Modification of the Bu/Cy myeloablative regimen using daily parenteral busulfan: reduced toxicity without the need for pharmacokinetic monitoring.

Pharmacokinetic and clinical outcome measures among three groups of patients undergoing hematopoietic transplant were assessed: group A: Parenteral busulfan (Bu) 3.2 mg/kg i.v. given qd, n=20; group B: parenteral Bu 0.8 mg/kg i.v. given every 6 h, n=11; group C: Bu 1 mg/kg p.o. given every 6 h, n=25. All groups received Bu over 4 days followed by Cy 60 mg/kg i.v. qd over 2 days; followed by an infusion of allogeneic stem cells. Median Bu clearance was 3.21 ml/min/kg and median daily AUC was 4071 micromol/min for the group A patients. The dosing formula for Bu i.v. qd was highly predictive of the AUC for patients whose mass < or =IBW+20%. For patients of greater mass, the dosing formula uniformly resulted in lower-than-predicted AUC. Neurologic toxicity, hepatic toxicity, hematologic engraftment, and relapse at 100 days were comparable across all three groups. Severe AGVHD was least among group A, followed by group B when compared with group C. Bu i.v. qd is a safe and effective regimen for allogeneic transplantation and is at least clinically equivalent to every 6 h dosing schemes using either oral or parenteral Bu.

Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group.

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer.

CONTEXT: Women with breast cancer are the most frequent recipients of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autotransplants) in North America. Despite widespread use, controversy exists about the benefits of and appropriate patients for this therapy. OBJECTIVE: To determine factors associated with disease progression or death after autotransplantation in women with metastatic breast cancer. DESIGN: Analysis of data collected retrospectively (January 1989 to 1992) and prospectively (1992 through January 1995) for the Autologous Blood and Marrow Transplant Registry. SETTING: Sixty-three hospitals in North America, Brazil, and Russia. PARTICIPANTS: A total of 1188 consecutive women aged 18 to 70 years receiving autotransplants for metastatic or locally recurrent breast cancer, with a median follow-up of 291/2 months. MAIN OUTCOME MEASURE: Time to treatment failure (disease progression, disease recurrence, or death) after autotransplantation. RESULTS: Factors associated with significantly (P<.05) increased risk of treatment failure in a Cox multivariate analysis included age older than 45 years (relative hazard, 1.17; 95% confidence interval [CI], 1.02-1.33), Karnofsky performance score less than 90% (1.27; 95% CI, 1.07-1.51), absence of hormone receptors (1.31; 95% CI, 1.15-1.51), prior use of adjuvant chemotherapy (1.31; 95% CI, 1.10-1.56), initial disease-free survival interval after adjuvant treatment of no more than 18 months (1.99; 95% CI, 1.62-2.43), metastases in the liver (1.47; 95% CI, 1.20-1.80) or central nervous system (1.56; 95% CI, 0.99-2.46 [approaches significance]) vs soft tissue, bone, or lung, 3 or more sites of metastatic disease (1.32; 95% CI, 1.13-1.54), and incomplete response vs complete response to standard-dose chemotherapy (1.65; 95% CI, 1.36-1.99). Receiving tamoxifen posttransplantation was associated with a reduced risk of treatment failure in women with hormone receptor-positive tumors (relative hazard, 0.60; 95% CI, 0.47-0.87). Women with no risk factors (n = 38) had a 3-year probability of progression-free survival of 43% (95% CI, 27%-61 %) vs 4% (95% CI, 2%-8%) for women with more than 3 risk factors (n = 343). CONCLUSION: These data indicate that some women are unlikely to benefit from autotransplantation and should receive this treatment only after being provided with prognostic information and in the context of clinical trials attempting to improve outcome.

Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation.

Tacrolimus has proved effective for preventing acute graft-vs.-host disease (GVHD) after unrelated donor marrow transplantation, but the therapeutic window is apparently narrow. Therapeutic drug monitoring could potentially be used to guide dose modifications, but the optimal target range of tacrolimus blood concentrations is unknown. We determined whether acute GVHD and renal dysfunction correlated with tacrolimus whole blood levels as measured by the IMx assay. Data were analyzed for 97 adults treated in a multicenter trial of tacrolimus and methotrexate or methylprednisolone as GVHD prophylaxis after unrelated donor marrow transplantation. The rate of grades II-IV GVHD was 49%; 81% of patients had a doubling of the serum creatinine; and 61% had a serum creatinine <2 mg/dL. The initial tacrolimus target range for the clinical trial was 10-60 ng/mL. Tacrolimus blood levels were averaged over a 14-day period, and Cox models were used with averaged blood levels as a time-dependent covariate. No significant change was observed in the risks of acute GVHD, doubling of creatinine, need for dialysis, or death over a tacrolimus blood level range of 5-40 ng/mL, but there was a direct correlation between risk of developing a creatinine <2 mg/dL and increasing tacrolimus blood levels (4.7% increased risk for each 1 ng/mL increase in blood concentration, p < 0.001). When the tacrolimus level exceeded 20 ng/mL, there was a 2.2-fold increase in the rate of renal toxicity (p < 0.001), a trend for an increase in mortality (relative risk 3.9, p=0.08), and no impact on the risk of GVHD. This analysis supports 10-20 ng/mL as the therapeutic range of tacrolimus whole blood steady state or trough levels for unrelated donor marrow transplantation.

Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.

We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.

A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation.

An observational study was conducted at 18 transplant centers in the United States and Canada to characterize the platelet recovery of patients receiving myeloablative therapy and stem cell transplantation and to determine the clinical variables influencing recovery, determine platelet utilization and cost, and incidence of hemorrhagic events. The study included 789 evaluable patients transplanted in 1995. Clinical, laboratory, and outcome data were obtained from the medical records. Variables associated with accelerated recovery in multivariate models included (1) higher CD34 count; (2) higher platelet count at the start of myeloablative therapy; (3) graft from an HLA-identical sibling donor; and (4) prior stem cell transplant. Variables associated with delayed recovery were (1) prior radiation therapy; (2) posttransplant fever; (3) hepatic veno-occlusive disease; and (4) use of posttransplant growth factors. Disease type also influenced recovery. Recipients of peripheral blood stem cells (PBSC) had faster recovery and fewer platelet transfusion days than recipients of bone marrow (BM). The estimated average 60-day platelet transfusion cost per patient was $4,000 for autologous PBSC and $11,000 for allogeneic BM transplants. It was found that 11% of all patients had a significant hemorrhagic event during the first 60 days posttransplant, contributing to death in 2% of patients. In conclusion, clinical variables influencing platelet recovery should be considered in the design and interpretation of clinical strategies to accelerate recovery. Enhancing platelet recovery is not likely to have a significant impact on 60-day mortality but could significantly decrease health care costs and potentially improve patient quality of life.

Treatment of T prolymphocytic leukemia with allogeneic bone marrow transplantation.

T prolymphocytic leukemia (T-PLL) is an unusual disease characterized by high white cell counts, older age at presentation, splenomegaly and a very aggressive clinical course. We describe a 47-year-old male with refractory T-PLL who was treated with high-dose chemoradiotherapy and allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling. The transplant was complicated by both acute and chronic graft-versus-host disease (GVHD). The patient achieved complete remission and remains in remission 3 years after the transplant.

Relationship of tacrolimus (FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation.

A randomized clinical trial comparing tacrolimus with cyclosporine, both with short-course methotrexate, as prophylaxis against graft-vs.-host disease (GVHD) in allogeneic HLA-matched sibling bone marrow transplant patients was conducted. Cyclosporine was dosed to achieve a target concentration range between 150 and 450 ng/mL during the first 8 weeks after transplant. For tacrolimus, the target concentration range was 10-30 ng/mL during the first 8 weeks after transplant. A gradual tapering schedule of 20% per month during months 3-6 was then conducted for patients in both treatment arms. The efficacy of the immunosuppressive regimen was determined by the rate of acute GVHD grades II-IV The toxicity of the immunosuppressive regimen was determined by the occurrence of the creatinine exceeding 2 mg/dL, the creatinine doubling the baseline value, or the necessity for hemodialysis. Correlations between blood concentrations and efficacy and toxicity parameters were assessed. For both tacrolimus and cyclosporine, increasing blood concentrations were associated with greater renal dysfunction. For cyclosporine, there was a nonsignificant trend to an increased incidence of grades II-IV acute GVHD with lower cyclosporine blood concentrations (<300 ng/mL). In contrast, there did not appear to be a relationship between the blood concentrations of tacrolimus and the occurrence of acute GVHD. This suggests that optimization of efficacy while minimizing the risk for nephrotoxicity could be achieved by dosing tacrolimus to a targeted range between 10 and 20 ng/mL.

Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients.

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.

Guidelines for systemic therapy of early stage breast cancer.

Optimal treatment of early stage breast cancer remains an active area of study. An expert multidisciplinary committee reviewed clinical data on systemic therapy for early stage, stage I and II breast cancer. Guidelines for treatment were developed for Texas Oncology. P.A., the largest private practice group of oncologists in the United States. This group of physicians treats approximately 5000 new breast cancer patients each year and has a major impact on oncology care in the state of Texas. These guidelines identify prognostic factors which help the practitioner in choosing treatment for patients. Subsets of patients are identified for whom no systemic therapy is warrented. Standard chemotherapy and hormonal therapy regimens are outlined for patients with early stage disease at increased risk for relapse. Dose intensification for high risk stage II patients is reviewed. Timing of therapy and the sequencing of chemotherapy and radiation therapy is addressed. Strategies for the follow-up of patients with a history of breast cancer are outlined.

High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.

PURPOSE: To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS: Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS: Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION: Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

Safeguarding the administration of high-dose chemotherapy: a national practice survey by the American Society for Blood and Marrow Transplantation.

Overdoses of high-dose chemotherapy before hematopoietic cell transplantation are serious adverse events, but their frequency and etiology are unknown. The American Society for Blood and Marrow Transplantation (ASBMT) conducted an anonymous national survey to identify errors in safety practices during the administration of high-dose chemotherapy. The questionnaire was returned from 115 (68%) of 170 hematopoietic transplant centers in the United States. Ninety-four of the programs were university or affiliated centers, 19 were community hospitals, and 41 were founded since 1990. A total of 7650 transplants were reported for 1994: 22% of the programs performed 1-20 transplants, 60% performed 21-100 transplants, and 18% performed more than 100 transplants. Fifteen of the 115 responding centers reported a total of 18 patients inadvertently given overdoses of cisplatin (n=3), carboplatin (n=2), busulfan (n=2), cytosine arabinoside (n=2), cyclophosphamide (n=2), interleukin-2 (n=2), or other agents (n=5) between 1989 and 1994. Cumulative drug doses given as a daily dose (six cases) and nursing infusion errors (six cases) were the most common errors. The estimated chemotherapy overdose error rate was 0.06%, or 6 cases/10,000 transplants, with 95% confidence limits of 0.03-0.11%. The overdose rate among more experienced centers in operation before 1990 was lower than that among newer centers (p < 0.01). Large centers (> 100 transplants performed in 1994) experienced errors at rates lower than those in medium-sized centers (21-100 transplants, p = 0.03). Although the number of events was small in this self-reporting survey, overdoses were noted in 13% of the responding centers, especially among more recently established units. Safety practices need to emphasize multidisciplinary checkpoints at the physician, pharmacist, nursing, and institutional levels. Based on these survey results, ASBMT recommendations for further safeguards for high-dose chemotherapy administration are proposed.

FK506 in combination with methotrexate for the prevention of graft-versus-host disease after marrow transplantation from matched unrelated donors.

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.

A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma.

IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered disulfide linker, N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) toluene (SMPT). In this report, we have used two regimens for the administration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four intermittent bolus infusions administered at 48-hour intervals. The other studied a continuous infusion (CI) administered over the same 8-day period. In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16 mg/m2/8 d and the dose-limiting toxicity (DLT) consisted of vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24 mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial distal digital skin necrosis in the absence of overt evidence of systemic vasculitis, occurred in 3 patients. Of 23 evaluable patients on the bolus schedule, there was 1 persisting complete response (CR; > 40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuous infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percent of the patients on the bolus infusion regimen and 30% on the CI regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is related to the serum level of the IT and does not differ with different targeting MoAbs.

High-dose etoposide, cyclophosphamide and total body irradiation with allogeneic bone marrow transplantation for resistant acute myeloid leukemia: a study by the North American Marrow Transplant Group.

We evaluated the toxicity and efficacy of high-dose etoposide, cyclophosphamide and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) for patients with resistant, acute myeloid leukemia (AML). Between 9/84 and 11/92 we treated 70 patients with etoposide (900-1800 mg/m2), cyclophosphamide (120-180 mg/kg) and TBI (1000-1200 cGy) followed by allogeneic BMT from histocompatible siblings. Forty patients were in untreated first relapse. Median time from diagnosis to transplant was 10 months. Toxicity was similar to that observed with cyclophosphamide/TBI with the median duration of neutropenia (ANC < 500/microliters) being 19 days (range 10-27) and the median duration of thrombocytopenia being 23 days (range 13-173). Twenty-three patients remain in continuous complete remission at a median of 56 months after transplant (range 36-132 months). Probabilities of disease-free survival, persistent/recurrent disease and transplant related mortality are .32, .47, and .37 respectively. Multivariate analysis indicated that grade > or = 2 acute graft-vs-host disease and transplant in untreated first relapse were associated with increased DFS due to reduced relapse risk. We conclude that high-dose etoposide with cyclophosphamide and TBI followed by allogeneic BMT is effective therapy for resistant AML, producing durable remission in approximately one-third of those treated. Disease persistence or recurrence was the major cause of treatment failure. Further improvement in DFS following allogeneic BMT for resistant AML might be achieved by using less intensive GVHD prophylaxis or through infusion of donor peripheral blood cells in patients who fail to develop significant acute GVHD.

Recombinant human interleukin-3 and granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for malignant lymphoma.

Recombinant human interleukin-3 (rhIL-3), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), and granulocyte colony-stimulating factor (rhG-CSF) enhance neutrophil recovery following autologous bone marrow transplantation (ABMT) for malignant lymphoma. Based on findings in preclinical studies, a phase I-II trial was conducted to assess the safety and efficacy of the sequential administration of rhIL-3 and rhGM-CSF after bone marrow ablative cytotoxic therapy and ABMT for patients with malignant lymphoma. Thirty-seven patients (20 with non-Hodgkin's lymphoma and 17 with Hodgkin's disease) were treated with intensive cytotoxic therapy before ABMT. Patients were treated in one of four cohorts to receive rhIL-3 (2.5 or 5.0 microg/kg/d) administered by subcutaneous injection for either 5 or 10 days following ABMT. Twenty-four hours after the last dose of rhIL-3, rhGM-CSF (250 microg/m2/d as a 2-hour intravenous infusion) administration was initiated. Sequential cytokine therapy post-ABMT resulted in fewer days of platelet and red blood cell transfusions than seen in historic controls with rhIL-3, rhGM-CSF, or rhG-CSF monotherapy. These data suggest that the sequential administration of rhIL-3 and rhGM-CSF after ABMT results in rapid recovery of multilineage hematopoiesis.

Dose-intensive chemotherapy with etoposide-cyclophosphamide for advanced breast cancer. North American Marrow Transplant Group.

Bone marrow and extensive bone involvement have limited the use of chemotherapy with stem cell support for treatment of women with metastatic breast cancer. The toxicity and efficacy of dose-intensive chemotherapy were studied using etoposide and cyclophosphamide without a stem cell support regimen for women with advanced breast cancer. The regimen was well tolerated, with treatment-related mortality similar to dose-intensive therapy with stem cell support. The overall 58% response rate is comparable to the response rate with dose-intensive chemotherapy regimens using stem cell support. The extent of disease, responsiveness to standard therapy, and dose of etoposide affected the response rate. Hematopoietic recovery was fairly prompt and was generally unaffected by the use of hematopoietic growth factors or the presence of breast cancer cells in the marrow. The use of stem cells or recombinant human interleukin-3 (rhIL-3) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) resulted in some benefit in neutrophil recovery. It was concluded that in many women with advanced breast cancer, a dose-intensive regimen of etoposide and cyclophosphamide results in response or stabilization of disease. Hematopoietic recovery, particularly platelet recovery, may be accelerated by a combination of rhIL-3 and rhGM-CSF.

FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation.

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6-month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.

Biological effects of recombinant human granulocyte colony-stimulating factor in patients with untreated acute myeloid leukemia.

Hematopoietic growth factors are being administered to patients with acute myeloid leukemia (AML) both to shorten the duration of chemotherapy-induced neutropenia and in an attempt to increase cytotoxicity of cell cycle-specific agents. However, limited information is available concerning the effects of growth factors in AML patients. To examine the in vivo effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on AML cells, laboratory studies were performed before and after a 72-hour intravenous infusion of G-CSF (10 micrograms/kg/d) administered to 28 untreated AML patients. Twenty-seven patients (96%) showed increases in at least one of the following parameters after G-CSF: blood blasts, bone marrow (BM) blasts, leukemia cells in S phase or interphase cells with leukemia-specific markers shown by fluorescence in situ hybridization. The median paired change in absolute blast count was +2.7 x 10(9)/L (P = .0001) after G-CSF, as compared with 0.0 during the 72 hours before initiation of G-CSF. The median percentage of BM leukemia cells in S phase increased from 6.0% to 10.7% after G-CSF (median change, %5.9%; P = .009). Interphase BM cells with trisomy 8 or monosomy 7 increased in 6 of 6 patients with these abnormalities (P = .02) with a median percent increase of 47%. Blood neutrophil counts also increased during G-CSF (median paired change, +2.8 x 10(9)/L; P < .0001). Trisomy 8 or monosomy 7 was shown by fluorescence in situ hybridization in post-G-CSF blood neutrophils from 4 of 6 patients but was also present in neutrophils before G-CSF. We conclude that the percentage of leukemia cells in S phase increases and that leukemia cell populations undergo expansion during short-term administration of G-CSF in almost all AML patients.