Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706.

B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR.

Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody.

The ability to deliver radiation selectively to lymphohematopoietic tissues may have utility in conditions treated by myeloablative regimens followed by bone marrow transplantation. Since the CD45 antigen is the most broadly expressed of hematopoietic antigens, we examined the biodistribution of radiolabeled anti-CD45 monoclonal antibodies in normal mice. Trace 125I or 131I-labeled monoclonal antibodies 30G12 (rat IgG2a), 30F11 (rat IgG2b), and F(ab')2 fragments of 30F11 were injected i.v. at doses of 5 to 1000 micrograms. For both intact antibodies, a higher percentage of injected dose/g (% ID/g tissue) in blood was achieved with higher antibody doses. However, as the dose of antibody was increased, the % ID/g in the target organs of spleen, marrow, and lymph nodes decreased. At doses between 5 and 10-micrograms, % ID/g in these tissues exceeded that in lung, the normal organ with the highest concentration of radiolabel. In contrast, thymus was the only hematopoietic organ in which the % ID/g increased with increasing antibody dose, although at high dose the % ID/g was still far below that achieved in the other hematopoietic organs. Antibody 30F11 F(ab')2 fragments were cleared more quickly than intact antibody from blood and from both target and nontarget organs, although the relationship between increasing antibody dose and decreasing % ID/g in spleen, marrow, and lymph nodes was observed. The time-activity curves for each dose of antibody were used to calculate estimates of radiation absorbed dose to each organ. At the 10-micrograms dose of 30G12, the spleen was estimated to receive a radiation dose that was 13 times more than lung, the lymph nodes 3 to 4 times more, and the bone marrow 3 times more than lung. For each antibody fragment dose, the radiation absorbed dose per MBq 131I administered was lower because the residence times of the fragments were shorter than those of the intact antibody. Thus these estimates suggested that the best "therapeutic ratio" of radiation delivered to target organ as compared to lung was achieved with lower doses of intact antibody. We have demonstrated that radiolabeled anti-CD45 monoclonal antibodies can deliver radiation to lymphohematopoietic tissues with relative selectivity and that the relative uptake and retention in different hematolymphoid tissues change with increasing antibody dose.

Localization of radiolabeled antimyeloid antibodies in a human acute leukemia xenograft tumor model.

Acute myeloid leukemia is an attractive disease to treat with radiolabeled antibodies because it is radiosensitive and antibody has ready access to the marrow cavity. In order to evaluate potentially useful radiolabeled antibodies against human acute myeloid leukemia, we have developed a nude mouse xenograft model using the human acute leukemia cell line, HEL. Mice with s.c. xenografts of HEL cells received infusions of radioiodinated anti-CD33 antibody. Examination of the biodistribution of the antibody showed that uptake in the s.c. tumor was maximal [16.9% injected dose (ID)/g at 1 h after infusion] following infusion of 1-10 micrograms of antibody and decreased following infusion of 100 micrograms (6.5% ID/g at 1 h) presumably as a result of saturation of antigen sites. The radiolabel was poorly retained in tumor (4.5-8.2% ID/g at 24 h after infusion). These results were consistent with in vitro studies demonstrating rapid internalization and catabolism of the anti-CD33 antibody. Uptake in tumor could be improved by using either a radiolabel that is retained intracellularly, 111In-DTPA (18.5% ID/g at 24 h), or by targeting a surface antigen that does not internalize upon antibody binding, CD45 (20.5% ID/g at 24 h). These results indicate that this model system will be useful in evaluating the interaction of radiolabeled antibodies with human acute myeloid leukemia cells in an in vivo setting.

Biodistribution and dosimetry following infusion of antibodies labeled with large amounts of 131I.

Dosimetry and treatment planning for therapeutic infusions of radiolabeled antibodies are usually performed by extrapolation from the biodistribution of trace-labeled antibody. This extrapolation assumes that the biodistribution of high specific activity antibody will be similar to that seen with trace-labeled antibody. However, high doses of radiation result in rapid depletion of lymphoid and hematopoietic cells in lymph nodes, spleen, and marrow with replacement by blood and plasma. If radiolabeled antibody is cleared slowly from blood, this replacement may result in increased radionuclide concentrations in these tissues following infusions of antibody labeled with large amounts of radionuclide. To examine the influence of deposited radiation on the biodistribution of radiolabeled antibody, we treated mice with a constant amount of antibody that was labeled with varying amounts of 131I. Survival was determined in normal specific pathogen-free AKR/Cum mice (Thy1.2+) after infusion of anti-Thy1.1 antibody labeled with 10 to 6500 muCi of 131I, to determine an appropriate range of 131I doses for further study. The dose producing 50% lethality within 30 days following infusion of 131I-labeled antibody was 530 muCi 131I. Biodistribution, bone marrow histology, and dosimetry were subsequently determined after infusion of 500 micrograms of antibody labeled with 10, 250, 500, or 3500 muCi 131I. The amount of 131I did not influence uptake or retention of antibody in blood, liver, lung, or kidney. In contrast, infusion of antibody labeled with 250 to 3500 muCi of 131I led to a dose-related increase in the concentration of 131I in marrow, spleen, lymph node, and thymus. For example, at 96 h after infusion of antibody labeled with 500 or 3500 muCi 131I, concentrations in marrow were 3- to 4-fold higher than after infusion of trace-labeled antibody. The increase in marrow 131I concentrations was associated with depletion of cells and hemorrhage within the marrow space. As a result, estimated mean absorbed doses to marrow, lymph node, spleen, and thymus were 1.2 to 3.1 times higher than would have been predicted from the biodistribution of trace-labeled antibody. These results suggest that the biodistribution of trace-labeled antibody should be an accurate predictor of the behavior of high specific activity antibody in blood and solid organs such as liver and kidney. In contrast, radiation from antibody labeled with large amounts of radionuclide can result in an alteration of the concentration of radiolabeled antibody in rapidly responding tissues such as marrow.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells.

Radiolabeled antibodies have produced encouraging remissions in patients with chemotherapy-resistant hematological malignancies; however, the selection of therapeutic radionuclides for clinical trials remains controversial. In this study, we compared the internalization, lysosomal targeting, metabolism, and cellular retention of radiolabeled murine and humanized monoclonal antibodies targeting the CD33 antigen (monoclonal antibodies mP67 and hP67, respectively) on myeloid leukemia cell lines (HEL and HL-60) and of anti-carcinoma antibodies (monoclonal antibodies hCTM01 and hA33) targeting breast cancer and colorectal carcinoma cell lines (MCF7 and Colo 205, respectively). Each antibody was labeled with 125I (by the IodoGen method) and with 111In and 90Y using macrocyclic chelation technology. Targeted tumor cells were analyzed for retention and metabolism of radioimmunoconjugates using cellular-radioimmunoassays, Percoll gradient fractionation of cell organelles, SDS-PAGE, and TLC of cell lysates and culture supernatants. Our results suggest that antibodies are routed to lysosomes after endocytosis, where they are proteolytically degraded. [125I]monoiodotyrosine is rapidly excreted from cells after lysosomal catabolism of antibodies radioiodinated by conventional methods, whereas small molecular weight 111In and 90Y catabolites remain trapped in lysosomes. As a consequence of the differential disposition of small molecular weight catabolites, 111In and 90Y conjugates displayed superior retention of radioactivity compared with 125I conjugates when tumor cells were targeted using rapidly internalizing antibody-antigen systems (e.g., hP67 with HEL cells and hCTM01 with MCF7 cells). When tumor cells were targeted using antibody-antigen systems exhibiting slow rates of endocytosis (e.g., hP67 on HL-60 cells and hA33 on Colo 205 cells), little differences in cellular retention of radioactivity was observed, regardless of whether 125I, 111In, or 90Y was used.

High dose radiolabeled antibody therapy of lymphoma.

A trial has been initiated testing the effects of high dose radiolabeled monoclonal antibody administered in conjunction with marrow transplantation for treatment of lymphoma. This study is based on observations in mice demonstrating that radiolabeled antibody against a normal lymphocyte-associate antigen can induce regression of lymphoma masses. These preclinical studies also showed that large amounts of antibody are needed to achieve adequate biodistribution in vivo and that potentially curative doses of radionuclide induce substantial hematopoietic toxicity. Consequently, in patients with recurrent lymphoma, we are first evaluating the influence of dose on the biodistribution of a pan B-cell antibody, MB-1 (anti-CD37). In four patients, the biodistribution studies indicated that at the highest amount of antibody tested 131I-labeled antibody MB-1 (10 mg/kg) could deliver more radiation to tumor than to normal organs. These patients were treated with antibody MB-1 labeled with 250 to 482 mCi 131I estimated to deliver 380 to 1570 cGy to normal organs and 850 to 4260 cGy to tumor. Myelosuppression occurred in all patients and required infusion of cryopreserved marrow in one patient. Complete tumor regressions were observed in each patient. In three other patients with splenomegaly and/or large tumor burden, biodistribution studies indicated that 131I-labeled antibody could not deliver more radiation to tumor than to normal organs and these patients were not treated. Thus, tumor burden and spleen size may determine the feasibility of treatment with radiolabeled antibody. Treatment with this antibody labeled with high doses of 131I was well tolerated and may prove therapeutically useful. These studies are being continued to determine the maximal doses of radiation that can be tolerated by nonhematopoietic tissues after infusion of 131I-labeled antibody.

Pre- and post-transplant quantification of measurable ('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid leukemia.

Measurable ('minimal') residual disease (MRD) before or after hematopoietic cell transplantation (HCT) identifies adults with AML at risk of poor outcomes. Here, we studied whether peri-transplant MRD dynamics can refine risk assessment. We analyzed 279 adults receiving myeloablative allogeneic HCT in first or second remission who survived at least 35 days and underwent 10-color multiparametric flow cytometry (MFC) analyses of marrow aspirates before and 28±7 days after transplantation. MFC-detectable MRD before (n=63) or after (n=16) transplantation identified patients with high relapse risk and poor survival. Forty-nine patients cleared MRD with HCT conditioning, whereas two patients developed new evidence of disease. The 214 MRD(neg)/MRD(neg) patients had excellent outcomes, whereas both MRD(neg)/MRD(pos) patients died within 100 days following transplantation. For patients with pre-HCT MRD, outcomes were poor regardless of post-HCT MRD status, although survival beyond 3 years was only observed among the 58 patients with decreasing but not the seven patients with increasing peri-HCT MRD levels. In multivariable models, pre-HCT but not post-HCT MRD was independently associated with overall survival and risk of relapse. These data indicate that MRD(pos) patients before transplantation have a high relapse risk regardless of whether or not they clear MFC-detectable disease with conditioning and should be considered for pre-emptive therapeutic strategies.

Review of the use of marrow transplantation in the treatment of non-Hodgkin's lymphoma.

High-dose chemoradiotherapy followed by marrow transplantation has become a widely used form of therapy for patients with acute leukemia. Because of the success of marrow transplantation in the treatment of this disease, there has been increased interest in the possible application of marrow transplantation to the treatment of other malignancies known to be sensitive to chemotherapy and radiotherapy. In this paper we review the rationale behind the application of marrow transplantation to the treatment of non-Hodgkin's lymphoma and the results that have been achieved to date.

The detection of bone marrow involvement by lymphoma using magnetic resonance imaging.

We used magnetic resonance (MR) to image the bone marrow of 31 patients with lymphoma. Images were obtained of the femoral, pelvic, and vertebral marrow with a 0.15 tesla imaging system using a T1-weighted spin echo sequence (TR600/TE 40). With this pulse sequence, normal marrow produces a high intensity signal that reflects the presence of marrow fat (short T1 relaxation time). We previously reported MR imaging of patients with leukemia in relapse and found a diffusely and symmetrically decreased marrow signal intensity due to the replacement of normal marrow fat by cellular material with a long T1. Unlike leukemia, patients with lymphomatous marrow involvement often had patchy, often discrete, areas of low signal intensity, representing focal marrow infiltration. Five of six patients in this study with lymphoma detected by histologic examination also had marrow lesions seen on MR. An additional four patients had marrow lesions detected by MR that were not detected on initial marrow biopsies; two of these had marrow involvement proven on subsequent biopsies, one had disease isolated to the vertebrae that was never pathologically documented, and one had progression of disease in the marrow documented by MR without biopsy confirmation. These results indicate that marrow involvement with lymphoma can be detected by MR imaging and that MR can complement bone marrow biopsy.

Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse. PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients. RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P =.006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P =.0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P =.02). CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.

Ovarian function following marrow transplantation for aplastic anemia or leukemia.

One hundred eighty-seven women between 13 and 49 years of age had ovarian function evaluated from 1 to 15 years (median, 4) after marrow transplant for aplastic anemia or leukemia. Among 43 women transplanted for aplastic anemia following 200 mg/kg cyclophosphamide (CY), all 27 less than 26 years of age, but only five of 16 greater than 26 years of age recovered normal ovarian function. Nine of the 43 have had 12 pregnancies, resulting in eight live births, and two elective and two spontaneous abortions. All eight children are normal. Nine of 144 women transplanted for leukemia following 120 mg/kg CY and 9.20 to 15.75 Gy total body irradiation (TBI) recovered ovarian function. Two of these nine have had three pregnancies, resulting in two spontaneous and one elective abortion. The probability of having ovarian failure was 0.35 by 7 years for patients receiving CY alone and was 1.00 at 1 year for patients receiving CY plus TBI (P less than .0001). By 7 years after transplant the probabilities of having normal ovarian function were 0.92 after CY alone and 0.24 after CY plus TBI (P less than .0001). Multivariate analysis showed that TBI was the only factor significantly influencing ovarian failure and that both TBI and greater patient age at transplant were significantly associated with a decreased probability of recovering normal ovarian function. These data demonstrate that after high-dose CY, recovery of ovarian function occurs in younger women and in a minority of older women, but after CY and TBI, recovery occurs in only a few younger women and none of the older women.

Regimen-related toxicity in patients undergoing bone marrow transplantation.

Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.

Marrow transplantation for acute nonlymphocytic leukemia following therapy for Hodgkin's disease.

Seven patients with acute nonlymphocytic leukemia (ANL) following therapy for Hodgkin's disease (HD) were treated with cyclophosphamide (Cy) alone or combined with 10.00 to 15.75 Gy total body irradiation (TBI) and marrow transplantation. Five patients were transplanted without an attempt at prior remission induction, one patient following failure of remission induction and one patient in first remission following successful induction. Four patients died of multiorgan failure, 15 to 70 days after transplant. Three patients died of progressive or recurrent leukemia 56, 120, and 280 days after transplant. These results illustrate the difficulty of treating patients for secondary leukemia with marrow transplantation and suggest that transplantation in the preleukemic phase should be studied.

Evaluation of intensive postremission chemotherapy for adults with acute nonlymphocytic leukemia using high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide.

In order to test the toxicity and efficacy of intensive postremission therapy with high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide in adults with acute nonlymphocytic leukemia (ANL), 100 adults (ages 19 to 75) with previously untreated ANL were entered into a study using six sequential cycles of chemotherapy. Cycles 1 (induction), 3, and 5 included conventional doses of daunomycin, cytosine arabinoside, 6-thioguanine, vincristine (VCR), and prednisone. Cycle 2 was cytosine arabinoside 3 g/m2 intravenously (IV) every 12 hours for four doses, followed by L-asparaginase 10,000 U intramuscularly (IM) at hour 42; this combination was repeated 1 week later. Cycle 4 included amsacrine 120 mg/m2/d and etoposide 100 mg/m2/d, both IV for five days, and cycle 6 was three monthly courses of VCR on day 1, and prednisone, mercaptopurine, and methotrexate each for five days. Seventy-four patients (74%) achieved complete remission (CR) (51 with cycle 1 and 23 after cycle 2). The overall disease-free survival (DFS) for patients achieving CR is 27% at 3 years by Kaplan-Meier analysis, while for patients achieving CR with cycle 1 it is 34%. The actuarial probability of being free from relapse at 3 years for patients achieving CR is 34%. Sixteen of the 74 CR patients (22%) died in CR while continuing to receive intensive chemotherapy, including 12 (18%) who succumbed to infection (nine bacterial, three fungal). After a median follow-up of 20 months, 36 patients have relapsed and 21 remain alive in CR. Intensive consolidation with high-dose cytosine arabinoside, amsacrine, and etoposide can modestly prolong DFS compared with historical controls. However, relapse continued to be a major problem and, in addition, with more aggressive consolidation therapy, infection during marrow aplasia resulted in a significant number of deaths.

High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia.

Twenty-nine patients were conditioned for allogeneic marrow transplant with cytarabine (ara-C) (3 g/m2 every 12 hours for 12 doses) and total body irradiation (TBI) (200 cGy daily for six days) with or without cyclophosphamide (CY) (60 mg/kg) to determine toxicity and efficacy. Four patients had chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and 25 patients had acute leukemia, 24 at stages later than first remission. Three patients (10%) had fatal regimen-related toxicity and another 10% experienced severe toxicity in at least one organ system. The addition of CY to the ara-C and TBI regimen was not associated with an increase in the frequency of severe toxicity. Twenty-five of 29 patients engrafted eight to 33 days posttransplant: three died early before engraftment, and one patient failed to engraft. Ten of 29 patients are alive without disease, and the actuarial probability of disease-free survival for the entire group at 3 years is 33%. Three of ten patients with acute nonlymphocytic leukemia (ANL), six of 15 with acute lymphocytic leukemia (ALL), and one of four with CML are alive and disease free 25 to 42 months (median, 30 months) after transplant. High-dose ara-C (HDara-C) and TBI with or without CY can be administered with approximately the same toxicity as CY plus TBI. Phase III studies appear warranted to determine if these newer regimens provide improved results compared with currently used regimens.

Effect of different chemotherapy regimens on peripheral-blood stem-cell collections in patients with breast cancer receiving granulocyte colony-stimulating factor.

PURPOSE: To evaluate the effects of chemotherapy regimens on peripheral-blood stem-cell (PBSC) yields in patients with breast cancer who receive granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: One hundred patients with breast cancer received cyclophosphamide 4 g/m2 for dose (CY) (n = 10), CY and etoposide 600 mg/m2 (CE) (n = 13), CE and cisplatin 105 mg/m2 (CEP) (n = 19), or CY and paclitaxel 170 mg/m2 (n = 58), followed by G-CSF. PBSC collections were initiated when the WBC count recovered to greater than 1 x 10(9)/L. A multivariate analysis was undertaken to evaluate the effects of different chemotherapy regimens and patient variables on PBSC collections as measured by the yield of CD34+ cells. RESULTS: The medians of average daily CD34+ cell yields for patients who received paclitaxel plus CY, CE, and CEP with G-CSF were 12.9, 11.03, and 5.37 x 10(6)/kg, respectively, compared with 2.02 x 10(6)/kg in the reference group that received CY with G-CSF (P = < .0001, .002, and .09, respectively). On first-day collections, patients who received paclitaxel plus CY, CE, and CEP with G-CSF yielded medians of 11.07, 8.09, and 3.52 x 10(6) CD34+ cells/kg, respectively, compared with 0.90 x 10(6)/kg in the reference group that received CY with G-CSF (P = .0006, .02, and .09, respectively). The number of previous cycles of chemotherapy, previous radiotherapy, marrow involvement, and phase and stage of disease did not have statistically significant effects on CD34+ cell yield. CONCLUSION: Combination chemotherapy regimens were superior to single-agent CY for the mobilization of CD34+ cells.

Phase I study of busulfan and cyclophosphamide in preparation for allogeneic marrow transplant for patients with multiple myeloma.

PURPOSE: To study the toxicity and potential efficacy of busulfan (BU) and cyclophosphamide (CY) as a conditioning regimen before allogeneic bone marrow transplantation (ABMT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: Twenty patients with MM underwent conditioning, which was followed by ABMT from 16 HLA-identical donors, three one-antigen-mismatched donors, and one HLA A, B, D-identical unrelated donor. Four levels of BU plus CY were evaluated. RESULTS: Severe regimen-related toxicity occurred in two of five patients who received BU 16 mg/kg and CY 120 mg/kg, in none of the four patients who received BU 14 mg/kg and CY 120 mg/kg, in one of eight patients who received BU 14 mg/kg and CY 147 mg/kg, and in two of three patients who received BU 14 mg/kg and CY 174 mg/kg. Twelve of 15 (80%) assessable patients achieved a complete remission with the disappearance of M-protein and the return of normal marrow morphology. Ten patients died of complications related to the ABMT, and two patients died of progressive or relapsed MM. Overall, eight of 20 patients were alive; seven (35%) were in complete remission 190 to 1,271 days after ABMT. CONCLUSIONS: The maximum-tolerable dose given in this setting was BU 14 mg/kg and CY 147 kg/mg. These results suggest that this regimen may have significant antimyeloma activity. Further phase II studies are warranted.

Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients.

PURPOSE: The pharmacokinetics of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (HCY) were studied in 14 patients being prepared for bone marrow transplantation with either busulfan (BU)/CY (n = 7) or CY/total-body irradiation (TBI) (n = 7) to determine whether exposure to CY and its proximate toxic metabolite HCY is modulated by other agents used in the preparative regimen. PATIENTS AND METHODS: HCY was assayed by a new method that stabilized the metabolite at bedside. In BU/CY patients (who also received phenytoin), CY clearance was 112% greater (P = .0014), half-life 54% less (P = .0027), peak HCY concentration in plasma/CY dose 113% greater (P = .0006), and the ratio of area under the plasma concentration-time curves (AUCs) of HCY to CY 166% greater (P = .0116) than in CY/TBI patients. The ratio of the AUC of HCY/CY dose was 48% greater in BU/CY patients than in CY/TBI patients when one CY/TBI patient with an apparent impaired ability to eliminate HCY was excluded from analysis. In CY/TBI patients, there was an inverse correlation between the AUC of HCY and that of CY (R2 = .740, P = .028). Also, the ratio of the AUC of HCY/CY dose was correlated with the average concentration of BU at steady-state (Css, Bu) (R2 = .646, P = 0.29). Variability in CY and HCY pharmacokinetics among the 14 patients overall was pronounced, with the highest variability (15-fold) observed in the ratio of the AUC of HCY to that of CY. CONCLUSION: Prior administration of BU and/or phenytoin significantly alters exposure to CY and HCY. Interpatient variability in HCY exposure at a given CY dose is substantial.

Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation.

Between July 1970 and January 1985, 100 patients with malignant lymphoma were treated with high-dose chemoradiotherapy and bone marrow transplantation. Twenty-eight of the 100 are alive and the actuarial probability of disease-free survival 5 years from transplantation is 22%. The most common reason for treatment failure was disease recurrence, with an actuarial probability of 60%. A proportional hazards regression analysis showed that the likelihood of disease-free survival was less in those patients transplanted in resistant relapse and in those previously treated with chest radiotherapy. Neither disease histology (Hodgkin's disease, high-grade lymphoma or intermediate-grade lymphoma), nor source of marrow (syngeneic, allogeneic, or autologous) significantly influenced either disease-free survival or probability of relapse. The use of high-dose chemoradiotherapy and marrow transplantation appears to offer a better chance for long-term survival than any other form of therapy for young patients with disseminated malignant lymphoma whose disease has progressed after initial combination chemotherapy. The best results with marrow transplantation were obtained in patients transplanted in early relapse or second remission who had not received prior chest radiotherapy.

Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia.

PURPOSE: The purpose of this report was to review the Seattle experience in bone marrow transplantation (BMT) for acute myeloid leukemia (AML) during untreated first relapse. PATIENTS AND METHODS: Through 1990, 126 patients were transplanted during untreated first relapse of AML. Several preparative regimens were used, two of which involved more than 20 patients. Regimen 1 (29 patients) consisted of cyclophosphamide (CY) 120 mg/kg and 15.75 Gy of fractionated total-body irradiation (TBI) with methotrexate (MTX) given intermittently during a 102-day period to prevent graft-versus-host disease (GVHD). Regimen 2 (22 patients) consisted of the same CY and TBI treatment and a combination of MTX and cyclosporine (CSP) for GVHD prophylaxis. The remaining 75 patients were treated with 17 other transplant regimens. Outcome was compared for patients who were treated with regimen 1, regimen 2, and any other regimen. RESULTS: The 5-year probabilities of relapse-free survival (RFS), relapse, and nonrelapse mortality for 126 patients were .23, .57, and .44, respectively. With regimen 1, relapse (.26) was significantly less than for regimen 2 (.70; P = .004) or any other regimen (.76; P = .004). Regimen 1 patients developed more acute GVHD (.67) than regimen 2 patients (.26; P = .02) or patients on other regimens (.41; P = .02), and had increased nonrelapse mortality. Nevertheless, regimen 1 patients had a significantly higher 3-year RFS (.38) than those treated with regimen 2 (.18; P = .04) or any other regimen (.20; P = .05). CONCLUSIONS: For patients who received 120 mg/kg CY and 15.75 Gy TBI, relapse incidence was less and survival was better after GVHD prophylaxis with MTX alone than after a combination of MTX and CSP, despite a significantly higher incidence of acute GVHD. The results of treatment with regimen 1 justify future studies of the optimal timing of allogeneic BMT in the treatment of patients with AML.