A prospective comparative trial of allogeneic versus autologous bone marrow transplant (BMT) was conducted. Sixty-six consecutive patients (median age, 41; range, 15 to 60; female:male ratio = 21:45) entered this clinical trial. Priority for allogeneic BMT was given to patients who were 55 or younger and had a major histocompatibility complex-matched or 1-antigen-disparate sibling donor. Autologous BMT was offered to all other patients whose age was 60 or younger. Patients who had no sibling donor and who had BM involvement at the time of evaluation were not eligible. Thirty-one patients received an allograft, and 35 patients received an autograft. Thirteen patients received a BM graft purged with 4-hydroperoxycyclophosphamide because of previous BM involvement. Patients who had previous radiation to the thoracic and/or abdominal areas of more than 20 Gy received a preparative regimen consisting of cyclophosphamide (1,800 mg/m2/d for 4 days), VP-16 (200 mg/m2 every 12 hours for 8 doses), and 1,3-bis(2-chloroethyl)-1-nitrosourea (600 mg/m2 as 1 dose). Other patients received cyclophosphamide 1,800 mg/m2/d for 4 days followed by total body irradiation of 12 Gy administered as a single daily fraction over 4 days. With a median follow-up of 14 months, the progression-free survival (PFS) for autograft and allograft recipients was 24% +/- 8% (+/- SE) and 47% +/- 9%, respectively, (P = .21). However, the probability of disease progression was significantly higher in the autologous group (69% +/- 9%) than in the allogeneic group (20% +/- 10%; P = .001). When other confounding prognostic factors were adjusted in the multivariate analysis, chemosensitive disease and allograft were found to have a significant favorable influence on probability of disease progression (P = .03 and .003), but only chemosensitive disease had a significant influence on the PFS (P < .002). Our results suggest the existence of graft-versus-lymphoma effect and also support the rationale of using immunotherapy after autologous BMT. Allogeneic BMT should be preferable to autologous BMT in younger patients with lymphoma.

Chronic anemia of cancer can be corrected in approximately 50% of the cases by treatment with recombinant human erythropoietin (rHuEPO). Early prediction of responsiveness would avoid the emotional and financial burden of ineffective medical intervention. Eighty patients with chronic anemia of cancer undergoing treatment with rHuEPO (150 U/kg, 3 times per week by subcutaneous injection; after 6 weeks without response, 300 U/kg) participated in this study. Response was defined as a gain of at least 2 g/dL hemoglobin (Hb) within 12 weeks. Multivariate discriminant analysis and logistic regression analysis of response were performed on routine blood tests; serum levels of EPO, iron, ferritin, transferrin, and its receptor; World Health Organization (WHO) performance status; various cytokines; neopterin; stem cell factor; C-reactive protein; and alpha 1-antitrypsin. At baseline, none of these factors showed sufficient prognostic power. The following predictive algorithm was developed: (1) If after 2 weeks of therapy both the serum EPO level is > or = 100 mU/mL and Hb concentration has not increased by at least 0.5 g/dL, unresponsiveness of the patient is very likely (predictive power, 93%); otherwise, response may be predicted with an accuracy of 80%. (2) If both the serum level of EPO is less than 100 mU/mL and Hb concentration has increased by > or = 0.5 g/dL, response is highly probable (predictive power, 95%). (3) Alternatively, a serum ferritin level of > or = 400 ng/mL after 2 weeks of rHuEPO therapy strongly indicates unresponsiveness (predictive power, 88%), whereas a level less than 400 ng/mL suggests response in 3 of 4 patients.

T-cell depletion of donor bone marrow has been associated with an increased risk of disease relapse after allogeneic bone marrow transplantation (BMT). Recombinant interleukin-2 (IL-2), which is capable of increasing the antileukemic activity of peripheral blood lymphocytes obtained from patients who have undergone BMT, has been proposed as a potentially useful agent to reduce the risk of relapse post-BMT. We have previously shown that IL-2 administered to patients at very low doses after BMT is both clinically tolerable and immunologically active. We now report on the clinical outcome of 29 patients treated with low-dose IL-2 after CD6-depleted allogenic BMT for hematologic malignancy. IL-2 was administered by continuous infusion for up to 3 months beginning at a median of 67 days post-BMT. Eligibility requirements for IL-2 therapy included demonstration of stable engraftment and absence of acute grade 2-4 graft-versus-host disease (GVHD). Low-dose IL-2 was well tolerated by the majority of patients, with only 4 of 29 subjects withdrawn early. Acute GVHD developed in only one individual. After 12 weeks of treatment, the mean number of circulating natural killer cells in patients increased 10-fold without any significant change in T-cell number. Of the 25 patients who received > or = 1 month of IL-2, only 6 have relapsed. Relapse rate and disease-free survival (DFS) were determined in the 25 patients who completed at least 4 weeks of IL-2 treatment and compared with historical controls transplanted at our institution for the same conditions and treated with an identical ablative regimen and method of T-cell depletion. Only control patients who had survived disease free for 100 days post-BMT were included in this analysis. Cox's proportional hazards regression model suggested that, compared with control patients without a history of GVHD, patients treated with IL-2 had a lower risk of disease relapse (hazard ratio 0.34; range, 0.14 to 0.82) and superior DFS (hazard ratio 0.39; range 0.18 to 0.87). A randomized controlled trial of IL-2 immunotherapy after T-cell-depleted BMT should now be undertaken.

Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B-cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T-cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.

Folylpolyglutamate synthetase (FPGS) is responsible for the metabolism of natural folates and a broad range of folate antagonists to polyglutamate derivatives. Recent studies indicated increased accumulation of methotrexate (MTX) polyglutamates (MTX-PG) in blast cells as a predictor of favorable treatment outcome in childhood acute lymphoblastic leukemia (ALL). We determined the expression of FPGS activity in blasts from children with ALL at diagnosis and after treatment with MTX as a single agent, before conventional remission induction therapy. The levels of enzyme activity in ALL blasts at diagnosis (median of 689 pmol/h/mg protein) were significantly higher (P = .003) than those found in acute nonlymphoblastic leukemia (ANLL) blasts (median of 181 pmol/h/mg protein). Comparable lineage differences in normal lymphoid versus nonlymphoid cells suggest a lineage-specific control of FPGS expression, FPGS activity increased in ALL blasts after in vivo exposure to MTX. The median increase in FPGS activity was significantly higher (P = .003) in B-lineage ALL (188%) than in T-lineage ALL (37%). Likewise, the percentage of intracellular long chain MTX-PG (Glu3-6) was significantly higher (P = .02) in B-lineage ALL (92%) than in T-lineage ALL (65%), consistent with higher FPGS activity in B-lineage blasts. This finding could explain, at least in part, the superior outcome in children with B-lineage ALL treated with antimetabolite therapy.

A phase I trial was conducted with recombinant human interleukin-1 beta (rhIL-1 beta) in patients undergoing autologous bone marrow (BM) transplantation for acute myelogenous leukemia. rhIL-1 beta was administered at 3 dose levels (0.01, 0.02, 0.05 microgram/kg) by 30 minute intravenous infusion once a day beginning on the day of BM infusion and continuing for a total of 5 doses. A total of 17 patients were entered on the trial, and their results were compared with those of 74 consecutive historical control patients that did not receive colony stimulating factors. Moderate toxicity was observed in all patients. All 17 patients developed fever and chills within 30 minutes after initiation of rhIL-1 beta, and hypotension was observed in 14 of 17 patients 5 to 8 hours after the infusion. A total of 30% of patients required therapy (normal saline or dopamine) for treatment of hypotension. Therefore, dose escalation was discontinued at the 0.05 microgram/kg dose level. The number of days required to achieve an absolute neutrophil count greater than 500 mL in patients who received rhIL-1 beta was less than in historical patients (25 v 34; P = .02). This appeared to correlate with a reduced incidence of infection between days 0 and 28 after BM infusion (12% v 23%; P = .049). Median bilirubin, median creatinine, platelet recovery, and days in the hospital were not different between study patients and historical controls. Survival of patients who received rhIL-1 beta compared with that of historical patients was improved (30% v 20%; P = .04). These possible benefits were achieved at the cost of moderate toxicity during rhIL-1 beta administration.

Presymptomatic central nervous system (CNS) treatment in children with a late isolated first bone marrow (BM) relapse of acute lymphoblastic leukemia (ALL) was based on intermediate-dose systemic and intrathecal (IT) methotrexate (MTX) in the multicenter trial, ALL-REZ BFM 85. Because this was associated with an excess of overt second CNS relapses, cranial radiotherapy (cRT) plus prolonged triple IT therapy with MTX, cytarabine, and prednisone was instituted during the course of the subsequent trial, ALL-REZ BFM 87. Results of children with or without cRT, but otherwise identical chemotherapy, are presented here. Between April 1985 and March 1990, 93 children with their first late isolated BM relapse of ALL were entered on protocols ALL-REZ BFM 85M and ALL-REZ BFM 87. An intensive 6-month phase of multiagent chemotherapy that included 8 courses of systemic MTX (1 g/m2) plus IT MTX was followed by 2 years of conventional maintenance therapy with daily 6-thioguanine and biweekly MTX. Children with bone marrow transplantation excluded, 73 were in complete remission at the end of intensive polychemotherapy, 40 of whom received fractionated cRT plus triple IT therapy during the following 6 months; 11 did not receive cRT but prolonged triple IT; 22 received neither cRT nor prolonged triple IT. Except for a higher percentage of children who had received cRT in front-line protocols (29 of 33 v 20 of 40), the patient groups without or with salvage cRT were comparable. Of 33 children without salvage cRT, 26 relapsed, compared with 21 of 40 who had received cRT (P < .05). The difference was solely attributable to second relapses with CNS involvement (10 of 33 v 1 of 40; P < .01). Estimated 6-year event-free survival rates were .18 for children without cRT and .46 for children with cRT (P < .01). In patients without cRT, no impact of prolonged IT therapy could be shown. The data suggest that second CNS prophylaxis with cRT and prolonged triple IT therapy in children with late isolated BM relapse of ALL is effective in preventing CNS relapses, in reducing the overall relapse rate, and in increasing the overall survival rate.

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

To test the efficacy of poststorage bedside leucodepletion of blood products in the prevention of primary HLA alloimmunization and its clinical sequelae, 172 patients with hematologic malignancy requiring intensive red blood cell and platelet support were randomized to receive either standard or filtered red blood cells and platelets. Quality control of bedside filtration was explored by sequential sampling downstream of the filter, but this did not predict the total number of leucocytes transfused. After exclusions, 123 evaluable patients were assessed every two weeks until the end of therapy. HLA antibodies developed in 21 of 56 (37.5%) nonfilter (NF) and 15 of 67 (22%) filter (F) patients (risk ratio estimate, 0.60 [95% confidence interval, 0.34 to 1.05]; P = .07). Patients with acute myeloid leukemia (AML; n = 53) had higher alloimmunization rates in both arms of the study, with a greater effect of filtration (62.5% NF and 31.0% F; P = .025). Bedside filtration did not affect the overall incidence of febrile transfusion reactions (FTRs; 37% NF and 34% F; P = .71) or of platelet refractoriness assessed in 50 patients (30% NF and 26% F), despite an association between broad HLA reactivity and both FTRs and refractoriness. However, FTRs were also seen in 28 patients without HLA antibodies. Five alloimmunized refractory patients (2 F and 3 NF) required HLA-selected platelets. This report, the first prospective study of bedside filtration, has failed to show clear clinical benefit. Methodological limitations may account in part for this failure, notably the difficulties in accurately assessing the number of leucocytes transfused.

Two hundred sixteen patients with a nonfollicular small cell lymphoma followed up in our department over a 5-year period have been reviewed to define the clinical behavior and survival of patients with each histologic subtype. The respective frequencies of major subtypes were: small lymphocytic/lymphoplasmacytoid lymphoma (immunocytoma, SL/LPL), 28%; large cell-rich immunocytoma (LCRI), 7%; mantle cell lymphoma (MCL), 24%; mucosa-associated lymphoid tissue-lymphoma (MALT-L), 20%; other rare subtypes, 6%; and nonclassified or nonreviewed, 14%. The SL/LPL patients and the MALT-L patients had a relatively indolent disease, usually disseminated for SL/LPL and usually localized for MALT-L. Both subtypes have a long time to treatment failure (TTF; median, 48 and 58 months, respectively) and long survival (median, 118 and 98 months, respectively). The LCRI patients or the MCL patients had more aggressive clinical or biologic features and experienced shorter TTF (median, 26 and 14 months, respectively) and shorter survival (median, 55 and 52 months, respectively). None of these histologic subtypes was associated with a significant cure rate. MALT-L patients did relapse regardless of the initial localization or treatment and at a similar rate to the SL/LPL patients. Factors associated with a worse outcome in nonfollicular small cell lymphoma patients are identical to those described in other lymphoma subtypes: advanced clinical stage, poor performance status, high tumor bulk, and high lactic dehydrogenase or beta 2microglobulin levels. For patients with disseminated disease, standard chemotherapy regimens did not allow a long TTF; therefore, new therapeutic strategies must be developed.

Peripheral blood stem cells (PBSCs) are being used as an alternative to autologous marrow rescue for hematopoietic reconstitution after high-dose chemotherapy in patients with neuroblastoma and other solid malignancies. Use of PBSCs is preferred by some because of the belief that there is less risk of tumor contamination. Because tumor stem cell contamination is thought to be one contributing cause of relapse after myeloablative therapy and autologous reconstitution, we examined the potential risk of reinfusing circulating neuroblastoma cells by in vitro evaluation of their clonogenicity. Immunocytologic and tumor cell clonogenic analyses were performed on 74 blood samples obtained from 56 children with advanced-stage neuroblastoma. Concurrently drawn bone marrow specimens were evaluated in 30 instances. Circulating neoplastic cells were detected in 19 of 74 (26%) for all specimens and by immunologic techniques (26%). Using a clonogenic assay, 13 grew identifiable tumor colonies. Comparing results with the two techniques showed tumor colony growth in 10 of the 19 positive specimens by immunocytology. However, 3 of 53 samples (6%) that were negative by immunocytology were positive by the clonogenic assay. Of the 11 positive blood samples, 9 concurrent marrows contained neuroblastoma cells; of the 19 negative blood specimens, 3 concurrent marrows had metastatic disease. We conclude that circulating neuroblastoma cells are present in peripheral blood and have clonogenic properties in vitro. This supports the view that tumor cell contamination may well be one cause of relapse after autologous reconstitution. Consequently, PBSC collections should also undergo meticulous monitoring for tumor contamination before autologous reinfusion.

Anemia is a universal finding in patients undergoing autologous bone marrow transplantation (BMT). Effective therapies to increase the number of autologous red blood cells could result in a lower morbidity and mortality associated with red blood cell transfusions. We examined whether the addition of erythropoietin (Epo) to intensive therapy supported by progenitor cell transplantation and granulocyte colony-stimulating factor (G-CSF) would result in a lower requirement for red blood cell transfusions. Thirty-five patients with lymphoma were randomized to receive Epo versus placebo. Epo (600 U/kg three times per week) or placebo was begun 3 weeks before administration of high-dose therapy. Epo was held during the week of the preparatory regimen, and restarted on the day after BMT. All patients also received G-CSF following BMT. No significant differences were noted between the two groups in terms of patient characteristics at pretreatment or post-BMT evaluation. There were no differences in the total number of red blood cell units transfused (median Epo: 8 v placebo: 6, P = .22) nor the number of platelet transfusions given (median Epo: 12 v placebo 5, P = .14). Engraftment of granulocytes (absolute neutrophil count > or = 500/microL) occurred in a median of 12 days (range, 9 to 33) for the patients receiving Epo and G-CSF, compared with a median of 10 days (range, 8 to 22) for those receiving placebo and G-CSF (P = .70). Likewise, there were no differences in the time to platelet count > or = 20,000/microL without further transfusions with a median of 22 days (range, 15 to 150+) for those receiving Epo and G-CSF compared with a median of 20 days (range, 11 to 54) for those patients receiving placebo and G-CSF (P = .28). The combination of G-CSF and Epo as administered in this study appears to be safe but does not result in an improvement in the total number of red blood cell transfusions or total number of single donor platelet units transfused.

Between October 1988 and December 1992, 167 patients with leukemia receiving marrow transplants from HLA-identical donors and conditioned with cyclophosphamide (120 mg/kg) were randomized to additional treatment with either busulfan (16 mg/kg, n = 88) or total body irradiation (TBI; n = 79). The busulfan-treated patients had an increased cumulative incidence of veno-occlusive disease of the liver, ie, 12% compared with 1% in the TBI group (P = .009). Furthermore, hemorrhagic cystitis occurred in 24% of the busulfan patients versus 8% in the TBI patients (P = .003). In patients with advanced disease beyond first remission or first chronic phase, transplantation-related mortality was 62% among the busulfan-treated patients compared with 12% among the TBI recipients (P = .002). These differences between the two groups were statistically significant in multivariate analysis. Seizures were seen in 6% of the busulfan-treated patients and were absent in the TBI group (P = .03). Grade II-IV of acute graft-versus-host disease (GVHD) was similar in the two groups, but grade III-IV and chronic disease was more common in the busulfan-treated group (P = .04). Death associated with GVHD occurred in 17% of the busulfan-treated group and 2% of the TBI group (P = .003). Patients treated with busulfan had a 3-year actuarial survival of 62%, which was worse than the 76% among those treated with TBI (P < .03). In multivariate analysis, poor survival was associated with advanced disease (P < .0001), no posttransplant septicemia (P = .0006), grade II-IV GVHD (P = .006), and busulfan treatment (P < .02). The incidence of relapse did not differ between the two groups. Relapse-free survival was also similar in the two treatment groups on analysis of data from all patients, children, patients with early disease, and those with acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia. However, in adults (P = .05) and patients with advanced disease (P = .005), leukemia-free survival was significantly better in those treated with TBI. We conclude that patients treated with busulfan have more early toxicity and an increased transplant-related mortality in patients with advanced disease. TBI is therefore the treatment of choice, especially in adults and patients with advanced disease. However, busulfan is an acceptable alternative for patients with early disease and for those in whom TBI is not feasible.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.

In July 1990, the Recombinate Study Group initiated a prospective, open-labeled investigation of recombinant factor VIII (r-FVIII) to assess its safety and efficacy and to characterize the natural history of inhibitor development in previously untreated patients (PUPs) with hemophilia A. All study subjects have severe FVIII deficiency (baseline FVIII level < or = 2% of normal) and no history of blood product exposure before study entry. Following the first r-FVIII infusion, plasma was screened for inhibitors once every 3 months, and plasma recovery of r-FVIII at 30 minutes and 24 hours postinfusion was assayed at least once every 6 months. As of May 1993, 73 of 79 patients originally enrolled in the trial continue to participate. The median number of r-FVIII exposure-days for the 71 subjects who have received at least one r-FVIII infusion is 11. A total of 1,785 infusions have been administered to treat 810 bleeding events. Ninety-two percent of bleeding events responded as anticipated to one or two infusions. Two, nonrecurring, acute adverse reactions occurred coincident with r-FVIII infusion, one of which was unrelated and the other, possibly related to the infusion. Seventeen (23.9%) subjects have developed inhibitors: five with peak titers more than 10 Bethesda units (BU) and 12 with peak titers < or = 10 BU (range, 0.5 to 10). Survival analysis showed that the probability of remaining inhibitor-free in this group of patients with severe hemophilia A is 88.4% after 8, 73.6% after 10, and 61.6% after 25 r-FVIII exposure-days. Inhibitors disappeared in five (29.4%) subjects on retesting 2 to 16 months after the last positive inhibitor assay. r-FVIII is safe and effective in the treatment of hemophilia A-related bleeding. To date, the inhibitor risk associated with its use is comparable to that in patients treated with plasma-derived concentrates. The majority of inhibitors identified are low in titer and do not preclude continued on-demand therapy with r-FVIII.

A phase II study was undertaken to assess whether continuous infusion of high-dose recombinant interleukin-2 (rIL-2) alone was active against different histologic subtypes of heavily pretreated lymphoma. Sixty one lymphomas were included in the study. rIL-2 (Roussel UCLAF, Romainville, France) was administered by continuous infusion at 20 x 10(6) IU/m2 for three cycles of 5 days, 4 days, and 3 days, during the first week, third week, and fifth week, respectively. Twenty-four low-grade non-Hodgkin's lymphomas (NHL) were resistant to an anthracycline-containing regimen. Twenty-three intermediate and high-grade NHL were refractory to initial treatment or to salvage therapy. Seven Hodgkin's diseases were refractory to at least three regimens or relapsed after autologous bone marrow transplantation. Seven mycosis fungoides were refractory to chemotherapy. In low-grade NHL, one complete response (CR) was observed. In aggressive NHL, there were three CRs and two partial responses (PRs). No response was noted in Hodgkin's disease. One CR and four PRs were observed in mycosis fungoïdes. Complete response durations were 23, 20, 17, 12, and 4 months. Grade 4 toxicity was observed in 29 patients leading to arrest of therapy in 12 patients. The response to rIL-2 therapy in lymphoma differs according to histologic subtypes. Five responses were observed in 23 aggressive lymphomas. Five of seven mycosis fungoïdes responded; these preliminary results warrant testing of a larger number of patients.

We conducted a prospective, double-blind controlled study to determine the efficacy of a recombinant granulocyte colony-stimulating factor (G-CSF, 200 microgram/m2) starting daily from 2 days before an induction therapy until neutrophils recovered to above 1,500/microL or until 35 days after the therapy in 58 patients with relapsed or refractory acute myeloid leukemia (AML). Twenty-eight patients in the G-CSF group showed significantly faster recovery of neutrophils (P < .001) than 30 patients in the placebo group. The incidence of febrile episodes and of documented infections was almost the same in both groups. However, among 39 patients who did not show any infectious episodes during the 2-week period after the start of chemotherapy, the incidence of documented infections after the third week tended to be lower in the G-CSF group, but not statistically significantly. There was no evidence that G-CSF stimulated the growth of AML cells in the bone marrow during the 2-day period before the chemotherapy, nor that G-CSF accelerated the regrowth of AML cells during the 5-week period after the therapy. Fifty percent of patients in the G-CSF group and 37% in the placebo group had complete remission (CR). Although the rate was higher in the G-CSF group, the difference was not statistically significant (P = .306). There was no difference between the two groups in event-free survival of all patients and in disease-free survival of patients who had achieved CR.