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Hodgkin's lymphoma (HL) patients with positive (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) post salvage chemotherapy or before high-dose chemotherapy and auto-SCT (HDC ASCT) have inferior outcomes. We reviewed 21 prognostic factors before salvage chemotherapy (at relapse/progression) and integrated post salvage FDG-PET results to develop a prognostic model for post HDC ASCT outcome. We used Fine and Gray method for competing risk analysis and regression model for risks assessment and outcome. One hundred and forty-one patients had post salvage FDG-PET before HDC ASCT (median age 25.5 years); male/female 55%:45%, relapsed/refractory 43%:57%, median follow-up 33 months. Multivariate analysis identified HL International Prognostic Score 3 (P=0.001; hazard ratio (HR): 3.7 (1.6-8.3)) and post salvage positive FDG-PET (P=0.011; HR: 3.4 (1.3-8.9)) with higher hazard of disease-specific death (model P=0.0001). Cumulative incidence of disease-specific death with 0, 1, 2 risk factors was 7%:29%:52%, respectively (P=0.00003). For disease-specific event (persistent, progressive or relapsed disease), mediastinal involvement (P=0.024; HR: 2.7 (1.14-6.5)), B symptoms (P=0.027; HR: 2.1 (1.09-4.2)) and positive post salvage FDG-PET (P=0.001; HR: 3.3 (1.7-6.7)) were significant (model P=<0.00001). Cumulative incidence of disease-specific event with 0, 1, 2, 3 risk factors was 8%:31%:50%:75%, respectively (P=0.0000006). Patients with higher scores have higher risk of treatment failure. They are potential candidates for newer therapies along with HDC ASCT.

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.

Our purpose was to assess efficacy and toxicity of high-dose chemotherapy (HDCT) and ASCT in patients with relapsed and refractory Hodgkin's lymphoma (HL) aged 60 years and older and compare the results with a group of younger HL patients treated in a similar manner. We identified 15 consecutive patients, with HL aged 60 years and older who underwent HDCT (etoposide 60 mg/kg+ melphalan 160 mg/m(2)) and ASCT at our institution from May 2001 to March 2008. The results were compared with a cohort of 157 younger HL patients treated in a similar manner from January 1999 to December 2006. After a median follow-up of 2.5 years, PFS at 3 years after ASCT was 73% (95% confidence interval (CI) 37-90) for the older group and 56% (95% CI 46-64) for the younger group (P=0.45); OS after ASCT was 88% (95% CI 39-98) for the older group and 84% (95% CI 75-90) for the younger group (P=0.80). No transplant-related deaths were seen. Our study suggests that ASCT is feasible for selected elderly patients with HL, giving similar results to younger patients in terms of survival and toxicity.

The CXCR4-inhibitor plerixafor mobilizes hematopoietic stem cells amplifying the effects of granulocyte-CSF (G-CSF). Before approval plerixafor was used in a compassionate use program (CUP) for patients who failed a previous mobilization. In the German CUP 60 patients from 23 centers (median age 56.5 years (2-75)) were given 240 μg/kg plerixafor SC 9-11 h before apheresis. A total of 78.3% (47/60) received G-CSF for 4 days before plerixafor administration; 76.6% of those (36/47) yielded at least 2.0 × 10(6) CD34(+) cells/μL. The median cell yield was 3.35 × 10(6) CD34+ cells/kg (0-29.53). Nine patients received plerixafor alone or with G-CSF for less than 4 days mobilizing a median of 3.30 × 10(6) CD34+ cells/kg (1.6-5.6). There was no significant difference between G-CSF application for 4 days and for a shorter period of time (P=0.157). A total of 47 patients received plerixafor plus G-CSF combined with chemotherapy yielding a median of 3.28 × 10(6) CD34+ cells/kg (0-24.79). In all, 40 of 60 patients (66.7%) proceeded to transplantation, and achieved a timely and stable engraftment. Side effects were rare and manageable. In conclusion, mobilization with plerixafor in poor mobilizers is safe and results in a sufficient stem cell harvest in the majority of patients.

PBSCs are usually mobilized using G-CSF with or without chemotherapy. With the emergence of newer mobilizing agents, predicting poor mobilization may allow early intervention and prevent the costs and complications associated with remobilization. We retrospectively evaluated a cohort of 1556 patients seen between January 2000 and September 2008 with multiple myeloma (565; 36%), non-Hodgkin's lymphoma (NHL) (562; 36%), amyloidosis (345; 22%) or Hodgkin's disease (94; 6%), who were initially mobilized with single agent G-CSF. Sensitivity and specificity analysis was used to identify ideal peripheral blood CD34 count (PB-CD34) cutoff points that predicted successful collection. In patients with plasma cell disorders, a PB-CD34 count of 11, 17, 21 and 28/μL by day 4 or 5 was required to collect a target of 2, 4, 8 or 12 million cells/kg, respectively. A CD34 yield of <0.8 million cells/kg on first apheresis also predicted for <2 million CD34 cells/kg. For patients with NHL or Hodgkin's disease, a PB-CD34 count of <6 and <15/μL on day 4 or 5 predicted failure to achieve a target collection of 2 and 4 million cells/kg, respectively. This study suggests that PB-CD34 thresholds should be based on collection target to allow for early intervention and to prevent collection failures.

Abnormalities in liver function tests are common in hematopoietic SCT (HSCT) recipients. We retrospectively investigated the role of liver biopsy in determining the cause of elevated liver enzymes and its impact on the management of patients in the post-HSCT setting. A total of 24 consecutive liver biopsies were obtained from 20 patients from September 2003 to December 2007. A definite histopathologic diagnosis was obtained in 91.7% of the biopsies. Iron overload (IO) was found in 75% and GVHD in 54.2% of the patients. The initial clinical diagnosis of GVHD was confirmed in 56.5% and refuted in 43.5% of the allogeneic HSCT recipients. The median number of post transplant transfusions, percent transferrin saturation and ferritin levels were found to be higher in patients who had histologically proven hepatic IO (p1=0.007, p2=0.003 and p3=0.009, respectively). Regression analysis showed a significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes. Our data suggest that hepatic IO is a frequent finding in the post-HSCT setting, which contributes to hepatic dysfunction and it should be considered in the differential diagnosis, particularly in patients with high serum ferritin levels.

Forty six patients with lymphoid malignancies receiving autologous transplants using three different sources of hematopoietic stem cells were compared for engraftment parameters. Thirteen patients (five with multiple myeloma, seven with non-Hodgkin's lymphoma and one with Hodgkin's lymphoma) received autologous marrow with post-transplant growth factors (group 1). During the same time interval, 14 patients (five with multiple myeloma, six with non-Hodgkin's lymphoma and three with Hodgkin's lymphoma) were transplanted with autologous marrow plus recombinant granulocyte colony-stimulating factor (rhG-CSF)-mobilized peripheral blood stem cells (PBSC) and post-transplant growth factors (group 2). Nineteen patients (seven with multiple myeloma and 12 with non-Hodgkin's lymphoma) received rhG-CSF mobilized PBSC and post-transplant growth factors (group 3). All PBSC were collected after G-CSF mobilization (16 micrograms/kg/day s.c. for 6 days) without prior chemotherapy. After high-dose myeloablative chemotherapy or chemoradiotherapy, the median days to recovery of neutrophils to levels of 0.5 and 1.0 x 10(9)/l were 12 vs. 9 vs. 9 days (P = 0.0003 (group 1 vs. group 2) and P = 0.53 (group 2 vs. group 3)) and 13 vs. 10 vs. 10 days (P = 0.0003 (group 1 vs. group 2) and 0.92 (group 2 vs. group 3)) for groups 1, 2 and 3, respectively. The median day to platelet transfusion independence was 22 vs. 11 vs. 11 days (P = 0.001 (group 1 vs. group 2) and P = 0.50 (group 2 vs. group 3)) for groups 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied 23 consecutive patients, median age 34 years, with relapsed or resistant aggressive lymphoma who underwent allogeneic BMT at the UCLA Medical Center Bone Marrow Transplantation Unit from 1 November 1984 to 30 March 1993. All patients were < 50 years of age and had sibling donors who were matched at the HLA-A, B and DR loci. Nine patients had Hodgkin's disease (HD) and 14 had non-Hodgkin's lymphoma (NHL); three of these had low grade histology and 11 had intermediate or high grade lymphoma histology. After a median follow-up of 34 months, eight patients are alive, seven without recurrent lymphoma. Five patients had early deaths. The disease-free survival for the entire group is 26% with an overall survival of 29%. There was no difference in survival rate on the basis of disease or histology. Comparing preparative regimens containing TBI to those without there was no difference in survival rate (P = 0.35). Neither age nor sex was a significant determinant of outcome (P = 0.63 and 0.36, respectively). Disease status at the time of transplantation proved to be the important determinant of outcome. Patients transplanted with chemotherapy sensitive disease (n = 9), defined as a partial or complete response to salvage chemotherapy, had a survival rate of 42%, which was significantly better than those who had refractory disease at transplantation (n = 14), who had a survival rate of 21% (P = 0.006). However, this small, but significant fraction of patients with refractory disease was curable. Thus, our data demonstrate that allogeneic bone marrow transplantation is an effective means of treatment for relapsed or aggressive Hodgkin's and non-Hodgkin's lymphoma.

We evaluated the effect of oral ciprofloxacin on neutrophil recovery in 20 consecutive patients undergoing autologous bone marrow transplantation (BMT) for malignant lymphoma and compared the results with a control group of 20 patients receiving co-trimoxazole and folinic acid. Both groups started the prophylactic antibiotic as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) the day after marrow infusion and continued the former until the onset of febrile neutropenia (median duration of treatment 6 days for co-trimoxazole and 7 days for ciprofloxacin). The time of attain an absolute neutrophil count > or = 0.5 x 10(9)/L was significantly shorter in patients receiving ciprofloxacin (16 days vs 22 days; P = 0.006). There was no difference in time to attain a platelet count > or = 20 x 10(9)/L independent of transfusion or in time to the first febrile episode or incidence of bacteremia. We conclude that antibiotic prophylaxis with ciprofloxacin results in more rapid neutrophil recovery than prophylaxis with co-trimoxazole. This may result from a myelosuppressive effect of co-trimoxazole or an enhancement of neutrophil recovery by ciprofloxacin, or both.

In 54 patients with malignant lymphoma, haematopoietic recovery after high-dose chemotherapy and autologous bone marrow transplantation (BMT) was compared between patients randomised to receive 10 or 30 micrograms/kg/day of r-metHuG-CSF (filgrastim) or no growth factor. After standard high-dose chemotherapy with cyclophosphamide, etoposide and BCNU (CVB regimen for patients with Hodgkin's disease) or BCNU, etoposide, cytosine arabinoside and melphalan (BEAM regimen for patients suffering from non-Hodgkin's lymphoma) followed by autologous BMT, r-metHuG-CSF was administered by continuous intravenous infusion from the first day after autologous BMT until neutrophil recovery. When the r-metHuG-CSF groups were compared with the control group the major findings were: the median time to reach an absolute neutrophil count (ANC) > or = 0.5 x 10(9)/L was 20 days in the control group and 12 and 14 days, respectively, in the r-metHuG-CSF groups (P = 0.0004). The duration of neutropenia (ANC < 0.5 x 10(9)/L) was reduced from 27 days in the control group to 11 and 13 days in the r-metHuG-CSF groups (P = 0.0001). In addition, fewer days of febrile neutropenia were observed in the r-metHuG-CSF groups (5 and 6 days) than in the control group (10 days; P = 0.036). No significant effects of r-metHuG-CSF administration on the number of days with fever, the use of intravenous antibiotics and hospitalisation were detected. R-metHuG-CSF was well tolerated without any serious side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Conditioning regimens for allogeneic bone marrow transplantation are designed to eradicate malignant cells and to provide sufficient immunosuppression for engraftment of donor marrow. Total body irradiation and high-dose cyclophosphamide are the most established immunosuppressive agents used for this purpose. It is uncertain whether other alkylating agent-based conditioning regimens are sufficiently immunosuppressive to allow engraftment of allogeneic marrow. We report four patients who had prompt engraftment after conditioning with melphalan-based chemotherapy regimens (BEAM or busulfan/melphalan). Two patients survived without disease for a prolonged period, indicating that these melphalan regimens are sufficiently immunosuppressive to allow sustained engraftment and donor hematopoiesis.

We investigated the incidence of peripheral neuropathy in 142 consecutive patients receiving high-dose etoposide between August 1988 and December 1991. A retrospective chart review was conducted. Six patients with hematologic malignancies presented with a new sensory polyneuropathy after receiving an intensive therapy regimen consisting of etoposide 60 mg/kg i.v. and melphalan 140-160 mg/m2 i.v. followed by autologous bone marrow transplantation. Neurologic symptoms began 2-8 weeks after transplant, were grade 2-3 in severity and pursued a chronic course with slow improvement over months. Electromyographic studies in three of the patients tested confirmed distal sensory polyneuropathy. All 6 patients had previously received vincristine 1-60 months prior to autotransplant. We conclude that peripheral neuropathy of moderate severity is a potential complication of high-dose etoposide therapy but appears to be self-limited.

We report a case of sustained disease-free survival following second autologous marrow transplantation (BMT) in a patient with Hodgkin's lymphoma which had recurred following several conventional chemotherapy regimens as well as a prior autologous transplant. The initial autologous BMT was performed in fourth complete remission and followed high-dose cyclophosphamide, etoposide and thiotepa. The disease recurred 8 months later and the patient underwent a second ABMT following conditioning with busulfan and cyclophosphamide 1 year after his first transplant. Aside from slow engraftment, his course was uncomplicated. This patient remains in complete remission more than 4 years and 6 months following the second transplantation. This case demonstrates that second autologous transplantation can result in sustained disease-free survival in individuals with Hodgkin's disease with recurrence following initial transplantation.

G-CSF and GM-CSF enhance the rate of neutrophil engraftment in autologous bone marrow transplantation (ABMT) without significantly affecting platelet engraftment. Peripheral blood progenitor cells (PBPC) may enhance rates of engraftment of both neutrophils and platelets. We treated 49 patients undergoing ABMT with a course of G-CSF to obtain PBPC and infused these cells post-transplant with G-CSF in an attempt to determine factors which might correlate with enhanced BM engraftment. Forty-nine patients with Hodgkin's disease, non-Hodgkin's lymphoma or breast cancer undergoing unpurged ABMT were studied. G-CSF priming consisted of an outpatient 8 day course of 5 micrograms/kg/day followed by three leukaphereses (on day 5, 7 and 8) to collect PBPC. Patients then received a chemotherapeutic BMT preparative regimen followed by an infusion of PBPC, autologous BM and the reinstitution of G-CSF (16 micrograms/kg/day). BM engraftment was rapid. The median time to achieve 0.5 x 10(9)/l neutrophils was 10 days compared with a historical BMT control patient population receiving the same preparative regimens of 19 days (p = 0.001). Time to achieve a platelet count of 20 x 10(9)/l was 16 days compared with a historical control of 22 days (p = 0.001). Neutrophil engraftment occurred in all patients by day +14. Marrow engraftment correlated with the total number of CD34+ cells infused as well as the total number of mononuclear cells infused but not the total number of CD34+/CD33- cells infused. The amount of total blood volume pheresed significantly correlated with yield of total mononuclear cells. Prior exposure to radiation therapy negatively correlated with progenitor cell yield.(ABSTRACT TRUNCATED AT 250 WORDS)

In the present study, plasma prostaglandin E2 (PGE2) levels were quantitated serially in 14 patients during the period preceding and following autologous bone marrow transplantation (ABMT) or autologous stem cell transplantation (ABSCT). In eight ABMT recipients, the pre-transplant conditioning regimen consisted of combined supralethal doses of chemo- and radiotherapy which was followed by ABMT using autografts purged in vitro either with mafosfamide or monoclonal antibodies (moAbs) plus immunomagnetic beads (IB). A further two ABMT recipients received only high-dose chemotherapy without irradiation as conditioning, followed by unpurged autologous BM. The four ABSCT recipients were also treated solely with chemotherapy followed by untreated autologous stem cell reinfusion. Elevation of plasma PGE2 levels occurred in all 14 patients, despite the difference in the pre-transplant conditioning. The peak levels of PGE2 ranged from about three times the mean value obtained with ten control individuals (29.8 +/- 3.7 pg/ml) to ten times this level. In all cases plasma PGE2 normalised with recovery of the peripheral leucocyte count.

We conducted a phase I/II study to determine the efficacy, toxicity and maximum tolerable doses of CY, etoposide and cisplatin (CEP) in the management of patients with relapsed or refractory malignant lymphoma. Thirty patients with relapsed or refractory Hodgkin's disease (n = 10) or non-Hodgkin's lymphoma (n = 20) received CY 6000 mg/m2, etoposide 900-2700 mg/m2 and cisplatin 150 mg/m2 followed by autologous BM or autologous peripheral blood stem cell rescue. The dose of etoposide was escalated after each 3 to 4 patients. The maximum tolerated dose of etoposide, when administered with the indicated doses of CY and cisplatin, was 2400 mg/m2. Three of the 30 patients (10%) died of treatment-related toxicity. Although 14 of the 30 patients had residual bulky and/or chemotherapy-resistant disease at the time of the transplant, 26 patients (87%) responded to this regimen, including 18 patients (60%) who achieved CR and 8 patients (27%) who achieved partial remission. Seven patients (23%) remain alive and free of progression at a median of 21 months post-transplant. Three additional patients relapsed after transplant but are enjoying prolonged disease-free survival at a median of 31 months post-transplant following additional post-transplant therapy. We conclude that high-dose CY, etoposide and cisplatin followed by autologous BM or peripheral blood stem cell rescue is an active and acceptably tolerated regimen in the treatment of relapsed or refractory malignant lymphoma.

The results of autologous and allogeneic BMT in 44 patients with Hodgkin's or non-Hodgkin's lymphomas who received preparative therapy consisting of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg are presented. Sixteen patients are surviving free of disease between 8 months and 6 years after transplantation. Thirteen patients either did not attain complete remission or experienced a recurrence of their disease. Fifteen patients died from treatment-related complications. Karnofsky score < or = 70, lactate dehydrogenase greater than twice normal and the development of hepatic veno-occlusive disease were associated with failure to achieve lymphoma-free survival.

Immunotherapy using subcutaneous injections of recombinant interleukin-2 (IL-2) and recombinant interferon alpha-2a (IFN-alpha) for advanced hematologic and solid tumors is rapidly developing. We report five patients with Hodgkin's and non-Hodgkin's lymphoma who developed a local cutaneous reaction consisting of inflammatory painful nodules with a central multiloculated vesicle at the site of sc injections of IL-2 and IFN-alpha immunotherapy following ABMT. This is the first report of a local cutaneous adverse reaction induced by IL-2 and IFN-alpha immunotherapy following ABMT.

We performed a retrospective analysis of 42 consecutive patients undergoing autologous BMT to determine the incidence of second and third degree heart block following the infusion of cryopreserved autologous bone marrow and to identify any predisposing characteristics. A decrease in heart rate > or = 10 beats/min was observed in 80.5% of patients, with a mean decrement of 27 +/- 7 beats/min. 48.8% of patients developed absolute bradycardia (< or = 60 beats/min). Four of 41 patients (9.7%) experienced high-grade heart block: 9.7% second degree and 4.8% third degree. Heart block patients did not differ from the non-heart block group with respect to age, interval from diagnosis or bone marrow harvest to transplant, cardiac risk factors, pretransplant electrocardiograms or radionuclide angiograms, transplant chemotherapy regimens or serum chemistry values. There was an increased incidence of heart block in patients with prior exposure to cyclophosphamide (p < 0.05) and vinca alkaloids (p < 0.05). There appears to be a high incidence of transient second and third degree heart block following autologous marrow infusion. This may be related to prior chemotherapy, but more likely is an effect of the infusate itself. Predisposing factors were not identified.

Thirty patients with relapsed pediatric solid tumors received high-dose carboplatin and etoposide with autologous marrow support in a dose-escalation trial. These patients had received extensive prior treatment, which included both cisplatin and etoposide in 25 cases. Six patient cohorts received carboplatin in doses of 1200-2100 mg/m2 and etoposide in doses of 960-1500 mg/m2. All courses were associated with severe neutropenia and thrombocytopenia. The median times from bone marrow infusion to granulocyte recovery (> 0.5 x 10(9)/l) and platelet recovery (> 50 x 10(9)/l) were 33 and 28 days, respectively, with similar findings for all dosage levels. The frequency of non-hematologic toxicities was generally low, although hyponatremia (Na+ < 129 mEq/l) was seen in one-third of the courses. Hepatoxicity was dose-limiting and was significantly associated with the cumulative prior cisplatin dose (p = 0.006). There were four toxic deaths (CNS hemorrhage, alfa-streptococcal sepsis, Candida sepsis, and enterocolitis). Eleven patients received a second course of therapy; toxicity profiles and times to hematologic recovery were similar for the two courses. Clinical responses were observed at all dosage levels. Eleven of 26 evaluable patients achieved a clinical response (one complete, 10 partial). The majority of responses were in patients with neuroblastoma (six of 16) or Hodgkin's disease (two of three). For phase II clinical trials, we recommend dosages of 2100 mg/m2 of carboplatin and 1500 mg/m2 of etoposide for children with prior cumulative cisplatin exposure < 960 mg/m2. This carboplatin dose represents a three- to four-fold increase over pediatric doses tolerated without bone marrow support.

Fourteen patients with relapsed Hodgkin's disease responded to a salvage therapy with Dexa-BEAM (dexamethasone, BCNU, etoposide, Ara-C and melphalan). In seven patients a continuous i.v. infusion with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was started subsequent to Dexa-BEAM (+rhGM-CSF) while the other seven patients received no hemopoietic growth factor (-rhGM-CSF). It was our objective to study the impact of rhGM-CSF on the collection of blood-derived hemopoietic stem cells in patients with extensive prior chemo- and radiotherapy not eligible for marrow harvest. Compared to baseline, we observed a significant increase of colony-forming units granulocyte-macrophage (CFU-GM) in the peripheral blood of patients receiving rhGM-CSF (p less than 0.05). On average, the yield of total nucleated cells and CFU-GM collected per single leukapheresis was 2.2 and 2.4-fold higher in the rhGM-CSF-treated patients respectively (p less than 0.05). With rhGM-CSF the interval from the start of chemotherapy to the end of blood stem cell collection could be reduced by 6 days (p less than 0.05). Following the CBV pretransplant regimen (cyclophosphamide, BCNU, etoposide), the reinfusion of rhGM-CSF-exposed stem cells resulted in a shorter time of leukocyte recovery (p less than 0.05). The number of CFU-GM/kg body weight transplanted was found to be predictive for the time of neutrophil recovery (p less than 0.05). In patients with bone marrow hypoplasia or fibrosis, rhGM-CSF as part of an effective salvage therapy improves the collection of blood stem cells that are capable of restoring hemopoiesis after high-dose pretransplant therapy.

Thirty-eight patients with refractory or relapsed non-Hodgkin's lymphoma (19 patients) or Hodgkin's disease (19 patients) were treated with salvage therapy. The peripheral stem cell collection was performed during hematologic recovery after myeloablative chemotherapy. In eight patients with Hodgkin's disease the number of CFU-GM collected was less than 0.5 x 10(4)/kg and these patients were excluded for stem cell transplantation. In the remaining 30 patients, a median of 4 x 10(4) CFU-GM/kg was collected (range 0.8-100 x 10(4)/kg) by three leukaphereses in 25 patients and six to 11 leukaphereses in five patients. Conditioning regimens were CBV (eight), BEAM (six), BEAC (10) and cyclophosphamide + total body irradiation (TBI) (six). Without TBI, the mean time for reaching a granulocyte count greater than 0.5 x 10(9)/l was 18 days and for a platelet count greater than 50 x 10(9)/l was 19 days in 23 out of 24 patients. With TBI, in five patients the mean time for reaching a granulocyte count greater tahn 0.5 x 10(9)/l was 37 days and for a platelet count greater than 50 x 10(9)/l was greater than 100 days. Complications were minor. There was only one toxic death. The outcome in these patients was similar to that observed in patients who received autologous bone marrow transplantation for advanced lymphomas. In conclusion, we observed good hematologic recovery except when TBI was used in the conditioning regimen.

To investigate the possibility that a hypercoagulable state develops during autologous bone marrow transplantation (BMT), we measured levels of circulating natural anticoagulants and fibrinolytic proteins before and weekly during the hospital course of 18 patients undergoing autologous BMT for Hodgkin's and non-Hodgkin's lymphoma. Patients received either weekly (standard dose group) or daily (high dose group) vitamin K supplements with their total parenteral nutrition. By day 14 there had been a significant drop in protein C activity (mean of 95% of normal to 52%), protein C antigen (mean of 105% of normal to 70%), and antithrombin 3 activity (111% of normal to 83%), and an increase in fibrinogen (471-621 mg/dl) and tissue plasminogen activator (6.9-13.8 ng/ml). No changes were seen in free or total protein S, plasminogen activator inhibitor, prothrombin time or partial thromboplastin time. The decreases in protein C and antithrombin 3 persisted through day 28 after transplantation. The drop in protein C correlated strongly with decrease in serum albumin, suggesting impaired synthesis of these proteins by the liver. No differences were seen in any of these parameters between the standard and high dose groups. Deficiencies in anticoagulant proteins antithrombin 3 and protein C and a rise in fibrinogen without a concomitant improvement in fibrinolytic variables create a potentially hypercoagulable state which may contribute to the thrombotic complications of autologous BMT.

Fifteen patients with very poor prognosis Hodgkin's disease in remission after MOPP/ABVD regimen, were treated with high-dose chemotherapy (HDC) and autologous marrow transplantation (ABMT) immediately after achieving complete remission (CR). Thirteen patients (86.6%) remain alive in unmaintained CR at a median time of 36 months (range 10-64 months) post-transplant. In the other two patients reasons for failure included relapse of Hodgkin's disease (one patient) and death due to interstitial pneumonitis secondary to carmustine therapy. These patients were compared with a historical control group consisting of 24 patients with the same poor prognostic factors, who achieved CR with MOPP/ABVD and did not receive other treatment. Eight out of 24 patients (33%) remain alive and well in unmaintained CR at a median time of 42 months (range 19-83 months). The administration of MOPP/ABVD combined with HDC and ABMT was not associated with an increased incidence of major toxicity. The results achieved support the early sequential treatment of a highly effective drug combination followed by HDC/ABMT that can substantially improve the likelihood of cure in these advanced stage very poor prognosis Hodgkin's disease patients.

We report the results of intensive therapy and autologous bone marrow transplantation (BMT) in 23 patients with malignant lymphoma (eight Hodgkin's disease and 15 non-Hodgkin's lymphoma) who failed primary therapy. All patients had evidence of disease prior to transplant therapy: 10 had never achieved a complete remission and 13 were in relapse. The preparative regimen included involved field radiation followed by fractionated total body irradiation and high dose cyclophosphamide. A complete remission was achieved in 15 patients, 11 of whom continue in unmaintained complete remission from 27 to 72 months after BMT (median follow-up of 52 months). Of the remaining patients, five did not achieve a complete remission and three died of early toxicity. The event-free survival of the entire group is 47%. Disease status at the time of BMT was significantly correlated with patient outcome. The event-free survival of 13 patients in whom there was no objective evidence of tumor growth on conventional dose therapy was 77% compared with only 10% in patients with tumors progressing on conventional dose therapy (p less than 0.002). All six patients transplanted in untreated relapse continue in unmaintained remission, suggesting that debulking chemotherapy may not be necessary before BMT. Alternative approaches are needed in patients whose tumors progress on conventional dose therapy.

Forty-six patients with refractory malignant lymphoma (Hodgkin's and non-Hodgkin's) admitted for autologous marrow or peripheral blood stem cell transplantation (ASCT) were evaluated for the presence of hemostatic abnormalities known to be associated with a hypercoagulable state in other patient populations. All patients had received numerous chemotherapeutic agents in the past and often radiation therapy as well. Hemostatic abnormalities were found to be common in these patients. The most frequent finding was hyperfibrinogenemia, present in 35% of patients. Decreased protein C activity was present in 32% of patients. Protein C antigen was low in only one individual and protein S was normal or increased in all patients. Low levels of antithrombin III were present in 16%. Plasminogen activator inhibitor was elevated in 20%. Anticardiolipin antibodies were present in 29% of patients; other evidence of a lupus anticoagulant was present in only eight patients. The frequency of each hemostatic abnormality was similar for patients with Hodgkin's disease (HD) and those with non-Hodgkin's lymphoma (NHL) despite the fact that significantly more patients with HD had received irradiation and/or previous splenectomy than patients with NHL. We conclude that multiple prothrombotic abnormalities of hemostasis are present in patients with refractory lymphoma referred for ASCT. Whether these are the result of lymphoma or the result of therapy cannot be determined from this study.

The incidence of varicella-zoster-virus infection/reactivation in adult patients with Hodgkin's disease undergoing autologous bone marrow transplantation (BMT) at the University of Minnesota Hospital and Clinic was determined. Seven of 28 evaluable patients (25%) developed varicella-zoster infections in the first 150 days post-transplant. Two additional patients developed zoster after day 150 for a total incidence of 32%. We evaluated analysed risk factors to determine if there were any characteristics that could identify patients at risk for zoster early (less than 150 days) in their post-transplant course. Sex, age, prior radiation, and lack of immunity as determined by viral antibody titers were not associated with an increased incidence. Ten of the 28 patients had a history of zoster at some time after the diagnosis of Hodgkin's disease. Six of these 10 patients (60%) again developed zoster post-transplant. This compared to only one episode of varicella-zoster post-transplant among the 18 patients without a history of zoster following the diagnosis of Hodgkin's disease (p less than 0.01, Fisher's exact). We conclude that a prior history of zoster any time after diagnosis of Hodgkin's disease is strongly associated with developing zoster in the first 150 days after autologous BMT.

A 27-year-old woman undergoing autologous bone marrow transplantation for relapsed, refractory Hodgkin's disease developed acute non-cardiogenic pulmonary edema immediately after transfusion of autologous bone marrow. A few similar cases in the literature are identified. Although the precise mechanisms for these rare reactions are not clear, several possibilities including anaphylaxis due to dimethylsulfoxide, leukoagglutination, complement activation, and transient left ventricular dysfunction are proposed and discussed. Features which might allow patients at risk for similar events to be identified include the presence of active pulmonary tumor, and a history of dyspnea and pulmonary infiltrates following transfusion of homologous blood products.

Long-term indwelling central venous catheters have eased the administration of drugs, blood products, and hyperalimentation to patients with cancer. However, their use is associated with thrombotic complications. We report here on the thrombotic complications prospectively observed in 46 patients with refractory lymphoma (22 Hodgkin's disease, 24 non-Hodgkin's lymphoma) who had placement of one or more catheters in preparation for autologous stem cell transplantation (ASCT). Thrombosis of 26 catheters in 19 patients was observed. Specific abnormalities of hemostasis were equally common in patients who developed thrombosis and in those who did not. Thrombotic complications were more common in patients with Hodgkin's disease (13/22) than in patients with non-Hodgkin's lymphoma (6/24, p = 0.04). Although more patients with Hodgkin's disease had received prior splenectomy and/or irradiation to the area involved by thrombosis than patients with non-Hodgkin's lymphoma, the incidence of splenectomy and irradiation was similar for patients with Hodgkin's disease who developed thrombosis and those who did not. Therefore, although the etiology remains unexplained, patients with Hodgkin's disease undergoing intensive chemotherapy and ASCT appear to have a higher incidence of catheter-related thrombosis than patients with non-Hodgkin's lymphoma undergoing similar therapy.

To test the value of recombinant human granulocyte-macrophage colony stimulating factor for the treatment of delayed engraftment following high dose therapy and autologous hematopoietic stem cell transplantation, we enrolled 12 patients with recurrent non-Hodgkin's lymphoma or Hodgkin's disease having an absolute granulocyte count less than 150 x 10(6)/l on day 30 after autologous hematopoietic stem cell infusion in an open-label, nonrandomized study. These patients were compared to 21 similar historical control patients who were not treated with colony stimulating factor. Overall, the patients treated with granulocyte-macrophage colony stimulating factor had a mean absolute granulocyte count of 704 x 10(6)/l on day 44 after stem cell infusion compared to a mean absolute granulocyte count of 408 x 10(6)/l in historical controls (p = 0.008). The number of documented bacterial and fungal infections occurring after day 30 (9 vs 0, p = 0.01) was significantly reduced in the study group. The toxicity attributed to the granulocyte-macrophage colony stimulating factor was minimal with only one patient experiencing chills. Recombinant human granulocyte-macrophage colony stimulating factor appears to be effective for the treatment of delayed engraftment following high-dose therapy and autologous hematopoietic transplantation for lymphoid malignancies, with most patients having accelerated granulocytic recovery and a reduced incidence of infections.

Evidence has accumulated which indicates that efficacy of chemotherapy correlates with dose intensity and with total dose. For most cytotoxic agents, the major limiting factor for escalation of dose intensity is myelotoxicity. Attempts have been made to circumvent myelotoxicity by autologous bone marrow transplantation. Recently, it has been demonstrated that progenitors enriched from the peripheral blood can also be used successfully for autografting. The concentration of progenitor cells in peripheral blood is lower than that in bone marrow but myelosuppressive chemotherapy or hematopoietic growth factors, or a combination of both can be exploited to enhance the progenitor cell yield. The studies reported here are sequential. In the first study, eight patients with advanced Hodgkin's disease received myelosuppressive regimen consisting of cytarabine (100 mg/m2/12h SC days 1 to 5) and daunorubicin (45 mg/m2/d, days 3 and 4). Progenitor cell leukapheresis was performed during the rebound phase of hematopoiesis. All eight patients were treated with super-dose chemotherapy with progenitor cell transplantation. One patient died of CNS toxicity 48 days after transplantation but all other seven had sustained engraftment. In the second study, human recombinant GM-CSF (at 250 micrograms/m2/d as continuous infusion) was administered to twelve patients. Leukapheresis was started at a white blood count (WBC) of greater than 10 x 10(9)/L and the dosage of rhGM-CSF adjusted to keep the WBC between 10 x 10(9)/L and 20 x 10(9)/L. The median duration of rhGM-CSF application was 11.5 days and a median number of six leukaphereses performed. The median increase in the number of granulocyte-macrophage colony forming units (CFU-GM)/ml of peripheral blood was 8.5 fold.(ABSTRACT TRUNCATED AT 250 WORDS)

We asked in a retrospective analysis whether patients with diabetes mellitus or impaired glucose tolerance are at increased risk for morbidity and mortality after high-dose therapy followed by an autologous bone marrow transplantation. Nine patients with diabetes mellitus (n = 7) or impaired glucose tolerance (n = 2) were identified who had been treated with high-dose therapy and autologous bone marrow transplant for lymphoid malignancies. At the start of the pretransplant conditioning all patients had a Karnofsky score of at least 80 and no clinically demonstrable organ dysfunction. One patient with diabetes mellitus type I (DM I) was transplanted without any complications. The patients with diabetes mellitus type II (DM II) or an impaired glucose tolerance had complications of life-threatening infections (in 6/8), acute renal insufficiency (in 3/8), liver abnormalities with elevated liver enzymes or liver failure (in 4/8) and congestive heart failure (in 1/8). Although the complications observed are not infrequent in the transplant setting, because of the good performance status before BMT and the absence of clinically demonstrable organ impairment before transplantation, it is our impression that the presence of diabetes mellitus or glucose intolerance might be an important co-factor in the morbidity of these patients.

A patient with refractory Hodgkin's disease whose persistent, dense marrow infiltration precluded autologous marrow harvest underwent peripheral blood stem cell harvest followed by intensive chemotherapy and re-infusion of the peripheral blood stem cells. Complete remission was followed by relapse 6 months later and death 13 months post-transplant. However, at no time post-transplant was evidence of marrow recurrence demonstrated. This case indicates that remission can be achieved using peripheral blood stem cell transplants despite persistent marrow involvement with Hodgkin's disease.

Based on observations that bulky disease at autologous bone marrow transplantation (ABMT) may be correlated with poor outcome in Hodgkin's disease, we have assessed the ability of conventional-dose chemoradiotherapy to reduce tumour burden to a minimum prior to ABMT. Thirty-seven patients with relapsed or refractory Hodgkin's disease referred for intensive therapy and ABMT were treated initially with one to five cycles of DHAP chemotherapy. All patients had previously received MOPP and ABVD chemotherapy or similar regimens. Four patients achieved complete remission (CR) and 12 partial remission (PR), for a total response rate of 43%. Eight partial responders and four non-responders to DHAP achieved significant further tumour reduction with local radiotherapy (five CR, seven PR). Six of 10 non-responders to DHAP responded to alternative salvage chemotherapy (mini-BEAM, CEP or augmented CVP). Overall, 24/37 patients (65%) achieved effective cytoreduction (nine CR, 15 PR with minimal disease) and have proceeded to ABMT. Patients with bulky disease at relapse or limited stage (II, IIIA) at diagnosis were less likely to respond to DHAP, but some of these could be cytoreduced with alternative therapy. In addition, the number of prior chemotherapy regimens correlated inversely with likelihood of response to DHAP. The results indicate that approximately two-thirds of patients with Hodgkin's disease who relapse after MOPP and ABVD-like regimens can achieve effective cytoreduction with conventional-dose chemoradiotherapy and proceed to ABMT in CR or PR with minimal disease.

The natural anticoagulants, protein C, protein S and antithrombin, were measured in 21 patients following bone marrow transplantation (BMT). The patients were divided into two groups, those with normal protein C concentration post-BMT and those with significantly reduced protein C concentrations; 12 cases fell into the second group. In addition there was an associated fall in protein S in this group of patients. In spite of the presumed hypercoagulable state only one patient developed overt veno-occlusive disease (VOD) of the liver and no other thrombotic events occurred. The fall in protein C and protein S was coincident with the peak incidence of VOD and is likely to be a contributing factor to the genesis of this condition. Only protein S measured pre-BMT was of predictive value in identifying patients likely to develop reduced levels of these anticoagulants post-BMT. Age, sex, diagnosis, type of conditioning and the pre-BMT measurement of protein C and antithrombin had no predictive value.

Thirty-one patients with resistant Hodgkin's disease were treated by an identical high dose chemotherapy regimen and autologous bone marrow transplantation. Twelve of these patients received recombinant human granulocyte/macrophage colony stimulating factor (rh GM-CSF) in a phase I/II study. rh GM-CSF was administered by continuous infusion into an indwelling central venous catheter for 3-21 days at doses of 100-400 micrograms/m2/day. The patients receiving rh GM-CSF did not differ significantly from those who did not receive growth factor with regard to age, previous therapy or number of bone marrow cells infused. rh GM-CSF resulted in more rapid neutrophil regeneration, the average time to achieve a neutrophil count of greater than or equal to 0.5 x 10(9)/l being 17.5 days compared to 24.9 days in the control group (p less than 0.01). Platelet recovery was very varied and not accelerated by rh GM-CSF. Patients receiving rh GM-CSF had a similar infection rate (58% vs 68% in the control group), similar number of febrile days (5.0 vs 4.7 days) and similar period of hospitalization to the control group (30.1 vs 30.2 days). Randomized controlled trials are now required to define the clinical value of rh GM-CSF in the setting of autologous bone marrow transplantation.

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation. Four patients are surviving 2-4 years post-transplant, three transplanted for IGL and one for HD. None of the patients transplanted for HGL survived. The result of this phase II study suggests that HDAC followed by TBI and marrow infusion offers no apparent advantage over cyclophosphamide + TBI for patients with relapsed advanced malignant lymphoma. Earlier transplantation currently is the only demonstrated method of achieving better results.