Plasma and cerebrospinal fluid pharmacokinetics of 1-beta-D-arabinofuranosylcytosine and 1-beta-D-arabinofuranosyluracil following the repeated intravenous administration of high- and intermediate-dose 1-beta-D-arabinofuranosylcytosine.

We examined the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) and 1-beta-D-arabinofuranosyluracil (ara-U) in 19 patients with acute leukemia in order to determine whether ara-C or ara-U accumulate in these fluid compartments over time. Plasma and CSF samples were obtained just prior to the conclusion of the first and seventh, and immediately before the second and eighth, 2-h, twice-daily i.v. infusions of 3 g/m2/dose of ara-C (n = 10), 2 g/m2/dose of ara-C (n = 3), and 0.75 g/m2/dose of ara-C (n = 6). There was no accumulation of ara-C in the plasma or CSF, or of ara-U in the plasma following repeated ara-C infusions, ara-U did accumulate in the CSF; the end-dose 1/end-dose 7 CSF ara-U ratio was 0.35 +/- 0.12 and significantly different from this ratio for CSF ara-C (2.10 +/- 3.01; P = 0.004). The end-dose 7 CSF ara-U level was greater than the end-dose 1 CSF ara-U level in all paired specimens. There was a significant correlation between the dose of ara-C administered and the end-dose plasma ara-C and the end-dose CSF ara-U levels (P less than 0.02). One patient who received 3 g/m2/dose of ara-C developed neurotoxicity; his plasma and CSF ara-C and ara-U levels were not extraordinary during the period of ara-C administration, but he had persistent CSF ara-U demonstrable 75 h after his final ara-C dose. CSF ara-U accumulation might underlie the pathophysiology of ara-C-induced neurotoxicity. Intermediate doses of ara-C given i.v. (0.75 g/m2/dose over 2 h) appeared to generate therapeutic CSF ara-C levels and cleared CSF leukemia in one patient.

The association between high-dose cytarabine neurotoxicity and renal insufficiency.

We reviewed the medical records of 110 consecutive patients at our institution who had acute leukemia and received high-dose cytarabine (Ara-C; HDAC) in order to analyze risk factors associated with HDAC neurotoxicity (NT). There were adequate records on 101 patients who received 147 courses of HDAC. Twenty-six treatment courses (18%) were complicated by NT. The median time of NT onset was 5 days (range, 1 to 10 days), and NT was reversible in 16 of 21 survivors (76%). Patients with severe NT (grades 3 to 4) were less likely to have complete reversal of their neurological deficit than those with mild NT (P less than .1). In our patients, there was no significant association between previously described risk factors (age over 49 years, male gender, CNS disorder, and cumulative HDAC dose greater than 48 g/m2) and incidence of NT. However, treatment courses involving HDAC given during renal insufficiency (serum creatinine greater than or equal to 1.5 mg/dL or an increase in serum creatinine greater than 0.5 mg/dL) were much more likely to be complicated by any degree of NT during administration of HDAC (62%) and severe NT (42%) than those given during normal renal function (8% and 3%, respectively; P less than .001). Of the treatment courses involving patients with estimated creatinine clearances less than 60 mL/min, 76% were complicated by NT compared with 8% of treatment courses involving patients with clearances greater than 60 mL/min (P less than .001). HDAC courses with neurotoxic patients had higher serum creatinines (2.1 +/- 1.4 v 1.1 +/- 0.6 mg/dL), greater increases in serum creatinine (+ 0.5 +/- 0.8 v + 0.07 +/- 0.3 mg/dL), and lower estimated creatinine clearances (61 +/- 35 v 91 +/- 29 mL/min) than those courses with nonneurotoxic patients (P less than .001, all parameters). Patients receiving HDAC during renal insufficiency are at high risk for developing NT. Dose reduction of HDAC should be considered for patients with renal insufficiency.

High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency.

PURPOSE: To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT). PATIENTS AND METHODS: We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d. RESULTS: Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT. CONCLUSION: HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.

Risk-adapted treatment of adult acute lymphoblastic leukemia (ALL).

Modern intensive chemotherapy programs have identified several important prognostic factors for treatment outcomes in adult acute lymphoblastic leukemia. This has allowed clinicians to tailor treatment regimens designed specifically for the various patient subgroups. Of adult ALL patients, 75% have B-lineage disease, and certain biologic characteristics in these patients, including older age and the incidence of mediastinal and CNS disease, differentiate them from T-cell patients. Most of the high-risk cytogenetics are found in the B-lineage group, making cytogenetics the single most powerful prognostic factor in ALL after failure to respond to initial treatment. Currently, there is no subgroup of ALL patients in which standard chemotherapy can be described as adequate, and improved treatment is needed for all groups of patients. These improvements will come from prospective randomized trials. At this time, allogeneic transplant remains the treatment of choice for high-risk ALL.

Post-remission cytopenias following intense induction chemotherapy for acute myeloid leukemia.

Forty-five patients with untreated, de novo acute myeloid leukemia (AML) were treated with high-dose cytosine arabinoside (Ara-C) plus mitoxantrone or daunorubicin. Forty-two patients entered complete remission with recovery of normal blood counts. Seven of these patients were excluded from further analysis (two, early consolidation chemotherapy; four, early relapse; one, hypersplenism). Of the remaining 35 patients, 20 (57%) developed thrombocytopenia and anemia (with or without neutropenia) a median of 3 weeks after entering complete remission. Post-remission cytopenias were more common in patients receiving mitoxantrone (81%) compared to those receiving daunorubicin (37%; p < 0.003). The cytopenias lasted a median of 54 days. Four of five patients in whom the cytopenias did not recover received mitoxantrone. Leukemia relapse or myelodysplasia did not explain these cytopenias. Post-remission cytopenias resulted in a greater than 90-day delay or prevention of planned autologous bone marrow transplantation in 13 of 17 otherwise eligible patients. We conclude that post-remission cytopenias are common following blood count recovery in AML patients entering complete remission with high-dose Ara-C and mitoxantrone or daunorubicin. Post-remission cytopenias do not necessarily imply leukemia relapse.

The effect of graft purging with 4-hydroperoxycyclophosphamide in autologous bone marrow transplantation for acute myelogenous leukemia.

BACKGROUND: Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported. METHODS: We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission. Analyses were restricted to patients transplanted less than 6 months after achieving remission. Using Cox proportional hazards regression, we compared time to treatment failure (death or relapse, inverse of leukemia-free survival) after 4HC-purged vs unpurged transplants while controlling for important prognostic factors. RESULTS: Median duration of posttransplant neutropenia was 40 (range, 10-200) days after 4HC-purged transplants and 29 (9-97) days after unpurged transplants (p < 0.01). Transplant-related mortality was similar in the two groups. In multivariate analysis, patients receiving 4HC-purged transplants had lower risks of treatment failure than those receiving unpurged transplants (relative risk, 0.69, p = 0.12 in the first posttransplant year; relative risk, 0.28, p < 0.0001 thereafter). Adjusted three-year probabilities of leukemia-free survival (95% confidence interval) were 56% (47-64%) and 31% (18-45%) after 4HC-purged and unpurged transplants in first remission, respectively. Corresponding probabilities in second remission were 39% (25-53%) and 10% (1-29%). CONCLUSION: Grafts purged with 4HC are associated with higher leukemia-free survival after autologous bone marrow transplants for AML.

Polymyositis as a manifestation of chronic graft-versus-host disease.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

Busulfan plus etoposide as a preparative regimen for autologous bone marrow transplantation for acute myelogenous leukemia: an update.

We have used a new preparative regimen prior to autologous bone marrow transplantation in patients in remission of acute myelogenous leukemia (AML). Sixty-two patients were treated with preparative chemotherapy consisting of 1 mg/kg of busulfan every 6 hours for 4 days (total dose 16 mg/kg) on days -7 to -4 followed by an intravenous infusion of 60 mg/kg of etoposide on day -3. Autologous bone marrow that had been purged with 4-hydroperoxycyclophosphamide was infused on day 0. Thirty-five of the treated patients were in first remission, 21 were in second or third remission, and six had primary refractory AML and required aggressive salvage regimens to achieve remission. Among patients in first remission, one treatment-related death and five relapses have occurred. With a median follow-up of 25 months, the actuarial relapse rate is 19% +/- 8% and the disease-free survival rate is 79% +/- 8% at 3 years. The 16 patients with favorable FAB subtypes (M3 or M4E0) showed an excellent response to this treatment protocol, with no relapses after median follow-up of 35 months. Among patients in second or third remission, there were five treatment-related deaths and five relapses. With a median follow-up of 41 months, the actuarial relapse rate is 30% +/- 11% and the disease-free survival rate is 52% +/- 11% at 3 years. Four of six primary refractory patients died during treatment and one remains in remission with short follow-up. These preliminary data indicate that aggressive preparative regimens followed by the infusion of purged autologous bone marrow may be a promising approach to improving the clinical outcome of adult patients with AML.

Fungal infections in patients with acute leukemia.

We reviewed the records of 32 patients with acute leukemia and proved invasive fungal infections to determine the clinical and pathologic characteristics of systemic mycosis in patients undergoing intensive induction chemotherapy. The incidence of invasive fungal infections among our patients was at least 27 percent, and Candida and Aspergillus accounted for the majority of these infections. Patients with systemic candidiasis generally had prolonged severe neutropenia, fever refractory to antibiotics, and evidence of mucosal colonization by fungi. At autopsy, Candida was always widely disseminated. Patients with aspergillosis generally had neutropenia, fever, and pulmonary infiltrates at the time of admission to the hospital and, at autopsy, their infections were primarily confined to the lungs. Patients infected with both Candida and Aspergillus had clinical and pathologic findings that were a combination of the features of each type of infection. A diagnosis of invasive fungal infection was established before death in only nine of the patients, all of whom had systemic candidiasis. Four of these patients were successfully treated and survived their hospitalization. The reasons for frequently misdiagnosing and unsuccessfully treating systemic mycosis in patients with acute leukemia are examined, and suggestions are made for improved management of patients at high risk for these infections. These suggestions are based upon recognition of the clinical settings in which fungal infections occur, the aggressive use of invasive diagnostic procedures, and the early empiric use of amphotericin B.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute myelogenous leukemia in 1st remission.

BACKGROUND: Despite considerable data, there is still controversy over which adults with acute myelogenous leukemia (AML) in 1st remission should receive high-dose therapy and a bone marrow transplant rather than conventional-dose chemotherapy. Analyses of data from randomized trials are complex, conclusions sometimes contradictory and results not sufficiently detailed to allow subject-level decisions. OBJECTIVE: To determine appropriate use of high-dose therapy and bone marrow transplants in persons with AML in 1st remission with specific features. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute myelogenous leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, WBC, cytogenetics and FAB-type were permuted to define 72 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a nine-point ordinal scale (1, most inappropriate, 9, most appropriate) considering 3 types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm developed. CONCLUSIONS: In people with an HLA-identical sibling, this type of transplant was rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. In people without an HLA-identical sibling, an alternative donor transplant was rated appropriate in those < 30 years with unfavorable cytogenetics, uncertain in those > 30 years and unfavorable cytogenetics and inappropriate in all other settings. Autotransplants were rated appropriate in people with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor, when available, was always preferred to an alternative donor transplant or autotransplant. In people without an HLA-identical sibling, an autotransplant was almost always favored over an alternative donor transplant with the magnitude of preference inversely correlated with transplant appropriateness.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in chronic myelogenous leukemia in chronic phase.

BACKGROUND: It is uncertain which people with chronic myelogenous leukemia (CML) in chronic phase should receive conventional treatment (interferon and/or chemotherapy) versus high-dose therapy and a bone marrow transplant. There are no randomized trials comparing these approaches and analyses of data from non-randomized studies are complex, contradictory without sufficient detail to allow subject-level treatment decisions. OBJECTIVE: Determine appropriateness of high-dose therapy and bone marrow transplants in persons with CML in chronic phase with specific features. Develop a treatment algorithm. PANELISTS: nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of chronic myelogenous leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, prognostic score, disease duration, and type of conventional therapy and response were permuted to define 90 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional therapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of similar settings and a treatment algorithm developed. CONCLUSIONS: In people with CML in chronic phase and an HLA-identical sibling donor and in those with an alternative donor (but no HLA-identical sibling), a transplant was rated appropriate in those with a < or = partial cytogenetic response to interferon and uncertain or inappropriate in all other settings. Autotransplants were rated uncertain or inappropriate in all settings. Most of the variance in appropriateness ratings between different clinical settings was accounted for by response to interferon: complete versus < or = partial response. An HLA-identical sibling donor, when available, was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling, an alternative donor was favored over an autotransplant at higher appropriateness indices and the converse at lower appropriateness indices.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute lymphoblastic leukemia in first remission.

BACKGROUND: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. OBJECTIVE: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. CONCLUSIONS: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.

Autologous stem cell transplantation for acute myeloid leukemia.

Autologous bone marrow transplant (ABMT) and stem cell transplantation (ASCT) are important treatment modalities for acute myeloid leukemia (AML). The role of ASCT in first remission patients remains controversial. Phase II and phase III studies demonstrate that patients with favorable-risk cytogenetics benefit from ASCT, with reduction in relapse and improvement in leukemia-free survival (LFS). Patients with poor-risk cytogenetics do not appear to benefit significantly from ASCT and should preferentially be treated with allogeneic transplant. The role of ASCT for patients with intermediate risk disease is uncertain. It appears that ASCT in first remission will improve disease-free survival compared to standard chemotherapy. Sufficient patients who relapse after chemotherapy treatment can be salvaged with ASCT in second remission such that the beneficial effect on overall survival is blunted. ASCT produces equivalent results to ABMT but with reduced morbidity. The collection of stem cells during recovery from intensive dose consolidation therapy appears to be an attractive strategy that can increase the percentage of patients who are able to receive their intended transplant. Consolidation therapy prior to stem cell collection and transplant has been shown to decrease the relapse rate and improve outcomes, but the optimal nature of this consolidation therapy is unknown. For patients with AML in second remission, ABMT/ASCT offers a substantial salvage rate, and is particularly effective for patients with acute promyelocytic leukemia.

Pure red cell aplasia complicating an ABO-compatible allogeneic bone marrow transplantation, treated successfully with antithymocyte globulin.

A patient underwent an HLA-identical ABO-compatible allogeneic bone marrow transplant for aplastic anemia. She then developed pure red cell aplasia which was treated successfully with antithymocyte globulin and methylprednisolone, after failing to respond to intravenous immune globulin infusion.

Immune globulin therapy in allogeneic bone marrow transplant: a critical review.

Various immune globulin products have been utilized in allogeneic bone marrow transplant (BMT) in an effort to decrease the incidence of cytomegalovirus (CMV) infection, infection due to other pathogens and graft versus host disease (GVHD). Controlled trials regarding the use of prophylactic immune globulin have been reviewed. Differences among products and use of various dosing regimens complicates the comparison of the results of one trial to another. Risk factors, such as donor and recipient CMV serology, GVHD prophylaxis, the use of white blood cell transfusions and conditioning regimens, vary significantly, further complicating the analysis. Autologous BMT patients do not appear to benefit from prophylactic globulin therapy. The effectiveness of immune globulin in the prevention of CMV disease in allogeneic BMT is questionable; other measures, including prophylactic ganciclovir and screening of blood products appear to be of greater value. Immune globulin inconsistently decreases the incidence of infection due to pathogens other than CMV. The best established role for prophylactic immune globulin in allogeneic BMT is in the prevention of GVHD.

Delayed engraftment of 4-hydroperoxycyclophosphamide-purged autologous bone marrow after induction treatment containing mitoxantrone for acute myelogenous leukemia.

We have previously documented that adults with de novo acute myelogenous leukemia (AML) who are induced into first complete remission with mitoxantrone and high-dose cytarabine are more likely than those induced with daunorubicin and high-dose cytarabine to develop a bone marrow injury pattern with delayed cytopenias after achieving initial complete remission, a phenomenon we have termed post-remission cytopenia syndrome. We therefore retrospectively compared the engraftment kinetics of mitoxantrone and daunorubicin patients following 4-hydroperoxycyclophosphamide (4HC) purged autologous bone marrow transplant (ABMT) with busulfan-etoposide conditioning. Despite equivalent graft colony forming units granulocyte macrophage (CFU-GM), mitoxantrone patients (n = 13) took a median 7 weeks longer to achieve 1.0 x 10(9)/l granulocytes, 5 weeks longer to achieve platelet transfusion independence, and 10 weeks longer to achieve red blood cell transfusion independence, and required more platelet transfusions (P = 0.008), than daunorubicin patients (n = 13). Patients experiencing the post-remission cytopenia syndrome (n = 11) had significantly slower engraftment than those not experiencing the syndrome (n = 15; P < or = 0.04). Two mitoxantrone and five daunorubicin patients have relapsed after ABMT (P = 0.38). We conclude that the type of induction chemotherapy used in untreated adults with de novo AML can influence subsequent engraftment after 4HC-purged ABMT. We believe that mitoxantrone combined with high-dose cytarabine should be avoided as induction chemotherapy in patients for whom 4HC-purged ABMT is planned.

Autologous bone marrow transplantation for acute myeloid leukemia using 4-hydroperoxycyclophosphamide-purged bone marrow and the busulfan/etoposide preparative regimen: a follow-up report.

We studied the use of autologous bone marrow transplantation (ABMT) as treatment for acute myeloid leukemia (AML) in adults up to age 60. We used a preparative regimen of busulfan 16 mg/kg plus etoposide 60 mg/kg and bone marrow purged with 100 microg/ml of 4-hydroperoxycyclophosphamide (4HC). We treated 50 first remission patients; there were two treatment-related deaths and 13 relapses. With median follow-up of 6.8 years (minimum 4.5) disease-free survival (DFS) is 70%, relapse rate 27% and overall survival 72%. Patients with favorable cytogenetics had DFS 78% and relapse 18% whereas unfavorable patients had DFS 63% and relapse rate 35%. For 25 patients in second or third remission there were five treatment-related deaths and seven relapses. DFS is 52% and relapse rate 35%. None of six patients with primary refractory AML had long-term disease control. These data support the use of ABMT with an intensive preparative regimen and purged bone marrow as a highly effective treatment for adults with AML.

Autologous stem cell transplantation for advanced acute myeloid leukemia.

We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (x10(6)/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment.

High-dose chemotherapy (CTM) for breast cancer.

We designed and implemented a new mitoxantrone-based high-dose chemotherapy regimen to minimize pulmonary injury (seen in carmustine-based regimens) in patients with breast cancer. One hundred and ninety-one breast cancer patients (99 stage II/IIIA; 27 stage IIIB; 65 stage IV responsive to conventional-dose chemotherapy) were treated with high-dose chemotherapy (CTM) delivered over 4 days (cyclophosphamide (6 g/m2), thiotepa (600 mg/m2), and mitoxantrone (24-60 mg/m2)) followed by autologous hematopoietic stem cell rescue. Stage II/III patients received chest wall radiation and tamoxifen (if hormone-receptor positive) after CTM. The 5-year event-free survival (EFS) for stage II/IIIA patients with 10 or more involved axillary lymph nodes (n = 80) was 62 +/- 12%. Hormone receptor-positive patients with 10 or more nodes did significantly better than negative patients. The EFS for stage IIIB patients at 5 years was 44 +/- 19%; for stage IV patients at 5 years was 17 +/- 10%. Stage IV patients achieving complete response in viscera and/or soft tissue prior to CTM did significantly better than those achieving a partial response. There were six (3%) treatment-related deaths including two due to diffuse alveolar hemorrhage. There were no episodes of delayed interstitial pneumonitis. There were six severe cardiac events in 91 patients (6.6%) but none after instituting mitoxantrone dose-adjustment in the final 100 patients. We conclude that CTM is associated with a low treatment-related mortality and little pulmonary toxicity. CTM produces excellent outcomes in stage II/IIIA patients with 10 or more involved axillary lymph nodes.

Kinetics and sensitivity of daunorubicin in patients with acute leukemia.

Leukemia cells isolated from eight patients with acute leukemia before treatment were examined for in vitro uptake of daunorubicin (DNR) and inhibition of DNA synthesis. In addition, plasma and cellular levels of DNR and daunorubicinol (DOL) were examined in six of the eight patients. Inhibition of DNA synthesis was determined with a 3H-thymidine incorporation assay. In vitro cellular 14C-DNR was quantified by means of liquid scintillation spectrometry, whereas in vivo DNR and DOL concentrations were determined by high-performance liquid chromatography. In vitro intracellular plateau concentrations of DNR were achieved within 1-2 h after continuous exposure to 0.01, 0.1, and 1.0 microgram/ml in the majority of cases. Based on our in vitro studies, a dose-response curve was found between increasing intracellular DNR and incorporation of 3H-thymidine. Peak intracellular levels of DNR after treatment occurred immediately after administration of the drug, whereas intracellular DOL levels accumulated over several hours. Plasma concentrations of DNR and DOL were not useful in estimating target tissue concentrations or inhibition of 3H-thymidine incorporation. Extrapolation of in vivo cellular DNR concentrations to the in vitro dose-response curve allows an estimate of DNR sensitivity.