reactivation of a recent invasive fungal infection in patients with hematological malignancies undergoing further intensive chemo-radiotherapy. A single-center experience and review of the literature.

BACKGROUND: Patients with hematologic malignancies and a history of an invasive fungal infection are considered to be at high risk of suffering reactivation of the infection during subsequent intensive chemotherapy. PATIENTS AND METHODS: From January 1993 to September 1996, nine patients with a hematologic malignancy and previous invasive pulmonary aspergillosis (IPA) or Pseudallescheria boydii pneumonia and five with invasive candidiasis received further intensive chemotherapy (n = 3) or a bone marrow or peripheral blood stem cell transplant (n = 11) four days to 13 months (median three months) from the start of therapy for the fungal infection. Five patients with IPA and all five with invasive candidiasis showed complete or good partial radiologic resolution of the infection with the primary antifungal therapy given, which was continued before, during and after the period(s) of subsequent neutropenia. RESULTS: Twelve of the 14 patients showed no signs of progression or reactivation of the fungal infection during therapy, while two patients with active IPA died with progressive aspergillosis shortly after an allogeneic transplant. A review of the literature revealed that in both types of infections the risk of reactivation and dissemination appears low after achieving clinical and radiologic signs of response, which takes several weeks or months before proceeding to further antileukemic therapy. INTERPRETATION AND CONCLUSIONS: Despite lack of definite evidence, administration of an active antifungal drug before, during and after the period of neutropenia appears to be useful. In IPA, residual masses, nodules or cavities in the lung usually contain viable invasive fungal elements and should be resected whenever possible. On the other hand, the risk of reactivation and progression of an active fungal infection during intensive chemoradiotherapy is very high, and novel therapeutic strategies appear warranted in this setting.

Adolescent↗

PubMed1992

The use of giant cell tumor conditioned media in cytogenetic studies of hematologic malignancies.

The use of conditioned media produced from solid tumor cell lines has been beneficial in the study of hematologic malignancies. Conditioned media from giant cell tumors (GCT), human lung adenocarcinoma, and human bladder carcinoma express growth factors that have been used to stimulate growth of bone marrow cells and improve the quality of the preparations. It has been reported that addition of Lu-CSF1-conditioned media from a lung adenocarcinoma cell line masks abnormalities in cases of acute leukemia [1.] Because we routinely use GCT-CM in bone marrow and leukemic blood cultures for chromosome analysis in our lab, we investigated this potential effect on our case analysis. We have performed a serial study of a 100 cases of hematologic malignancies received for analysis in our lab to determine the effect of the addition of GCT-CM to our culture media with respect to 1) mitotic index, 2) quality of preparation, and 3) differential selection of either chromosomally normal or abnormal cell lines. Our results indicate that the mitotic index and quality of metaphases is enhanced with the addition of GCT media and that there is no difference in the rate of abnormality detection with or without the addition of GCT media.

Chromosome Aberrations↗

PubMed2006

Unrelated cord blood transplants in adults with hematologic malignancies.

BACKGROUND AND OBJECTIVES: We analyzed outcomes and risk factors after unrelated cord blood transplantation (CBT) in adults with hematologic malignancies. DESIGN AND METHODS: One hundred and seventy-one patients were transplanted after 1997. Their median age was 29 years (15-55), and the median follow-up time was 18 months (1-71). Most patients had acute or chronic leukemia (n=142, 83%), 91 (53%) were transplanted in advanced phase and an autologous transplant had failed in 32 (19%). Most patients (87%) received an HLA-mismatched cord blood unit with 1-2 HLA disparities. At infusion, the median number of nucleated cells and CD34(+) cells was 2.1x10(7)/kg and 1x10(5)/kg, respectively RESULTS: The cumulative incidence of neutrophil recovery at day 60 was 72+/-3% with a median of 28 days (11-57). A higher neutrophil count and use of hematopoietic growth factors were independently associated with faster neutrophil recovery. The cumulative incidence of grade II-IV acute graft-versus-host disease was 32+/-4% and this complication was not associated with the number of HLA mismatches. The 2-year cumulative incidence of chronic graft-versus-host disease, transplant related-mortality and relapse were 36+/-10%, 51+/-4% and 22+/-4%, respectively. At 2-years, disease-free-survival for patients transplanted in early, intermediate and advanced phases of disease was 41+/-9%, 34+/-10% and 18+/-4%, respectively. In multivariate analyses, advanced disease status was an adverse factor for relapse and disease-free survival. INTERPRETATION AND CONCLUSIONS: Unrelated CBT is a clear alternative for adults with hematological malignancies lacking an HLA-matched related or unrelated donor. The choice of units containing a higher neutrophil count and a policy of earlier transplantation are likely to provide better results.

Adolescent↗

PubMed1982

Vindesine in the treatment of refractory hematologic malignancies: a phase II study.

A phase II evaluation of vindesine (VDS) was carried out in 46 patients with hematologic malignancies refractory to conventional chemotherapy. Two VDS schedules were employed (at random): (A) a weekly bolus (5 mg/m2 i.v. X 4); (B) fractionated daily injections (0.5 mg/m2 i.v. q.12 h X 10, course to be repeated after 10-15 days). Complete and partial remissions were observed in acute lymphocytic leukemia (3/14 patients), acute non-lymphocytic leukemia (2/12 patients), chronic myelocytic leukemia in blastic crisis (4/12 patients) and non-Hodgkin's lymphoma (4/8 patients). Responses were seen with higher frequency in patients treated with the weekly bolus (42.8 vs 16%). Myelosuppression was the most relevant side effect in both schedules. Neurotoxicity occurred infrequently and was generally mild in degree. Further trials with VDS in combination with other drugs are recommended in hematologic malignancies.

Acute Disease↗

PubMed1997

Cytokine therapy for hematological malignancies.

Recently various cytokines have been introduced into the clinic and have played important therapeutic roles in the treatment of hematological malignancies. Among these cytokines, we have focused on interferon (IFN) and granulocyte (G) or granulocyte-macrophage (GM) colony stimulating factor (CSF), which are currently the most useful cytokines in this review. IFN-a is one of most useful and wide-ranging antitumor agents in hematological malignancies. The most striking effects have been studies in chronic phase CML. Cytogenetic responses are seen in 30-40% of the treated patients, and a complete cytogenetic response can be seen in about 10%. Long-term survival can be expected in these patients. Considering the risk of graft-versus-host disease-associated mortality in allogeneic bone marrow transplantation, the most appropriate category of treatment is difficult to determine in IFN-responsive patients. Elucidation of the antitumor mechanism of IFN, as a prototype for other biological response modifiers, may revolutionize cancer treatment. G- and GM-CSF (CSFs) have reduced the duration of neutropenia, incidence of infectious episodes and days of hospitalization following cancer chemotherapy or stem cell transplantation. CSFs have also been used to mobilize peripheral blood stem cells and to increase the dose intensity of chemotherapeutic agents. Leukemic cells from many patients with acute myelogenous leukemia (AML) have surface receptors for CSFs and may proliferate in response to CSFs. However, several randomized studies showed that CSFs can be used safely and effectively in augmenting neutrophil recovery in patients with AML when given after induction chemotherapy. Various trials have been conducted to sensitize leukemic cells by CSFs, making them more susceptible to chemotherapy; but no convincing evidence has been obtained.

Antineoplastic Agents↗

PubMedDate not supplied

Pharmacokinetics of high dose methylprednisolone and use in hematological malignancies.

The pharmacokinetics of oral and intravenous high dose methylprednisolone (Solu-medrone, Upjohn) were compared in patients with hematological malignancies. The aim of the study was to determine the oral bioavailability of high dose methylprednisolone and to establish whether this is a feasible and more convenient route of administration. The plasma pharmacokinetics were described by a one-compartment open model with peak plasma levels of 6.9 +/- 2.5 micrograms/ml. Total area under the plasma concentration versus time curve was similar by either route. Mean relative oral bioavailability was generally high (91 +/- 27 per cent). Retrospective analysis of 34 patients with chronic lymphocytic leukemia (CLL), non-Hodgkin's and Hodgkin's lymphoma treated with high dose methylprednisolone showed 11 responses including two complete remissions among nine patients with CLL. There was significant improvement in platelet counts in thrombocytopenic patients and treatment was well tolerated and toxicity was relatively low. High dose methylprednisolone may therefore be a useful palliative treatment for hematological malignancies, particularly where marrow suppression is a problem.

Administration, Oral↗

PubMed1979

The influence of chemotherapy on response of patients with hematologic malignancies to influenza vaccine.

Bivalent influenza vaccine (containing antigens A/Victoria and A/New Jersey) was administered to 52 patients with hematologic malignancies, and pre- and postvaccination antibody titers to both antigens were determined by hemagglutination-inhibition. In comparison to healthy controls, mean antibody titer elevations were lower for both antigens in all disease groups, being significant (p less than 0.05) for A/Victoria in patients with non-Hodgkin's lymphoma, acute leukemia and lymphoproliferative diseases, and for A/New Jersey in patients with Hodgkin's and non-Hodgkin's lymphomas. In comparison to controls, significant depression of antibody response to both antigens was seen in patients on combination chemotherapy (p less than 0.0005), to a lesser extent in patients on daily single alkylating agent chemotherapy (p less than 0.05), while untreated patients did not differ significantly. Lymphopenia and depressed immunoglobulin levels were associated with a higher failure rate in eliciting "protective" greater than or equal to fourfold antibody titer increases. The findings suggest that patients with hematologic malignancies who are receiving chemotherapy at the time of vaccination are unlikely to attain seroconversion to protective antibody levels with influenza vaccine.

Antibodies, Viral↗

PubMed1994

Association of 17p loss with late-stage or refractory disease in hematologic malignancy.

Twenty-five patients with loss of part or all of 17p were selected from 701 patients with hematologic malignancies karyotyped either at diagnosis and/or at relapse and/or in refractory disease. Loss of 17p resulted from partial arm deletion (eight cases), unbalanced translocation (12 cases), i(17)(q10)(five cases) or monosomy 17 (four cases). In three cases, both 17ps were missing; in one case, two sublines independently acquired loss of 17p. In eight cases, loss of 17p was confirmed as a secondary change. The karyotypes generally were complex, with an average of 4.0 structurally abnormal chromosomes in the simplest lines showing 17p loss. The incidence at diagnosis was acute lymphoblastic leukemia (ALL) 2.2%, acute myeloid leukemia (AML) 2.4%, and myelodysplastic syndrome (MDS) 3.4%. The incidence in relapse and refractory disease was ALL 8.9%, AML 3.3%, and MDS 6.3%. The increased incidence of 17p loss in relapse and refractory disease was statistically significant (p < 0.05). Loss of 17p appears to be a feature of late-stage or resistant disease in hematologic malignancy.

Adolescent↗

PubMed2003

Rasburicase: potential role in managing tumor lysis in patients with hematological malignancies.

Acute tumor lysis syndrome with hyperuricemia and renal failure usually occurs during the initial period of chemotherapy in patients with aggressive hematological malignancies. Standard therapy for hyperuricemia includes hydration, urine alkalinization and pharmacoreduction of uric acid with allopurinol. In the USA, rasburicase has recently been approved by the US Food and Drug Administration for the reduction of uric acid. Rasburicase is a recombinant urate oxidase enzyme that converts uric acid to allantoin, which has increased urine solubility. It is administered intravenously once-daily and leads to rapid, dramatic declines in serum uric acid values. The toxicity profile is excellent, with rare incidence of bronchospasm and allergies and a known contraindication for patients with glucose-6-phosphate dehydrogenase deficiency. A Phase III trial in high-risk pediatric patients conclusively demonstrated that rasburicase is more effective than allopurinol in controlling uric acid. Ongoing evidence is accumulating suggesting that the drug is also safe and effective in adults with hematological malignancies.

Clinical Trials as Topic↗

PubMed2002

Histone deacetylases as therapeutic targets in hematologic malignancies.

During the past 5 years, it has become increasingly apparent that deregulated transcriptional control is a root cause of hematologic malignancy. Chromosomal translocations yield novel fusion transcription factors that in turn either activate genes critical for cell growth or repress genes important for normal cellular differentiation. Many of the fusion proteins of myeloid leukemia are aberrant transcriptional repressors and share the property of recruiting histone deacetylases (HDACs) to target genes. HDACs, by acting on chromatin and on transcription factors themselves, can modulate gene regulation. HDACs also play major roles in the function of well-characterized tumor suppressors such as p53 and Rb. Thus, HDACs are a compelling therapeutic target for cancer therapy. Several classes of HDAC inhibitors induce differentiation and cell death in myeloid and lymphoid model systems. Some of these are now in clinical trials for hematologic malignancies. The nature of HDAC function, the classes of inhibitors available, and recent experimental and clinical data will be reviewed.

Animals↗

PubMed1996

Cytokine therapy for hematological malignancies.

Recently various cytokines have been introduced into the clinic and have played important therapeutic roles in the treatment of hematological malignancies. Among these cytokines, I have focused on interferon (IFN) and granulocyte (G) or granulocyte-macrophage (GM) colony stimulating factor (CSF), which are currently the most useful cytokines, in this review. IFN-alpha has been approved for chronic myelogenous leukemia (CML), multiple myeloma and hairy cell leukemia. In addition, IFN-alpha has therapeutic potentials for low grade non-Hodgkin's lymphoma, cutaneous T cell lymphoma and adult T cell leukemia/lymphoma. Thus, IFN-alpha is one of the most useful and wide-ranging antitumor agents in hematological malignancies. Most striking effects have been studied in chronic phase CML. Cytogenetic responses are seen in 30-40% of the treated patients and a complete cytogenetic response can be seen in about 10%. Long-term survival can be expected in these patients. Considering the risk of graft-versus-host disease-associated mortality in allogeneic bone marrow transplantation, the category of treatment is difficult to choose in IFN-responsive patients. Elucidation of the antitumor mechanism of IFN, as a prototype for other biological response modifiers, may revolutionize cancer treatment. G- and GM-CSF (CSFs) have reduced the duration of neutropenia, incidence of infectious episodes and days of hospitalization following cancer chemotherapy or stem cell transplantation. CSFs have also been used to mobilize peripheral blood stem cells and to increase dose intensity of chemotherapeutic agents. Leukemic cells from many patients with acute myelogenous leukemia (AML) have surface receptors for CSFs and may proliferate in response to CSFs. However, several randomized studies showed that CSFs can be used safely and effectively in augmenting neutrophil recovery in patients with AML when given after induction chemotherapy. Various trials have been made to prime leukemic cells by CSFs to make them more susceptible to chemotherapy, but no convincing evidence has been obtained.

Clinical Trials as Topic↗

PubMed2001

Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4--anaplastic lymphoma kinase gene fusion.

This report describes an unusual extramedullary hematologic malignancy in an 18-month-old child who presented with a capillary leak syndrome that evolved into hyperleukocytosis with malignant cells. The circulating tumor cells did not express an antigen profile typical of any subtype of leukemia commonly observed in children. Tumor cells were CD3(-)/CD56(+); had germline TCR genes; and strongly expressed CD30, epithelial membrane antigen, and anaplastic lymphoma kinase (ALK) consistent with a null cell anaplastic large cell lymphoma (ALCL). The malignant cells contained a t(2;19)(p23;p13.1) that interrupted ALK and translocated it to the der(19). Reverse transcriptase-polymerase chain reaction and nucleotide sequence analysis revealed fusion of ALK to tropomyosin 4, an ALK fusion partner not described previously in hematologic malignancies. The clinical presentation and phenotypic features of this malignancy were not typical for ALCL because tumor cells expressed both myeloid (CD13, CD33, HLA-DR) and natural killer (NK) cell antigens. The neoplastic cells most resembled NK cells because in addition to being CD3(-)/CD56(+) with germline TCR genes, these cells were CD25(+)/CD122(+)/granzyme B(+) and possessed the functional properties of immature NK cells. The unusual clinical presentation, immunophenotype, and functional properties of these neoplastic cells suggest that this malignancy may be derived from the putative myeloid-NK precursor cell. Furthermore co-expression of NK and ALCL features supports the concept that a minority of null-ALCL may be derived from NK cells and expands the spectrum of phenotypes that can be seen in tumors produced by ALK fusion proteins. (Blood. 2001;98:1209-1216)

Anaplastic Lymphoma Kinase↗

PubMedDate not supplied

Comparative outcomes of reduced intensity and myeloablative allogeneic hematopoietic stem cell transplantation in patients under 50 with hematologic malignancies.

We have conducted a direct comparison of the outcomes of reduced intensity and myeloablative conditioning in younger adults with hematological malignancies<50 yr. One hundred and five patients received transplants from human leukocyte antigen (HLA)-matched donors, via either reduced intensity (n=35) or myeloablative conditioning (n=70). The median ages of the reduced intensity and myeloablative groups were 36 and 33 yr (p=0.014). Neutrophil engraftment (i.e. time to absolute neutrophil count>0.5x10(9)/L) occurred more rapidly in the reduced intensity group (median: 10 d; range: 0-21 d) than in the myeloablative group (median: 18 d; range: 11-38 d; p<0.0001). The incidence of grades 2-4 acute graft-vs.-host disease were similar between the reduced intensity and myeloablative groups, at 17% vs. 24% respectively (p=0.40). The cumulative incidence of day 100 non-relapse mortality was 18% in the reduced intensity group, and 21% in the myeloablative group (p=0.88). The overall two-yr survival rates were 43% in the reduced intensity group, and 35% in the myeloablative group (p=0.72). In conclusion, reduced intensity transplantation yielded outcomes comparable with those of myeloablative transplantation in patients under 50 with hematological malignancies.

Adult↗

PubMed2003

Modulation of cellular signaling pathways: prospects for targeted therapy in hematological malignancies.

The high remission rates observed in patients with chronic myelogenous leukemia who receive Imatinib mesylate (Gleevec) indicate that targeted therapy for hematological malignancies is achievable. At the same time, progress in cellular biology over the past decade has resulted in a better understanding of the process of malignant transformation, a better classification of subtypes of each disease on the basis of molecular markers, and a better characterization of the molecular targets for drug development. These advances have already spawned the development of such effective agents as monoclonal antibodies and specific enzyme inhibitors. This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in hematological malignancies.

Antineoplastic Agents↗

PubMedDate not supplied

Improved prognosis of Pseudomonas aeruginosa bacteremia in 127 consecutive neutropenic patients with hematologic malignancies.

OBJECTIVES: Although decreasing in frequency, Pseudomonas aeruginosa bacteremia is still a major challenge for neutropenic cancer patients. In patients with hematologic malignancies, the prognosis of P. aeruginosa bacteremia is particularly poor due to the prolonged and severe neutropenia, mucosal damage, and other defects in immunity related both to the underlying disease and to the cytotoxic therapy. METHODS: To verify the outcome of P. aeruginosa bacteremia and to try to define possible prognostic factors, the authors reviewed the medical records of 127 consecutive episodes of P. aeruginosa bacteremia observed in the hematologic unit of the Verona University School of Medicine. RESULTS: Presence of pneumonia and septic shock, persistence and severity of neutropenia, delayed and inappropriate antibiotic therapy, and unresponsive underlying disease had negative impact on clinical outcome of P. aeruginosa bacteremia. CONCLUSIONS: With recognition of the risk factors and more careful management, the prognosis of P. aeruginosa bacteremia in neutropenic patients with hematologic malignancies has improved in recent years.

Adolescent↗

PubMed1996

Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation.

Allogeneic peripheral blood stem cell (PBSC) transplants from HLA-identical siblings were performed in 37 patients with advanced hematologic malignancies. Outcomes were compared to a historical group of 37 similar patients with advanced hematologic malignancies receiving bone marrow (BM) transplants from HLA-identical donors. The PBSC group and historical BM group were well matched for diagnosis, disease stage, age, and graft-versus-host disease (GVHD) prophylaxis. Patients received PBSC transplants between 1993 to 1995 while BM patients were treated between 1989 to 1994. Engraftment, measured by the time to reach a peripheral neutrophil count > 500/L and platelet count > 20,000/microL without transfusions, occurred on days 14 and 11 in the patients transplanted with PBSC compared to days 16 and 15 in the patients receiving BM (P = .00063, .00014). The PBSC group required a median of 8 U of red blood cells and 24 U of platelets compared to 17 U of red blood cells and 118 U of platelets for BM transplant recipients (P = .0005, .0001). The estimated risks of developing grades 2 to 4 acute GVHD were 37% for the PBSC group and 56% for the BM group (P = .18), while the estimated risks of grades 3 to 4 acute GVHD were 14% for the PBSC group and 33% for the BM group, P = .05). Chronic GVHD occurred in 7 of 18 evaluable patients receiving PBSC and 6 of 23 evaluable patients receiving BM, P = .5. The estimated risks of transplant-related mortality at 200 days were 27% versus 45% (P = .33) relapse were 70% versus 53% (P = .27) and of overall survival were 50% and 41% (P = .39) for patients transplanted with PBSC or BM, respectively. This retrospective comparison suggests that compared to marrow transplantation from HLA-identical donors, allogeneic PBSC transplantation from HLA-identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of acute or chronic GVHD.

Adult↗

PubMed2006

Psychosocial adaptation and quality of life among Brazilian patients with different hematological malignancies.

This study aims to investigate the prevalence of posttraumatic stress disorder (PTSD) symptoms, anxiety, and depression in patients with hematological malignancies, and to investigate the possible relationship between these symptoms and variables such as demographic data, social support, and quality of life (QOL). We studied 107 patients: 54 with non-Hodgkin's lymphoma (NHL), 18 acute myelogenous leukaemia (AML), 10 acute lymphoblastic leukaemia (ALL), and 25 multiple myeloma (MM). Demographic data were collected, and three standardized instruments were applied to this group of patients: Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire of QOL. The results showed a significant percentage of patients presenting with symptoms: 13% had high levels of intrusive thoughts, 20.5% had high levels of anxiety, and 16.8% had high levels of depression. Patients with MM had the lowest QOL scores in the EORTC physical functioning subscale. Patients under intravenous chemotherapy treatment had a higher level of anxiety than the monitoring patients. Patients with recent diagnosis had a level of intrusion symptoms (IES) relevantly higher than the others. The unemployed patients and those with lower social support had levels of stress, anxiety, and depression significantly higher than the others. Our results confirm the high incidence of intrusion, avoidance, anxiety, and depression in patients with hematological malignancies and highlight the importance of a multidisciplinary staff to complement the treatment of these patients, including psychosocial assistance.

Adaptation, Psychological↗

PubMed1991

Hemolytic-uremic syndrome following bone marrow transplantation in adults for hematologic malignancies.

One hundred and sixty eight adult patients with B-cell non-Hodgkin's lymphoma (NHL) and other hematologic malignancies who underwent autologous or allogeneic bone marrow transplantation (BMT) were investigated for the subsequent development of hemolytic-uremic syndrome (HUS). All patients were conditioned with cyclophosphamide and total body irradiation. When examined at 3-month intervals for the first year post-BMT, all patients had uniform measurements of hematocrit (Hct) and serum creatinine. Sixteen patients who initially exhibited Hct and creatinine values that were normal range for the BMT populations developed a sudden decrease in Hct and increase in creatinine between 3 and 11 months post-BMT and fulfilled the clinical and laboratory criteria for HUS. None of these patients had known active cytomegalovirus infection, graft-versus-host disease, or cyclosporine administration. The degree of decrease in Hct and creatinine elevation ranged from solely laboratory abnormalities to a clinically significant syndrome. Twelve of the 16 patients developed acute clinical complications of congestive heart failure, hypertension (HTN), or peripheral edema. Twelve patients required red blood cell support, whereas only four patients required platelet transfusions. Both hemolytic anemia and thrombocytopenia have resolved in virtually all cases. At a mean follow up of 18 months postdiagnosis, creatinine elevations have persisted along with HTN. All patients have survived without life-threatening long-term sequelae. With the increasing use of BMT as a curative modality for patients with hematologic malignancies, it becomes important to prospectively monitor patients for the development of HUS and its potential long-term impact on renal function.

Adult↗