Ronald S. Walters

Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer.

PURPOSEnTo determine the efficacy (objective response rate and duration of response and survival) and toxicity of docetaxel in patients with strictly defined anthracycline-resistant metastatic breast cancer (MBC).nnnPATIENTS AND METHODSnThirty-five patients with bidimensionally measurable MBC who had progressive disease while receiving anthracycline-containing chemotherapy were registered onto the phase II trial. Docetaxel was administered at a dose of 100 mg/m2 over 1 hour every 21 days.nnnRESULTSnThirty-four patients were assessable for disease response; 18 (53%; 95% confidence interval [CI], 35% to 70%) achieved a partial response. The median times to disease progression and survival duration were 7.5 and 13.5 months, respectively, for responding patients. The median overall survival duration was 9 months. Two hundred eight cycles (median, five) of docetaxel were administered. Neutropenia with less than 500 cells/microL developed in 31 of 35 patients; it was complicated by fever in 30 (14%) of 208 cycles and in 18 (51%) of 35 patients, including one treatment-related death. Fluid retention was seen in 15 (43%) of 35 patients, including pleural effusions in 11 patients (31%). Moderate skin toxicity, asthenia, and myalgia were observed in 16%, 58%, and 37% of cycles, respectively.nnnCONCLUSIONnDocetaxel has the highest reported antitumor activity in anthracycline-resistant MBC. High objective response rates were seen in patients with visceral-dominant involvement, multiple metastatic sites, or extensive previous therapy. Docetaxel is associated with severe but reversible neutropenia, asthenia, and cumulative dose-related fluid retention. Dexamethasone decreased the frequency and severity of skin toxicity and appeared to ameliorate fluid retention.

Characteristics of accelerated disease in chronic myelogenous leukemia

Determination of the characteristics of accelerated disease in chronic myelogenous leukemia (CML) helps in individual prognostication, and in the introduction and analysis of investigative approaches based on risk‐benefit ratios. The outcome of 357 patients with Philadelphia chromosome‐positive CML was analysed from the time of development of suspected features of accelerated disease. Median survivals shorter than 18 months were associated with the appearance of any of the following: cytogenetic clonal evolution; extramedullary disease; peripheral blasts ⩾ 15%, peripheral blasts and promyelocytes ⩾ 30%, or peripheral basophils ⩾ 20%; platelet count < 1.0 × 105/μl; marrow blasts ⩾ 15%, marrow blasts and promyelocytes ⩾ 30%, or marrow basophils ⩾ 20%. Relative hazard ratios, or risk of death per unit time, were calculated based on the relative survivals of patients who did or did not develop the particular feature of accelerated disease, after accounting for the time to development of the characteristic. Further analysis identified five features that have additive independent prognostic importance: cytogenetic clonal evolution; peripheral blasts ⩾ 15%; peripheral basophils ⩾ 20%; peripheral blasts and promyelocytes ⩾ 30%; and thrombocytopenia. By providing an objective estimate of prognosis in accelerated disease, the model identifies patients in need of different therapeutic interventions before the development of blastic crisis.

Chronic myelogenous leukemia in blast crisis: Analysis of 242 patients

Two hundred forty-two patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis were reviewed to identify significant biologic and prognostic associations. Twenty percent of patients had lymphoid blast crisis. Clonal evolution was present in 60 percent of patients at blast crisis and involved most frequently the development of a double Philadelphia chromosome, trisomy 8, or isochromosome 17. The overall median survival from blast crisis was 18 weeks. Patient characteristics demonstrated to have significant association with short survival were: anemia; thrombocytopenia; myeloid or undifferentiated blast cell morphology; clonal evolution involving the presence of a double Philadelphia chromosome, trisomy 8, or isochromosome 17; and low marrow blast percentage. Of 195 patients who received therapy for blast crisis, complete remission was achieved in 44 (23 percent) patients, and 24 (13 percent) patients had a partial remission or hematologic improvement. Lower complete remission rates were associated with old age, thrombocytopenia, myeloid or undifferentiated blast cell morphology, clonal evolution--especially isochromosome 17 and trisomy 8--and long interval from diagnosis to onset of blast crisis. A multivariate analysis identified two characteristics to have independent prognostic importance for both survival and remission: platelet counts and blast cell morphology. In addition, clonal evolution had additive prognostic value for survival (double Philadelphia chromosome) and for response (isochromosome 17). The beneficial association of therapy with survival was demonstrated by the significantly longer median survival of patients treated since 1981 compared with those treated earlier, even after accounting for the pretreatment prognostic factors, and by the significant improvement in survival of patients achieving remission using the landmark analysis technique.

Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features.

One hundred twelve patients who developed acute leukemia or a myelodysplastic syndrome (MDS) after chemotherapy or irradiation for another malignancy were reviewed. The median time from initial therapy to development of secondary leukemia or MDS was 71 months (range, 7 to 331 months). The initial malignancy was hematologic in 43%. An MDS presentation occurred in 57 patients (51%), 55% of whom subsequently transformed to acute leukemia. Chromosomal abnormalities were documented in marrow specimens from 70 of 89 patients with analyzable metaphases (79%; 69% of the total group). Compared with 34 patients with metachronous secondary leukemia without prior chemotherapy or irradiation, those with therapy-related leukemia exhibited a significantly higher frequency of abnormalities of chromosomes 5 and/or 7 (43% v 18%), and lower incidence of diploid karyotypes (18% v 50%). Chromosome 5 and/or 7 abnormalities were also significantly higher in patients previously treated with alkylating agents, procarbazine, and nitrosoureas (72% to 83%), compared with those who had received cyclophosphamide-based regimens (29%), other chemotherapies (14%), or irradiation alone (29%). The median overall survival from diagnosis of the secondary leukemia or MDS was 30 weeks. Survival was significantly shorter for patients with acute leukemia compared with MDS presentation (21 v 45 weeks); in the latter category, it was similar whether evolution to acute leukemia occurred or not. Of 72 patients treated with antileukemia therapy, 29% achieved complete remission (CR). A multivariate analysis of prognostic factors demonstrated the cytogenetic pattern to be the most important characteristic determining remission rate and survival. Other important prognostic features were the morphologic presentation (MDS v acute leukemia) for probability of achieving remission, and patient age and marrow blasts percentage for survival.

Acute promyelocytic leukemia: M.D. Anderson hospital experience☆

Sixty patients with acute promyelocytic leukemia were treated between 1973 and 1984. The overall median survival was 16 months with a five-year survival rate of 31 percent. The complete remission rate was 53 percent and was similar whether they received amsacrine- or anthracycline-based regimens (60 percent versus 51 percent). The median remission duration was 29 months. At five years, 43 percent of patients with responses to treatment had continuous remission and 57 percent were alive. Salvage therapy produced remissions in 53 percent of patients during first relapse, with two long-term survivors after further consolidation with bone marrow transplantation. Early fatal hemorrhage associated with disseminated intravascular coagulopathy during induction therapy occurred in 16 patients (26 percent). Multivariate analysis of the pretreatment patient characteristics significantly associated with an increased risk of fatal hemorrhage identified four that have primary prognostic importance: thrombocytopenia, elevated absolute blast and promyelocyte counts, old age, and anemia. Patients having up to two unfavorable features had a low risk of fatal hemorrhage compared with those who had more than two (5 percent versus 58 percent; p less than 0.0001). Overall, patients who received heparin had a lower incidence of fatal hemorrhage than those who did not (19 percent versus 32 percent). Heparin therapy was not beneficial to those at low risk but was associated with a trend towards decreased hemorrhagic deaths among high-risk patients (45 percent versus 67 percent). Cytogenetic studies demonstrated the characteristic 15;17 translocation in 73 percent of patients with analyzable metaphases, whereas 12 percent had other karyotypic abnormalities. Remission induction was often associated with a gradual atypical morphologic evolution into remission without intermediate hypoplasia with the interim marrows showing a high proportion of blasts. It is concluded that acute promyelocytic leukemia is a unique disease with a high potential for cure. Knowledge of its prognosis using present frontline and salvage therapy, of the factors related to fatal hemorrhage, and of the unusual patient marrow profiles during remission induction may improve the therapeutic approach.

Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.

PURPOSEnTo determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially.nnnPATIENTS AND METHODSnTen patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly.nnnRESULTSnEight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3.nnnCONCLUSIONnWhen paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.

Response to salvage therapy and survival after relapse in acute myelogenous leukemia.

The response to and survival following first salvage therapy regimens for 243 patients with acute myelogenous leukemia (AML) treated between 1974 and 1985 were evaluated. Eighty (33%) patients obtained a complete remission (CR), 24% died prior to achieving a response, and 43% were resistant on their first salvage regimen. The median survival was 18 weeks. Five percent overall and 16% of the CR patients are predicted to survive for more than 5 years. The factor most strongly associated with response and survival was the duration of the initial remission with 49 of 82 (60%) patients whose initial CR duration was at least 1 year in duration obtaining a second CR v 31 of 161 (19%) for patients with a shorter remission (P less than .01). Age, liver function, serum lactic dehydrogenase (LDH), karyotype, and the proportion of blasts plus promyelocytes present at the time of starting salvage therapy were strongly associated with probability of response and survival. Multivariate analysis was used to develop logistic regression and proportional hazard models to predict probability of response and survival, respectively. The major regimens used were conventional-dose cytarabine (ara-C) (combined with anthracyclines or amsacrine), high-dose ara-C, rubidazone, amsacrine (AMSA), other anthracyclines, and autologous or allogeneic transplant programs. After allowing for the prognostic factors in the models, specific treatment regimens were not strongly associated with prognosis.

Toward a clinically relevant cytogenetic classification of acute myelogenous leukemia

Cytogenetic studies with Giemsa banding were performed on the bone marrow cells of 384 patients with acute myelogenous leukemia treated between 1975 and 1983. An abnormal karyotype was detected in 54% of patients, being present in 100% of metaphases (AA) in 31% and only a proportion of cells (AN) in 22%. Specific translocations or other abnormalities were noted in 22% of patients, the most common of which were t(8;21) (q22;q22) in 7%, t(15;17) (q22;q21) and inv (16) (p13q22) in 5.5%, t(9;22) (q34;q11) in 3% and abnormalities of 11q23 in 1.3%. Loss of the Y chromosome was noted in 21 patients, associated with t(8;21) in 11 patients and the sole abnormality in eight patients (45, X, -Y). Most (66%) of the other abnormalities involved addition of chromosome 8 or loss or deletion of 5 or 7 (+8, -5 or -7, 5q- or 7q- group). The remaining patients had miscellaneous abnormalities (MA). A marked assymetry was noted in the distribution of important clinical prognostic variables such as age, sex, history of an antecedent hematologic disorder and presence of Auer rods within the various cytogenetic categories. The specific translocation/abnormalities were more common in younger patients (p less than 0.01). Analysis of response, remission duration and survival demonstrated that inv 16 and t(8;21) were favorable prognostic categories; diploid, t(15;17) and 45,X,-Y had intermediate prognosis, and all other categories were unfavorable prognostic groups. The response rate and survival for diploid patients (NN) was superior to patients with abnormalities. No difference in response rate, CR duration or survival was noted between the AA and AN groups. A prognostic classification according to cytogenetic category based on clinical associations is proposed which will be tested prospectively in subsequent studies.

Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia.

One hundred five untreated adult patients with acute lymphocytic leukemia (ALL) were entered on the vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and Decadron (dexamethasone; Merck Sharp and Dohme, West Point, PA) (VAD) regimen. Induction therapy with VAD and VAD plus cyclophosphamide (CVAD) was followed by a 2-year rotating maintenance program with multiple antileukemic combinations, and included early intensifications with Adriamycin and high-dose cytarabine (ara-C) and a late intensification with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologous bone marrow transplantation (BMT). Duration of therapy was 24 to 30 months. Eight-eight patients (84%) achieved complete remission (CR) with VAD-CVAD, and 94 (90%) ultimately had CR with continuation of the maintenance as planned. Induction mortality was 3%; only half of the patients required prolonged hospitalization of 1 week or longer, or intravenous antibiotics. Maintenance therapy was given to 79 patients, while nine with histocompatibility locus antigen (HLA)-matched related donors underwent allogeneic BMT. The median remission duration was 22 months, and the median survival was 19 months. Factors associated with significantly worse CR rates were older age, the presence of hypoalbuminemia or hyperbilirubinemia, L2 or L3 morphology, and myeloid markers on leukemic cells. Those associated with significantly worse remission durations were the presence of elevated leukocyte or absolute peripheral blast counts, Philadelphia chromosome (Ph)-positive or B-cell ALL, L2 morphology, and more than one course to achieve CR. Patients could be divided into standard-risk ALL (28% of patients) and high-risk ALL (72% of patients) with long-term remission rates of 70% versus less than 30%. The 26 patients who underwent CBV autologous BMT had similar long-term outcome compared with 21 patients who did not (older age, medical contraindications, or socioeconomic problems). The presence or absence of myeloid markers on leukemic cells did not affect long-term prognosis. We conclude that VAD therapy is a well-tolerated effective induction regimen. High-risk ALL patients require alternative maintenance investigational approaches.

Phase I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia

Sixty-four patients with refractory acute leukemia were treated with high-dose cytosine arabinoside given at a dosage of 3 g/m2 intravenously over two hours every 12 hours for four to 12 doses, repeated at two- to three-week intervals. Complete remissions were observed in 16 patients (25 percent), and the median duration of remission was three months (range, one to 10 months). Remission rates were similar for patients with acute myelogenous and acute lymphocytic leukemia (24 and 27 percent, respectively). Response rates were significantly higher in patients with initial remission durations of more than six months than in those with shorter remissions or those in whom there was no response to front-line therapy (41 and 9 percent; p less than 0.01). Similarly, patients with disease sensitive to conventional cytosine arabinoside had higher response rates than did those with resistant disease (54 and 17 percent; p = 0.03). Serial in vivo measurements of intracellular concentrations of the active metabolite of cytosine arabinoside in peripheral blasts following the initial dose demonstrated considerable individual variation. Favorable intracellular pharmacology of this active metabolite, manifested by its higher intracellular concentrations 12 hours after the first dose, by longer half-lives of active metabolite levels, and by higher values of the measured area under the curve of its accumulation and retention, was associated with higher response rates. Central nervous system toxicity occurred in 24 percent of patients, and pulmonary toxicity occurred in 22 percent; both were dose-limiting and dose-related. Other toxicities included nausea, vomiting, diarrhea, conjunctivitis, photophobia, cytosine arabinoside fever, skin rashes, and hepatic dysfunction. Response rates were similar for schedules utilizing four to six doses at two-week intervals or nine doses at three-week intervals (27 percent versus 25 percent). The schedule of 12 doses had a more rapid antileukemic effect but resulted in significantly higher toxicity and mortality rates during therapy with a similar overall response rate (21 percent). Thus, high-dose cytosine arabinoside is an effective regimen with substantial toxicity in patients with acute leukemia.