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PubMed2002

Update on non-myeloablative stem cell transplantation for hematologic malignancies.

Allogeneic stem cell transplantation is an established treatment modality for a variety of hematologic malignancies. Unfortunately it carries a high risk of complications and toxicities related to the intensive preparative regimen which is traditionally used for pre-transplant myeloablation and the graft versus host disease, which may be life threatening. Thus allogeneic stem cell transplantation has been used only for younger patients with a good performance status, excluding many other potential candidates due to advanced age or comorbid conditions. Non ablative or reduced intensity preparative regimens for allogeneic stem cell transplantation (NST) have been proposed as a strategy that would allow exploiting the graft versus tumor effect of allogeneic transplantation without the toxicity of myeloablative therapy. After more than five years of cumulative clinical experience, it is now well established that NST is a feasible treatment option for patients with suboptimal performance status and is mostly effective in slow proliferating malignancies, which gives time for a graft versus malignancy effect to take place. Additionally achievement of stable donor cell engraftment with NSTs provides a platform for adoptive immune cell treatments and may allow to extend indications of stem cell transplantation in the future.

Animals↗

PubMed2002

Update on non-myeloablative stem cell transplantation for hematologic malignancies.

Antineoplastic Agents↗

PubMedDate not supplied

Diagnosis and treatment of fungal infections in patients with hematologic malignancies.

A diagnosis of deep-seated mycosis was made in 54 patients with hematologic malignancies, severe neutropenia and fever, based on a set of clinical and laboratory criteria. Standardized antifungal treatment was started in 31 patients who seven days after onset of fever had not responded to antibiotics; the fungal infection was cured in 13, all of whom had a simultaneous remission of neutropenia, whereas the other 18 who did not respond to antifungal treatment, all had a falling or static neutrophil count. None of the 23 patients who were given no or inadequate antifungal treatment survived regardless of the neutrophil count and/or phase of the hematologic disease. We discuss the suitability of utilizing empirical criteria for a diagnosis of disseminated fungal infection as a basis for starting antifungal therapy in this type of patient.

Adolescent↗

PubMed1995

Gene transfer for the therapy of hematologic malignancy.

Gene transfer has allowed a number of biologic issues in the therapy of hematologic malignancy to be addressed. In autologous bone marrow transplantation, gene marking studies have shown that infused marrow contributes to relapse in acute myeloid leukemia, neuroblastoma, and chronic myeloid leukemia. In addition, double gene marking with distinguishable retroviral vectors has allowed comparison of purging techniques and the ability of different sources of stem cells to repopulate. In allogeneic bone marrow transplantation, genetically modified T cells have proven valuable for the prophylaxis and treatment of viral diseases and may be of use to treat disease relapse. Gene transfer is also being used to modify tumor function, enhance immunogenicity, modify function of adoptively transferred immune system cells, and confer drug resistance to normal hematopoietic stem cells.

Drug Resistance, Neoplasm↗

PubMed1984

[A clinical study on cefoperazone in serious infections associated with hematological malignancy].

Clinical and bacteriological efficiencies of cefoperazone (CPZ) in 19 serious infections associated with hematological malignancy were studied. CPZ was clinically effective in 13 cases (68.4%). Excellent effects were obtained in 3 cases (15.8%), good effects in 7 cases (36.8%) and fairly good effects in 3 cases (15.8%). The rate of clinical effectiveness by CPZ was not dependent on neutrophils number in peripheral blood. Bacteriological effectiveness to isolated organisms in 15 cases was obtained in 9 cases (60%). Clinically significant serum concentrations of CPZ persisted over 6 hours after injection (1 g/l hour, d.i.v.). In comparative study of MIC against clinically isolated P. aeruginosa, CPZ was superior to other cephalosporins. Adverse reactions were not significant except for 3 cases with abnormalities of hepatic function.

Adult↗

PubMed1997

Age and sex distributions of hematological malignancies in the U.K.

This paper reports on an analysis of nearly 27,000 hematological malignancies diagnosed in the U.K. in the 10-year period 1984 to 1993. The unique observations provided in this analysis are the similarity of the sex-specific curves by age for acute myeloid leukemia, myelodysplasia types, polycythemia rubra vera, and myelofibrosis (or myelosclerosis). The unusual age-sex-specific distribution of essential thrombocythemia, suggesting a unique epidemiology, has never been reported before. The unusual female excess of the nodular sclerosing adolescent peak in Hodgkin's disease and its rapid fall with time is potentially of great importance. An even younger childhood peak of acute lymphoblastic leukemia is presented. Overall these data represent the most reliable available in the U.K., being population based, specially collected and will form the basis of considerable further investigations.

Acute Disease↗

PubMed2004

The role of NUP98 gene fusions in hematologic malignancy.

Chromosomal aberrations occur with great frequency and some specificity in leukemia and other hematologic malignancies. The most common outcome of these rearrangements is the formation of a fusion gene, comprising portions of 2 genes normally present in the cell. These fusion proteins are presumed to be oncogenic; in many cases, animal models have proven them to be oncogenic. One of the most promiscuous fusion partner genes is the newly identified NUP98 gene, located on chromosome 11p15.5, which to date has been observed fused to 15 different fusion partners. NUP98 encodes a 98 kD protein that is an important component of the nuclear pore complex, which mediates nucleo-cytoplasmic transport of protein and RNA. The fusion partners of NUP98 form 2 distinct groups: homeobox genes and non-homeobox genes. All NUP98 fusions join the N-terminal GLFG repeats of NUP98 to the C-terminal portion of the partner gene, which, in the case of the homeobox gene partners, includes the homeodomain. Clinical findings are reviewed here, along with the findings of several in vivo and in vitro models have been employed to investigate the mechanisms by which NUP98 fusion genes contribute to the pathogenesis of leukemia.

Acute Disease↗

PubMed2006

T-cell depleted peripheral blood stem cell allotransplantation with T-cell add-back for patients with hematological malignancies: effect of chronic GVHD on outcome.

One hundred thirty-eight patients with hematologic malignancies received myeloablative T cell-depleted peripheral blood stem cell transplant (PBSCT) from an HLA-identical sibling donor. The T cell dose was adjusted to 0.2-1 x 10(5) CD3(+) cells/kg. The CD34 dose was 2.7-16 x 10(6)/kg. Patients with acute graft-versus-host disease (GVHD) grade <2 received 1 or 2 donor lymphocyte infusions of 10(7) CD3(+) cells/kg between days 45 and 100. Patients were designated according to relapse probability as standard or high relapse risk (77 and 61, respectively). Overall survival (OS), relapse-free survival, relapse, and transplant-related mortality (TRM) were 58%, 46%, 40%, and 20%, respectively, after a median follow-up of 4 years. Fifty-three (39%) and 21 (15%) patients developed grade 2-4 and 3-4 acute GVHD. Forty-two (36%) had limited and 29 (25%) had extensive chronic GVHD. In multivariate analysis, disease risk was an independent factor for OS and relapse, day-30 lymphocyte count for OS and TRM, and chronic GVHD for OS and relapse. PBSCT with early T cell add back leads to comparable rates of chronic GVHD compared with T cell-replete PBSCT. However, this chronic GVHD after T cell add back is associated with less mortality and retains a protective effect in terms of relapse, at least in the standard-risk patients.

Adolescent↗

PubMed1989

Analysis of T-cell receptor delta chain gene in hematological malignancies.

We analyzed the rearrangement of TcR delta chain gene in 179 cases of hematological malignancies. In 17 T-cell lines, RPMI 8402, DND41, Peer, and Molt 13 had delta rearranged band (s). Except for RPMI 8402, these cell lines expressed functional delta gene. All of those gamma delta-T-cell lines had short message (1 kb) of TcR beta gene. These findings suggest differences between alpha beta-T-cells and gamma delta-T-cells. All 9 cases of T-ALL/LBL, of which 4 had neither gamma nor beta gene rearrangement, had a new rearranged band of TcR delta locus. This rearrangement was observed in 63% of B-lineage ALL/LBL. In the other T-lymphoproliferative disorders, only 2 cases of AILD and 1 of T-cell lymphoma had the rearranged band (s), showing derived T-cell neoplasm from gamma delta-T-cell as minority. In B-leukemia/lymphoma and myelocytic leukemia, 15% of the cases had the delta rearrangement. Heterogenous findings of TcR delta locus analysis were observed in ATLL without proviral HTLV-I DNA, T-cell lymphoma, AILD and HD. The J delta 1 region was frequently used and the J delta 2 region was rearranged in one AILD. It is suspected that J delta 3 was used in one T-ALL/LBL. There was no correlation between the phenotypic pattern of CD3, CD4, and CD8 in T cell disorders and the rearrangement of the TcR delta gene. These findings suggest that the newly identified TcR delta chain gene rearranges at a very early stage of T cell ontogeny; prior to the other TcR genes and perhaps at almost the same differentiation level as that of CD7 expression. The TcR delta gene is useful in evaluating clonality for the most immature T cell neoplasms not showing rearrangement of the other TcR genes. This gene is not lineage specific, however, when used in conjunction with IgHC gene, it may be a useful tool for the study of ALL/LBL.

Gene Rearrangement, T-Lymphocyte↗

PubMed1982

Bone marrow transplantation for hematologic malignancies.

Allogeneic and syngeneic bone marrow transplantation has developed into an important treatment for hematologic malignancies such as acute myelogenous or lymphoblastic leukemia, chronic granulocytic leukemia in accelerated phase, acute malignant myelosclerosis, and various forms of lymphoma. So far, more than 500 patients with these disorders have been transplanted at centers throughout the world. Marrow transplantation is still surrounded by several significant clinical problems. However, optimal results are obtained when marrow grafting is performed early during the clinical course of the respective disorders.

Acute Disease↗

PubMed1989

The safety of dental extractions in patients with hematologic malignancies.

Dental disorders have been recognized as major sources of infection in patients with hematologic malignancies (HM). Management of severe dental infections usually includes dental extractions (DE), but the safety of extractions in patients with HM who are at risk for bleeding, sepsis, and poor wound healing has not been well established. In conjunction with an aggressive program of dental care, 142 DE were performed in 26 patients with acute leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Granulocytopenia (less than 1,000 granulocytes/microL) was present during or within ten days following surgery in 14 patients. In these 14 patients (101 DE), the mean granulocyte count was less than 450/microL, with a median duration of granulocytopenia following surgery of 32 days (range, four to 169 days). Thrombocytopenia (less than 100,000 platelets/microL) occurred during or within two days following surgery in 13 patients (80 DE), with a mean platelet count of 63,500/microL. Transfusions were given for platelet counts less than 50,000/microL. All DE were performed without significant complications. Bleeding was minor to moderate and easily controlled with local measures; no patient required transfusion due to hemorrhage. Average maximum temperature 24 hours after DE was 37.7 degrees C. No episodes of bacteremia were documented within ten days of DE. Minor delay in wound healing was observed in two patients. We conclude that DE can be safely performed in patients with HM in combination with aggressive supportive care.

Agranulocytosis↗

PubMed1991

Allogeneic bone marrow transplantation for patients with hematologic malignancies.

Allogeneic marrow transplantation is an effective modality for the treatment of patients with hematologic malignancies. Limitations of success are donor availability, posttransplant relapses, and transplant-related morbidity and mortality. Progress is being made in improving the results of partially HLA matched family member donor transplants and in the use of HLA matched unrelated donors. Increases in dose intensity of pretransplant regimens are limited by toxicity and in order to be effective methods need to be developed to ameliorate side effects. The use of anti-inflammatory agents and recombinant growth factors show promise in decreasing transplant-related deaths.

Animals↗

PubMed1984

[Treatment of hematological malignancies with recombinant leukocyte A interferon (rIFN-alpha A)].

Twenty-three cases of hematological malignancies (18 plasma cell neoplasm, 2 leukemia and 2 malignant lymphoma) were treated with recombinant human leukocyte interferon (rIFN-alpha A). Among plasma cell neoplasms, excellent and good responses were obtained in 1 case of IgG myeloma and 1 case of Bence-Jones myeloma respectively and fair response was obtained in 5 other cases. Response rats was 11.4%, or 38.9% if fair response was included. Partial remission was obtained in 1 case of chronic lymphocytic leukemia. In one of 2 cases of acute lymphoblastic leukemia, marked reduction of peripheral leukemia cells was noted. Side effects included fever (65%), malaise (20%), nausea-anorexia (43%), leukopenia (52%) and thrombocytopenia (52%). However, all were not serious and disappeared quickly after discontinuation of rIFN-alpha A.

Adult↗

PubMed1983

[Phase II study of mitoxantrone for hematologic malignancies].

A phase II study of mitoxantrone (MIT) was performed in 21 patients with hematologic malignancies refractory to combination chemotherapy including anthracyclines. MIT was administered intravenously at doses of 8 to 13 mg/m2 on day 1 for 12 malignant lymphoma patients, and 1 to 3.3 mg/m2 on day 1 through 5 for 7 acute leukemia patients and 2 malignant lymphoma patients. Four malignant lymphoma patients (2 each of Hodgkin's disease and non-Hodgkin's lymphoma) achieved partial response lasting 19, 14, 8+, and 4 weeks, respectively. Although no definite response was obtained in acute leukemia patients, a marked cytoreduction was observed in 2 patients. Myelosuppression was a major toxicity, however, life-threatening toxicities were not observed in this study.

Acute Disease↗

PubMed1995

[P-glycoprotein expression in hematological malignancies].

To clarify the common characteristics among P-glycoprotein (P-gp)-expressing hematological malignancies and whether chemotherapies could or could not induce P-gp expression, we analyzed P-gp/MDR1 expression in tumor cells from 200 Japanese patients (104 with acute myeloblastic leukemia (AML); 30 with acute lymphoblastic leukemia (ALL); 66 with mature lymphoid malignancies). Functional P-gp expression was examined by Rhodamine-123 efflux test, and estimated with the data by RT-PCR method. In mature lymphoid malignancies, the cells of T or natural killer (NK) cell malignancies frequently expressed P-gp/MDR1. In AML, frequent P-gp/MDR1 expression was associated with the expression of CD7 or c-kit and with 8; 21 chromosomal translocation (p < 0.01), which were thought to be the characteristics of the hematopoietic stem cell. Though the expression of P-gp/MDR1 was more frequent at onset than at relapse phase, the increase is thought to result from the expansion of blastic fraction expressing P-gp/MDR1. In ALL, P-gp/MDR1 expression was not frequent in B-cell precursor lineage (three of eighteen patients), but the incidence was high in CD7(+) surface CD3(-) cases (seven of the cases). These results indicate P-gp/MDR1 expression is more frequently in the tumor of T, NK cell and stem cell, reflecting the characteristics of its normal counterpart.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood.

p53 mutations are found in a wide variety of cancers, including hematologic malignancies. These alterations apparently contribute to development of the malignant phenotype. We analyzed a large series of lymphoid (330 cases) and a smaller series of myeloid (29 cases) malignancies of childhood for p53 mutations by single-strand conformational polymorphism (SSCP) following polymerase chain reaction. Samples with abnormal SSCP were reamplified and analyzed by direct sequencing method. p53 mutations were detected within the known mutational hotspots (exons 5 to 8) in 8 of 330 lymphoid malignancies, and in none of 29 myeloid malignancies, showing that the frequency of p53 mutations in childhood lymphoid malignancies was very low (8 of 330 cases [2%]). Four of these patients had very aggressive, fatal acute lymphocytic leukemia (ALL). None of 13 infants and none of 48 patients with T-lineage leukemia had detectable p53 mutations in their ALL cells. Exceptionally, p53 mutations were comparatively frequent in a small sample of B-cell non-Hodgkin's lymphomas (2 of 8 cases). Mutations were detected in samples from two patients with ALL at relapse; these were not detected in samples at initial diagnosis from the same patients, suggesting that p53 mutations may be associated with progression to a more malignant phenotype. Seven of eight alterations of p53 were missense mutations, and seven of eight samples may be heterozygous for the mutant p53, indicating that p53 protein may act in a dominant negative fashion.

Adolescent↗

PubMed1999

A group of previously not recognized cytogenetic abnormalities in myeloid hematological malignancies.

We have identified a group of previously not reported chromosome abnormalities related to myeloid hematological malignancies. Cases 1 and 2 were observed to have an additional i(4)(p10) as the sole anomaly with similar clinical features of myeloid disorders; that is, acute nonlymphocytic leukemia (ANLL-M2) and myelodysplastic syndrome (MDS)-refractory anemia with an excess of blasts in transformation, respectively. Fluorescence in situ hybridization studies with the use of a 4p-specific microdissection probe further confirmed the presence of an i(4)(p10) in these patients. Case 3 was diagnosed with ANLL-M1 and had an additional i(8)(p10) as the only change, also confirmed by a whole-chromosome painting procedure. In cases 4-6, deletions of 18q at breakpoints q12, q23, and q21 were identified as the sole anomaly in a myeloproliferative disorder (MPD), MPD, and MDS, respectively. X-autosome translocations other than t(X;10)(p11;p11) and t(X;11)(q13;q23) have not been reported as recurrent or primary changes in hematological disorders. In the present study, a t(X;9)(q26;q22) and t(X;5)(q13;q33) as the sole anomaly were found in cases 7 and 8, respectively. Both cases had the same diagnosis of MDS. Considering that trisomies 4 (+4) and 8 (+8) are common anomalies in MDS and ANLL, our findings strongly indicate that amplification of genes on 4p and 8p, but not on 4q and 8q, may play a crucial role in the pathogenesis of MDS and ANLL. In addition, genes on 18q12-23 and on Xq13-26 may be involved in the pathogenesis of myeloid disorders.

Adult↗

PubMed2001

[Modern therapy of hematologic malignancies].

Remarkable progress has been done during the last three decades in the therapy of hematological malignancies. It is now possible to cure significant number of patients by chemotherapy, radiotherapy, and stem cell transplantation. However, there is still a large group of patients and situations where our approaches are failing. It is evident that in some circumstance chemotherapy and radiotherapy get close to their limits. A short insight into the group of novel therapeutic methods is given in this review. Such promising methods of treatment include the new chemotherapeutic drugs, new molecules that specifically act on the level molecular mechanisms (STI 571, ATRA, arsenic trioxide, etc.), immunotherapy (monoclonal antibodies, vaccination strategy, exploration of dendritic cells etc.), gene therapy and innovations in stem cell transplantation (graft versus leukemia/lymphoma effect). The future treatment will include combination of standard or intensified chemo/radiotherapy and the new methods, which allow better control of the disease.

Antineoplastic Agents↗