Unique gene expression and clinical characteristics are associated with the 11q23 deletion in chronic lymphocytic leukaemia.

Chromosome abnormalities influence prognosis and tumour progression in B-cell Chronic Lymphocytic Leukaemia (CLL). This study sought to determine whether these different disease subgroups were associated with unique gene expression patterns. Thirty-four cases of CLL were screened for the 11q23, 13q14, 17p13 deletions, and trisomy 12 by fluorescence in situ hybridization (FISH). Expression of 205 cell signalling and apoptosis genes were compared by cDNA array among cases with different chromosome abnormalities. A majority of the statistically differentially expressed genes were present in the 11q23 deletion group by hierarchical clustering. CDC2, a serine/threonine kinase, was overexpressed in the 11q23 deletion group (P = 0.0004) and confirmed by Taqman real-time polymerase chain reaction. Several other genes associated with cell signalling were overexpressed in the 11q23 deletion group. A strong overall correlation existed between the presence of different chromosome abnormalities and a number of prognostic factors including immunoglobulin heavy chain variable region mutation status (P = 0.011), time to treatment (P = 0.025) and lymphocyte doubling time (P = 0.034). This study confirmed the prognostic impact of chromosome abnormalities identified by FISH in CLL, particularly the 11q23 deletion and trisomy 12. In addition, the 11q23 deletion group was associated with a unique gene expression pattern involving cell signalling and apoptosis genes.

Immunological and clinical effects of post-transplant G-CSF versus placebo in T-cell replete allogeneic blood transplant patients: results from a randomized double-blind study.

BACKGROUND: Immunological and clinical effects of post-transplant growth factor administration have not been well studied. This report describes the outcome and immune functions of a total of 50 HLA-matched related donor allogeneic blood stem-cell transplantation patients who received post-transplant G-CSF (10 microg/kg) or placebo. METHODS: Immune status, including number of lymphocyte subsets and their functions, and serum immunoglobulin levels and clinical status--including GvHD, rate of relapse, event-free survival, and overall survival--were determined in the patients enrolled in this study. RESULTS: Twenty-eight patients survived 1 year after transplant, and 15 patients had available results to compare immune function by randomization assignment. At 12 months post-transplant, immune parameters in G-CSF versus placebo groups showed no statistically significant differences in number of circulating lymphocyte subsets CD3, CD4, CD8, CD19 and CD56 in the two groups. There was no significant (NS) difference in immunoglobulin IgG, IgA and IgM levels, NK or LAK cell-mediated cytotoxicity levels, and mitogen-induced proliferation between post-transplant G-CSF and placebo group. In addition, the analyses of immune parameters at earlier time-points on Days 28, 100, 180, and 270 revealed that, except for LAK cytotoxicity at Day 100, there was no differences between the two groups. Fourteen of 26 patients are alive in the G-CSF arm and nine of 24 in the placebo arm. Median follow-up of surviving patients is 43 months. Four year overall and event-free survival in the G-CSF and the placebo group were 53% and 35% (NS), and 44% and 36% (NS) respectively. Bacterial or fungal infections were the cause of six of 12 deaths in the G-CSF arm (all bacterial) and of four of 15 deaths in the placebo arm (two deaths from Aspergillus) (P=0.26). Two patients relapsed in the G-CSF arm and three in the placebo arm. Four year cumulative incidences of relapse were 8% versus 13% in G-CSF versus placebo arms, respectively, (NS). Chronic GvHD developed in 14 of 19 100-day survivors after G-CSF (11 extensive stage), and in 17 of 20 (14 extensive stage) in the placebo arm. The 4-year cumulative incidence of chronic GvHD was 56% [95% confidence interval (CI) 24-88%] after G-CSF and 71% (95% CI 48-94%) after placebo; this difference was not statistically significant (log rank P=0.41). CONCLUSION: In summary, there were no significant immunological or alterations in clinical benefit of post-transplant G-CSF administration in T-replete allotransplant recipients.

Increased apoptosis in B-chronic lymphocytic leukemia cells as a result of cyclin D3 down regulation.

B-cell chronic lymphocytic leukemia (CLL) is a clonal B cell malignancy of morphologically mature, functionally immature B cells. B-cell CLL cells are known to be resistant to killing by anticancer and other agents. This resistance is associated with alterations in apoptosis and cell cycle regulated genes. In our earlier studies, we have demonstrated that CLL cells have differential expression of genes that are associated with apoptosis and cell cycle regulation, including elevated expression of Bcl-2, DAD-1, Cyclin D3 and cyclin dependent kinase 4 inhibitor. Therefore, in this study, in an attempt to study the role of Cyclin D3 in the resistant behavior of CLL cells, Cyclin D3 was down regulated using antisense oligonucleotide (AS-ODN) in WSU-CLL, a human CLL cell line. The down regulation of Cyclin D3 was confirmed by RT-PCR and flow cytometry techniques. The Cyclin D3 expression down-regulated WSU-CLL cells were then tested for their susceptibility to fludarabine, a chemotherapeutic agent. Our results showed that the Cyclin D3 expression down-regulated WSU-CLL cells were more susceptible to fludarabine mediated killing. Following treatment with fludarabine, there was a significant increase in the number of cells undergoing apoptosis in Cyclin D3 expression down-regulated WSU-CLL cells as determined by Annexin-V assay, cell cycle analysis for DNA content, and cytomorphology. Thus, our results indicate Cyclin D3 down regulation increases the killing of WSU-CLL cells with fludarabine by increasing the number of cells undergoing apoptosis.

A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation.

Blood stem cell transplantation (BSCT) results in rapid hematopoietic recovery in both the allogeneic and autologous transplant settings. Because of the large numbers of progenitor cells in mobilized blood, the administration of growth factors after transplantation may not provide further acceleration of hematopoietic recovery. A randomized, double-blind, placebo-controlled study was performed to determine the effects of filgrastim (granulocyte colony-stimulating factor; G-CSF) administration on hematopoietic recovery after allogeneic BSCT. Fifty-four patients with hematologic malignancies undergoing a related, HLA-matched allogeneic BSCT were randomly assigned to receive daily filgrastim at 10 microg/kg or placebo starting on the day of transplantation. A minimum of 3 x 10(6) CD34(+) cells/kg in the allograft was required for transplantation. All patients received a standard preparative regimen and a standard regimen for the prevention of graft-versus-host disease (GVHD). The median time to achieve an absolute neutrophil count greater than 0.5 x 10(9)/L was 11 days (range, 9-20 days) for patients who received filgrastim compared with 15 days (range, 10-22 days) for patients who received placebo (P =.0082). The median time to achieve a platelet count greater than 20 x 10(9)/L was 13 days (range, 8-35 days) for patients who received filgrastim compared with 15.5 days (range, 8-42 days) for patients who received placebo (P =.79). There were no significant differences for red blood cell transfusion independence, the incidence of acute GVHD, or 100-day mortality between the groups. The administration of filgrastim appears to be a safe and effective supportive-care measure following allogeneic BSCT.

Filgrastim as an alternative to donor leukocyte infusion for relapse after allogeneic stem-cell transplantation.

PURPOSE: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT. PATIENTS AND METHODS: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse. RESULTS: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively. CONCLUSION: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT.

Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia.

The objective of this study was to describe the outcome of allogeneic stem cell transplantation (alloSCT) in a series of patients with B cell chronic lymphocytic leukemia (B-CLL). Twenty-three B-CLL patients were transplanted between 1988 and 1997 using stem cells from a related (n = 20) or an unrelated donor (n = 3). The median age of the patients was 46 years, and the median number of prior chemotherapy regimens received was two. At transplantation, 14 patients had chemorefractory disease and 12 of these were refractory to fludarabine. The preparative regimens included total body irradiation (TBI) in 22 of the 23 cases. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine and methotrexate. Twenty patients (87%) achieved a complete remission (CR). The incidence of grade II-IV acute GVHD was 54%. Fourteen (61%) patients are alive and disease-free, including two with unrelated donors, at a median of 26 months (range, 9-115 months). Nine patients (39%) have died, one of whom had progressive B-CLL. The only favorable prognostic factor for failure-free survival (FFS) and overall survival (OS) after alloSCT was the use of a cyclophosphamide/TBI rather than an etoposide/cyclophosphamide/TBI regimen (P = 0.03). The projected 5-year FFS, OS, and relapse rates after alloSCT were 65% (95% CI, 48-88%), 62% (95% CI, 43-88%), and 5% (95%, CI 0-13%), respectively. These findings demonstrate the potential of high-dose therapy and alloSCT for inducing and maintaining a remission in patients with advanced or chemorefractory B-CLL. The low relapse rate may be due to an allogeneic graft-versus-leukemia effect.

Central nervous system dysfunction as the first manifestation of multiple organ dysfunction syndrome in stem cell transplant patients.

Development of CNS dysfunction in the setting of hematopoietic stem cell transplant (HSCT) has been previously shown to predict for subsequent second organ dysfunction and death. In this paper, we describe the characteristics of this isolated CNS dysfunction, and its relationship to multiple organ dysfunction syndrome (MODS) after HSCT. Twenty-one of 186 patients undergoing HSCT developed CNS dysfunction as their first organ dysfunction a mean of 22.8 +/- 0.9 days after the start of the preparative regimen. Compared with 137 patients who developed no organ dysfunction, patients presenting with CNS dysfunction were more likely to have undergone allogeneic HSCT (P = 0.001) and to have received a total body irradiation-based regimen (P = 0.001), and were less likely to have been transplanted for lymphoma (P = 0.008). Patients who developed CNS dysfunction were more likely to die than those with no organ dysfunction (P < 0. 001). Of the 21 patients who developed CNS dysfunction, 48% resolved their dysfunction by a mean of 4.6 days later without progression to second organ dysfunction, and 90% of these patients survived to day 100. Fifty-two percent of patients with CNS dysfunction progressed to second organ dysfunction (pulmonary or hepatic) a mean of 5.5 days later, and only 36% survived to day 100 (P = 0.02). The patients who progressed to second organ dysfunction and those who did not were not different in terms of type of HSCT (allogeneic vs autologous), stem cell source (blood vs bone marrow), age, diagnosis or preparative regimen. Development of CNS dysfunction in the setting of HSCT, as with other organ dysfunctions (such as hepatic veno-occlusive disease), probably represents an early manifestation of a systemic disorder predisposing for MODS, increasing the risk of transplant-related mortality. Early systemic therapies directed at modulating this systemic disorder are probably indicated. Bone Marrow Transplantation (2000) 25, 79-83.

Blood stem cell transplantation: factors influencing cellular immunological reconstitution.

Recovery of immune function following stem cell transplantation is necessary for a good outcome. Immune recovery is facilitated by transplanting higher numbers of cells than neutrophil or platelet reconstitution requires. Estimates from studies in the allogeneic setting suggest the minimum stem cell dose to achieve optimal lymphocyte recovery is about 10(7) CD34+ cells/kg. Increasing the number of autologous stem cells infused potentially increases the risk of reinfusing tumor cells. Transplanted mature immune cells apparently have very limited early contribution to cellular immune recovery. Mobilizing cytokines permit collection of greater numbers of stem cells, but they also can polarize T cells with potentially significant consequences, for example, granulocyte colony-stimulating factor (G-CSF) decreases the antitumor cytotoxic effector functions of cells. Although this could be a disadvantage in the autologous setting, it might decrease graft versus host disease in the allogeneic setting. Thus, identification of cytokines, which alone or in combination provide the most potent mobilizing effect to permit the collection of the highest number of stem cells without inadvertent detrimental polarization of the responses of immune cells, and employment of cytokines posttransplantation, which direct differentiation of the stem cells along the most desirable pathways, for example, to generate antitumor immune responses, might improve immunological outcome. A future emphasis should be to better define the cytokines and target cell populations that provide optimal immune reconstitution rather than focusing solely on rapid hematological recovery. More complete immunological reconstitution in a greater proportion of patients should be accompanied by improvements in outcomes of blood stem cell transplantation.

Increased cytotoxicity against B-chronic lymphocytic leukemia by cellular manipulations: potentials for therapeutic use.

B-cell chronic lymphocytic leukemia (CLL) is characterized by profound immune dysfunction and a marked resistance to apoptosis. Understanding the cellular biology of immune effector cells from CLL patients as well as leukemic target cells is essential to developing immune mediated therapeutic strategies for CLL. In this study, an immortal CLL cell line called WSU-CLL has been used to study the characteristics of B-cell CLL as a tumor target for natural killer (NK), activated natural killer, and lymphokine activated killer (LAK) cells. The WSU-CLL cells were significantly less (p<0.001) susceptible to NK cell mediated cytotoxicity compared to K562, a standard tumor target cell line. In vitro activation of effector cells with either short term, low dose IL-2 or long term, high dose IL-2 significantly increased the susceptibility of CLL cells for cell mediated killing. The addition of CD1a+/CD3-/CD4+/CD80+/CD83+ dendritic cells derived from human umbilical cord blood increased the cytotoxicity of LAK cells against WSU-CLL. There is an increased expression of Bcl-2 and decreased expression of Fas on WSU-CLL cells as determined by RT-PCR techniques indicating possible roles for these genes in exerting resistance to immune cell mediated lysis. When Bcl-2 expression was downregulated in WSU-CLL cells using gene specific antisense oligonucleotides, the susceptibility of WSU-CLL cells to the cytotoxicity of chemotherapeutic agent Fludarabine was increased. Thus, our results suggest that in vitro activation with cytokines, addition of accessory cell populations such as dendritic cells and/or manipulation of key gene expression i.e. down regulation of Bcl-2 might be potential strategies to increase the antitumor cytotoxicity against CLL cells.

Valuing clinical strategies early in development: a cost analysis of allogeneic peripheral blood stem cell transplantation.

Allogeneic peripheral blood stem cell transplantation (alloPBSCT) is an emerging technology. As this technology develops, transplant centers are concerned with looking for technologic advances that will result in improvements in clinical outcomes and lower costs. We provide comparative estimates of costs and resource use for alloPBSCT in comparison to allogeneic bone marrow transplantation (alloBMT) for persons with hematologic malignancies from the time of harvest to 100 days post transplant. A retrospective, cost-identification analysis was conducted for patients in two consecutive phase II clinical trials at the University of Nebraska Medical Center. Identical preparative regimens, graft-versus-host disease prophylaxis, post-transplant hematopoietic colony-stimulating factor treatment regimens, and discharge criteria were used. Total median costs were $18,304 lower for alloPBSCT, with lower costs during recovery; specifically for hospitalization, platelet products, hematopoietic growth factors, intravenous hyperalimentation, supportive care agents, supplies, and antibacterial agents. This study provides preliminary evidence for short-term cost savings associated with alloPBSCT. However, concerns exist over the potential for higher costs due to preliminary reports of higher rates of chronic graft-versus-host disease, as well as more intensive induction regimens that may result in lower relapse rates. The premature adoption of new technologies based on short-term economic factors, in the absence of adequate clinical trial data, may prove to be ill-advised, particularly for complex medical treatments such as allogeneic transplantation.

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.

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.

A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation.

Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of <90%), central nervous system dysfunction (drop of >4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of <84% were double-blind randomized to receive ATIII concentrate, 70 units/kg within 24 hours of recognition of initial organ dysfunction followed by 50 units/kg 8, 16, 48, and 72 hours later, or albumin placebo. The group randomized to ATIII had a lower severity-of-illness score (15.7 +/- 19.2 vs. 28.6 +/- 25.2, p = 0.03), shorter duration of hospitalization (14.9 +/- 16.7 vs. 25.7 /- 17.9 days, p = 0.03), and lower hospital charges ($138,700 +/- $23,500 vs. $206,400 +/- $34,000). ATIII concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome.

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.

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.

Drug-induced parkinsonism after allogeneic bone marrow transplantation.

We report a severe case of drug-induced parkinsonism (DIP) after allogeneic BMT successfully treated with levodopa. BMT patients typically receive numerous medications which can cause DIP, and mild cases of DIP may remain unrecognized or be misdiagnosed. Physicians should be aware of DIP as a potential neurological complication after BMT to avoid further administration of drugs that could aggravate symptoms.

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.

Induction by interleukin-7 of lymphokine-activated killer activity in lymphocytes from autologous and syngeneic marrow transplant recipients before and after systemic interleukin-2 therapy.

Therapy with recombinant lymphokines after autologous bone marrow transplantation (ABMT) is being explored as a way to prevent relapse. Lymphokine therapy may exert an antitumor effect through a variety of mechanisms, including the induction of lymphokine-activated killer (LAK) cell cytotoxicity. We tested the ability of interleukin-7 (IL-7) to induce LAK cytotoxicity in peripheral blood mononuclear cells (PBMC) from healthy subjects and from patients early after ABMT. LAK activity was defined as lysis of Daudi by PBMC after incubation with IL-7 at 10 to 100 ng/mL or IL-2 at 1000 U/mL. PBMC from four healthy subjects were cultured with either IL-7 or IL-2. IL-7 induced LAK activity in two of the four, whereas IL-2 induced LAK activity in all four. The median percent lysis (effector-to-target ratio [E:T] 40:1) with IL-7 (23%) was lower than with IL-2 (67%). PBMC were obtained from 15 patients 27 to 84 days after autologous (n = 13) or syngeneic (n = 2) bone marrow transplantation (BMT) and tested for IL-7-induced LAK activity. Eleven exhibited significant activity (10% to 77% lysis at E:T 40:1). In contrast to the results in PBMC from normal subjects, in PBMC from ABMT patients IL-7 induced LAK activity of a magnitude similar to that induced by IL-2. Studies were also performed on PBMC from eight patients who had received IL-2 after ABMT (3.0 x 10(6) U/m2/d) for 4 days by continuous intravenous (IV) infusion. In seven of the eight patients, IL-7 induced significant LAK activity, which was higher than that seen in PBMC from ABMT patients who had not received IL-2. Thus, IL-7 reproducibly induced significant LAK activity in cells obtained early after autologous or syngeneic BMT. Indeed, such LAK activity was comparable quantitatively to that induced by IL-2. Finally, IL-7 induced an even greater LAK activity in vitro in PBMC obtained after ABMT and preactivated in vivo by IL-2 therapy. The results suggest that IL-7 may have a potential immunotherapeutic role, alone or with IL-2, after ABMT.

Prostaglandin E2 for prophylaxis of oral mucositis following BMT.

Between October 1988 and December 1990, 60 patients with leukaemia (25 with AML, 19 ALL and 16 CML) undergoing BMT were randomised in a double-blind clinical trial to receive prostaglandin E2 (PGE) (Prostin E2, 0.5 mg per tablet) or placebo for prophylaxis of oral mucositis. Patients had to dissolve tablets in the mouth three times daily starting 7 days before BMT and continuing until 21 days after BMT. The incidence of severe oral mucositis was similar for both groups, 55% in patients receiving PGE and 52% in patients receiving placebo. The duration of severe mucositis did not differ between PGE and placebo groups (chi-square 0.95, p = NS). The incidence of HSV infection was significantly higher in patients receiving PGE. Patients with HSV infection receiving PGE also had a higher incidence of severe oral mucositis. The results presented indicate that PGE is not effective for prophylaxis of oral mucositis in BMT recipients.