The risk of secondary leukemias following autologous stem cell transplantation.
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Hematopoietic Stem Cell Transplantation↗
Biomedical subjects
M R Bishop
Publications and source records attributed to M R Bishop.
The association between physician reimbursement in the US and use of hematopoietic colony stimulating factors as adjunct therapy for older patients with acute myeloid leukemia: results from the 1997 American Society of Clinical Oncology survey. Health Services Research Committee of the American Society of Clinical Oncology.
BACKGROUND/OBJECTIVES: Financial considerations play an important role in the delivery of medical care in the US. In 1996, revised guidelines from the American Society of Clinical Oncology (ASCO) indicated that granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) were unlikely to be harmful for older acute myeloid leukemia (AML) patients and suggested that physicians could consider their use in this setting. In 1997, the ASCO health services research committee evaluated whether physician reimbursement was a primary determinant in the decision to use G-CSF and GM-CSF in this clinical situation. PATIENTS AND METHODS: A questionnaire describing clinical scenarios for a 67-year-old man with newly diagnosed de novo AML was mailed to 1500 ASCO members who practiced medical oncology and hematology. Physicians were queried about their preferences for adjunctive CSF use following induction and consolidation chemotherapy. RESULTS: Of 1020 potentially eligible respondents, returned surveys were received from 672. Following induction chemotherapy, support for CSF use was 40%, similar in magnitude for that for non-use of these agents. The most important determinant of support for CSF use was being in a fee-for-service practice (P < 0.001). CONCLUSIONS: Physicians in the US are mixed in their support for CSFs for older AML patients. Support was high in settings where CSF use was accompanied by financial profit to the physician practice, and support was low otherwise.
Age Factors↗
Allogeneic bone marrow transplantation for low-grade lymphoma.
Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS >/=90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.
Adolescent↗
Laparoscopic bladder autoaugmentation in children.
Answering the need for a simple, nonenteric method of increasing bladder capacity, this article offers a new laparoscopic procedure for autoaugmentation of the bladder in children. An outline of the technical design is given. Experience with seven children is delineated. Postoperative voiding control and function capacity were greatly improved; this procedure is judged worthy of addition to the surgical armamentarium.
Adolescent↗
High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.
BACKGROUND: High-dose therapy followed by autologous stem-cell transplantation (autoSCT) induces complete remissions in the majority of patients with advanced B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma (B-CLL). However, the long-term utility of this therapy for B-CLL is unknown. PATIENTS AND METHODS: Sixteen previously treated patients with B-CLL were transplanted using autologous blood (n = 13) or bone marrow (n = 3). The median age of the patients was 49 f1p4s (range 44-60 years), and the median number of prior chemotherapy regimens was two. Patients were eligible for transplantation if they had chemosensitive disease and no morphologic evidence of malignant cells in the graft. Preparative regimens included cyclophosphamide and total-body-irradiation, with or without cytarabine, or BEAC. RESULTS: All patients engrafted and achieved a complete remission posttransplant. Ten patients were alive at a median of 41 months (range 22-125 months), and five were disease-free. Eight patients have relapsed and six have died (three from progressive malignancy). The projected three-year overall survival, failure-free survival and relapse rates were 68%, 37%, and 56%, respectively. CONCLUSIONS: AutoSCT for advanced B-CLL is associated with a high relapse rate. Whether this therapy can prolong life or produce cures is uncertain.
Adult↗
Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies.
Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) >500/microl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8+ ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8+ cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.
Adult↗
Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.
The first case of disseminated aspergillosis caused by Aspergillus ustus in an allogeneic peripheral stem cell transplant patient is described. The patient, a 46-year-old female with a history of myelodysplastic syndrome, underwent high-dose chemotherapy and total body irradiation prior to transplantation. She was released from the hospital 49 days posttransplant (p.t.) in a stable condition with an absolute neutrophil count (ANC) of 2,700 cells per microl. Multiple antimicrobial agents, including itraconazole (ITR), were prescribed during hospitalization and at the time of discharge. Three days after discharge, the patient was readmitted with hemorrhagic cystitis, persistent thrombocytopenia, and bilateral pulmonary consolidation, although no fever was present. The ANC at the time of readmission was 3,500. Upon detection of a pulmonary nodule (day 67 p.t.), a bronchoalveolar lavage was performed; the lavage fluid was positive for both cytomegalovirus and parainfluenza virus and negative for fungus. The patient was placed on ganciclovir. A biopsy specimen from a leg lesion also noted on day 67 p.t. revealed septate hyphae consistent with Aspergillus species, and a culture subsequently yielded Aspergillus ustus. Confirmation detection of A. ustus was made by demonstration of characteristic reproductive structures with the presence of Hülle cells. On day 67 p.t., ITR was discontinued and liposomal amphotericin B (AMB) was initiated. The patient's condition worsened, and she died 79 days p.t. At the time of autopsy, septate hyphae were present in heart, thyroid, and lung tissues, with lung tissue culture positive for A. ustus. In vitro susceptibility testing indicated probable resistance to AMB but not to ITR. This case supports the need for the development of rapid methods to determine antifungal susceptibility.
Aspergillosis↗
Regulation of the sympathetic nerve discharge bursting pattern during heat stress.
Frequency-domain analyses were used to determine the effect of heat stress on the relationships between the discharge bursts of sympathetic nerve pairs and sympathetic and phrenic nerve pairs in chloralose-anesthetized rats. Sympathetic nerve discharge (SND) was recorded from the renal, splanchnic, splenic, and lumbar nerves during increases in core body temperature (Tc) from 38 to 41.4 +/- 0. 3 degreesC. The following observations were made: 1) hyperthermia transformed the cardiac-related bursting pattern of SND to a pattern that contained low-frequency, non-cardiac-related bursts, 2) the pattern transformation was uniform in regionally selective sympathetic nerves, 3) hyperthermia enhanced the frequency-domain coupling between SND and phrenic nerve bursts, and 4) low-frequency SND bursts recorded during hyperthermia contained significantly more activity than cardiac-related bursts. We conclude that acute heat stress profoundly affects the organization of neural circuits responsible for the frequency components in sympathetic nerve activity and that SND pattern transformation provides an important strategy for increasing the level of activity in sympathetic nerves during increased Tc.
Animals↗
Antitumor activity of human umbilical cord blood cells: A comparative analysis with peripheral blood and bone marrow cells.
Although the hematopoietic reconstituting ability of human umbilical cord blood cells (UCBC) is well documented, their antitumor cytotoxic potential has not been well studied. Therefore, UCBC were compared to normal peripheral blood stem cells (PBSC) and bone marrow (BM) stem cell harvests for cytomorphology, antitumor cytotoxic activity before and after ex vivo cytokine manipulation, response to T and B cell mitogens, expression of adhesion molecules and immunophenotypes using flow cytometry, cytokine production and in vivo antitumor activity. BM and PBSC, but not UCBC, did not form cellular clusters in culture. More cytotoxic granules were present in the cytoplasm of UCBC than PBSC following activation in vitro. Ex vivo manipulation of UCBC with cytokines produced more cytotoxicity to K562 and Raji tumor cells than PBSC or BM (p<0.001). Most cytotoxic cells in UCBC cultures were T lymphocytes, and a correlation existed between the number of CD56+ cells and cytotoxicity levels, particularly after in vitro activation with interleukin-2. No significant difference in adhesion molecule expression was noted among UCBC, PBSC and BM cells. However, there was a significantly decreased expression of CD54 molecules (ICAM) on UCBC compared to PBSC (p<0.05). IL-2 activated UCBC showed significant antitumor effects against K562 leukemic cells grown in SCID mice. Thus UCBC contained more antitumor effector cells and precursors than cells from marrow or peripheral blood cells which might be capable of providing a therapeutic effect.
Animals↗
Depletion of EBV-infected cells in donor marrow by counterflow elutriation.
Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disease (PTLD) is a well-recognized complication of T cell-depleted (TCD) allogeneic bone marrow transplantation (BMT). Certain methods of TCD, such as counterflow elutriation (CE), have not been associated with an increased incidence of PTLD. Since CE depletes B cells as well as T cells, the hypothesis that CE depletes donor marrow of EBV-infected cells was tested in this study. Marrow samples from 70 donors were assayed by qualitative and semi-quantitative polymerase chain reaction (PCR) amplification to detect EBV DNA in four cellular fractions produced by elutriation: a small cell fraction (F70), two intermediate-sized cell fractions (F110 and F140), and a large cell (hematopoietic precursor-enriched, lymphocyte-depleted) rotor-off (R/O) fraction. The distribution of B cells in elutriation fractions was 21% (F70), 59% (F110), 18% (F140), and 2% (R/O). Qualitatively, the frequency of EBV DNA detected in fractions was 49% (F70), 57% (F110), 73% (F140), and 44% (R/O). The relative concentration of EBV DNA in each fraction was determined by semiquantitative PCR. The mean number of EBV DNA copies per 150,000 cells was 0.57 (F70), 4.6 (F110), 5.7 (F140), and 0.61 (R/O). Relative EBV DNA load in each fraction was calculated by multiplying the mean concentration of EBV DNA per fraction and mean mononuclear cell content in each fraction. The relative distribution of EBV DNA was 0.5, 58, 40, and 1.5% in the F70, F110, F140, and R/O fractions, respectively. No correlation between the amount of EBV in the graft and development of PTLD could be made, because only one of the 70 recipients developed PTLD and this was following autologous hematopoietic recovery. Although these results demonstrate that the majority of EBV-infected cells in marrow are separated from the TCD graft by counterflow elutriation, further studies are required to differentiate the role of this phenomenon from that of other potential factors, such as the amount of T cell depletion and recovery of EBV immunity in the pathogenesis of PTLD after BMT.
Bone Marrow Cells↗
Potential use of hematopoietic stem cells after radiation injury.
Bone marrow transplantation has been used for several years in the treatment of hematopoietic system malfunction. However, this particular therapy option has had minimal benefit when the hematopoietic system failure results from radiation exposure, such as that after the Chernobyl accident. In the last ten years, there has been considerable progress in the development of methods to encourage stem cell repopulation with the application of hematopoietic growth factors, and to reconstitute the hematopoietic system with stem cells extracted from the peripheral blood. Problems with allogeneic bone marrow or peripheral blood stem cell transplantation as a therapy option include graft-versus-host disease and a shortage of human leukocyte antigen (HLA)-matched donors. These problems can be overcome if an autologous bone marrow or peripheral blood transplant is performed, but this is not always practical. Another approach to combat these difficulties is the use of umbilical cord blood as a source of donor cells, since placental blood is rich in stem cells and less prone to lead to graft-versus-host disease than mature blood.
Bone Marrow Transplantation↗
Combination of antisense oligonucleotide and low-dose chemotherapy in hematological malignancies.
Current conventional chemotherapy for the treatment of hematological malignancies, although quite effective, has associated toxicities to normal tissue and organs, which is still a major dose limiting factor. In addition, high dose chemotherapy followed by autologous stem cell transplantation is limited by tumor cell contamination in the stem cell harvest. The use of conventional chemotherapy alone to purge these tumor cell contaminants is known to damage normal hematopoietic progenitor cells, resulting in delayed engraftment. The combination of antisense oligodeoxynucleotides (ODN) and low doses of chemotherapy offer a potential regiment which may lower the doses of conventional therapeutics required to effectively combat disease, thus lowering cytotoxicity experienced by normal cells. Transient downregulation of genes by ODN treatment, which are involved in the transformation or perpetuation of the cancerous disease state, can remove the growth and survival advantages exploited by tumor cells. Many groups are currently investigating this combination and have produced intriguing results. This review article discusses the current research investigating the combination of antisense ODN therapy with conventional chemotherapy in the treatment of hematological malignancies. Although further improvements in this strategy are required, the results thus far support a future for this strategy in clinical management of hematological malignancy.
Antineoplastic Combined Chemotherapy Protocols↗
Ex vivo treatment of bone marrow with phosphorothioate oligonucleotide OL(1)p53 for autologous transplantation in acute myelogenous leukemia and myelodysplastic syndrome.
Effective ex vivo purging techniques can decrease the likelihood of infusing bone marrow contaminated with leukemic cells during autologous transplantation. In preliminary studies, OL(1)p53, a 20-mer phosphorothioate oligonucleotide directed against p53 mRNA, decreased the number of acute myelogenous leukemia (AML) cells in vitro, suggesting a possible role for OL(1)p53 in purging bone marrow harvests of leukemia cells. To demonstrate that OL(1)p53 was nontoxic to hematopoietic progenitor cells, normal bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h, and hematopoietic progenitor cell survival was determined by in vitro colony assays. OL(1)p53 had no toxic effect on the growth of either myeloid (CFU-GM) or erythroid (BFU-E) progenitor cells. OL(1)p53 was then used to ex vivo purge bone marrow harvests from nine patients with either AML or myelodysplastic syndrome (MDS). Bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h before transplantation. The median times posttransplantation for the patient to recover an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet transfusion independence were 30 days and 56 days, respectively. Incubation of bone marrow cells with OL(1)p53 had no detrimental effect on the growth of hematopoietic progenitor cells, and transplantation of autologous bone marrow cells treated with the phosphorothioate oligonucleotide, OL(1)p53, resulted in successful recovery of circulating neutrophils following high-dose therapy in patients with AML or MDS. The data show that OL(1)p53 can be used safely to purge autologous bone marrow harvests from patients with leukemia.
Adult↗
High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma.
PURPOSE: This study evaluated the results of high-dose therapy followed by autologous bone marrow or peripheral-blood stem-cell transplantation for patients with follicular low-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: We performed a retrospective review of 100 patients undergoing autologous transplantation for follicular low-grade lymphoma between April 22, 1983 and December 31, 1993. RESULTS: Sixty-seven patients remained alive and 48 were failure-free. The median follow-up duration of surviving patients was 2.6 years (range, 1.0 to 11.7). There were eight (8%) deaths within 100 days of transplantation. Six additional patients died of nonrelapse causes up to 912 days after transplantation. Overall survival at 4 years was estimated to be 65% (95% confidence interval [CI], 54% to 75%) and failure-free survival was estimated to be 44% (95% CI, 33% to 55%). There was no definite evidence of a plateau in the failure-free survival curve. The only factor significantly associated with overall survival and failure-free survival was the number of chemotherapy regimen received before transplantation. No significant differences in outcome were observed between patients with follicular small cleaved-cell lymphoma and follicular mixed lymphoma, or between patients who received peripheral-blood stem-cell transplants and unpurged autologous bone marrow transplants. CONCLUSION: Prolonged failure-free survival is possible following high-dose therapy and autologous hematopoietic rescue for follicular low-grade lymphoma. It is unclear whether patients are cured with this therapy or if survival is prolonged.
Adult↗
Allogeneic-blood stem-cell collection following mobilization with low-dose granulocyte colony-stimulating factor.
PURPOSE: The optimal dose of granulocyte colony-stimulating factor (G-CSF) for mobilization of allogeneic-blood stem cells (AlloBSC) has yet to be determined. As part of a prospective trial, 41 related human leukocyte antigen (HLA)-matched donors had blood cells mobilized with G-CSF at 5 micrograms/kg/d by subcutaneous administration. The purpose of this trial was to monitor adverse effects during G-CSF administration and stem-cell collection, to determine the optimal timing for stem-cell collection, and to determine the cellular composition of stem-cell products following G-CSF administration. PATIENTS AND METHODS: The median donor age was 42 years. Apheresis began on day 4 of G-CSF administration. At least three daily 12-L apheresis collections were performed on each donor. A minimum of 1.0 x 10(6) CD34+ cells/kg (recipient weight) and 8.0 x 10(8) mononuclear cells/kg were collected from each donor. All collections were cryopreserved in 5% dimethyl sulfoxide and 6% hydroxyethyl starch. RESULTS: Toxicities associated with G-CSF administration and the apheresis process included myalgias/arthralgias (83%), headache (44%), fever (27%), and chills (22%). The median baseline platelet count of 242 x 10(4)/ mL decreased to 221, 155, and 119 x 10(6)/mL on days 4, 5, and 6 of G-CSF administration, respectively. Median numbers of CD34+ cells in collections 1, 2, and 3 were 1.99, 2.52, and 3.13 x 10(6)/kg, respectively. The percentage and total number of CD4+, CD8+, and CD56+/CD3- cells remained relatively constant during the three collections. Median total numbers of cells were as follows: CD34+, 7.73 x 10(6)/kg; and lymphocytes, 6.93 x 10(8)/kg. CONCLUSION: Relatively low doses of G-CSF can mobilize sufficient numbers of AlloBSC safely and efficiently.
Adult↗
Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.
PURPOSE: To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT. RESULTS: The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654). CONCLUSION: In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.
Adult↗
Blood stem cell transplantation in non-Hodgkin's lymphoma.
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Hematopoietic Stem Cell Transplantation↗
Bone marrow transplantation in chronic lymphocytic leukemia and lymphomas.
Until recently younger patients with B-cell chronic lymphocytic leukemia (CLL) have not been considered for treatment with high-dose therapy and bone marrow transplantation (BMT). Current results show that both autologous and allogeneic bone marrow transplantation can induce a high percentage of long lasting remissions in younger patients with poor-risk CLL. Because of the investigational character of BMT for CLL, all eligible patients should be enrolled in clinical trials. Autologous BMT or peripheral blood stem cell transplantation (PSCT) have become standard therapies for relapsed patients with Hodgkin's disease (HD) or intermediate- and high-grade non-Hodgkin's lymphoma (NHL). Data on autologous transplantation for low-grade NHL are not mature enough and more experience is needed in order to assess the long-term value of such approach. Ongoing studies of high-dose therapy in lymphomas are focused on performing BMT earlier in the course of the disease and exploring alternative sources of hematopoietic rescue such as allogeneic stem cell transplantation.
Adult↗