Stephanie F. Williams

Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin's disease

PURPOSE To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy and autologous bone marrow transplantation for relapsed/refractory Hodgkins disease with emphasis on the impact of involved-field radiotherapy. METHOD AND MATERIALS Fifty-four adult patients with refractory (25) or relapsed (29) Hodgkins disease underwent high-dose chemotherapy with either autologous bone marrow (32) or peripheral stem cell (23) transplantation. Twenty patients received involved-field radiotherapy either prior to (7) or following (13) high-dose chemotherapy. Patients treated prior to the high-dose chemotherapy received radiation to bulky or symptomatic sites, and those treated following the transplantation were treated to sites of disease persistence (10) or to consolidate a complete response (3). Twenty-six patients had purely nodal disease, 10 had lung involvement, 7 liver, 5 bone, and 3 bone marrow. A total of 147 sites were present prior to high-dose chemotherapy. Nineteen were bulky (> or = 5 cm), and 42 arose in a previous radiotherapy field. RESULTS Twenty-five of the 54 patients (46.3%) relapsed. Seventeen (68.0%) relapsed in sites of disease present prior to high-dose chemotherapy. Patients treated with involved-field radiotherapy had a lower rate of relapse in sites of prior disease involvement (26.3 vs. 42.8%) (p < 0.05) than those not treated with radiotherapy. Twenty-one patients had disease persistence following high-dose chemotherapy, of which 10 received involved-field radiotherapy and were converted to a complete response. Patients with disease persistence who received involved-field radiotherapy had a better progression-free survival (40.0 vs. 12.1%) (p = 0.04) than those who did not. Moreover, the patients converted to a complete response had similar progression-free and cause-specific survival as those patients achieving a complete response with high-dose chemotherapy alone. Of the initial 147 sites, 142 (97.3%) were amenable to involved-field radiation therapy. The addition of involved-field radiotherapy improved the 5-year local control of all sites (p = 0.008), nodal sites (p = 0.01), and sites of disease persistence (p = 0.0009). CONCLUSIONS Patients with relapsed/refractory Hodgkins disease undergoing high-dose chemotherapy and autologous bone marrow rescue have a high rate of relapse in sites of prior disease involvement. Involved-field radiotherapy is capable of improving the control of these sites, the majority of which are amenable to radiotherapy. In addition, the use of radiotherapy to sites of disease persistence following high-dose chemotherapy may improve the outcome of these patients.

Paradoxical relationship between acetylator phenotype and amonafide toxicity

Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration—time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.

Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors

We sought to define risk factors predisposing breast cancer and lymphoma patients to cardiac and pulmonary toxicity when undergoing high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR). Additionally, we evaluated in depth the predictive value of the ejection fraction measured prior to HDC in determining cardiac toxicity. In this retrospective analysis, 24 variables were examined in 138 patients undergoing HDC and ASCR from 1990 until 1995. Logistic regression models were used to model the probability of experiencing cardiac and pulmonary toxicity as a function of the 24 prognostic covariates. Cardiac toxicity occurred in 12% of patients and pulmonary toxicity in 24% of patients. Bivariate analyses showed that patients with lymphoma (as opposed to breast cancer) and those with a higher cardiac risk factor score were more likely to experience cardiac toxicity. Multivariate logistic regression models predicted lymphoma and older age to be risk factors for cardiac toxicity. History of an abnormal ejection fraction and higher doses of anthracyclines prior to HDC may also contribute to cardiac toxicity. Pulmonary toxicity occurred more commonly in lymphoma than breast cancer patients, likely due to the busulfan used in the HDC regimen. No other risk factors for pulmonary toxicity were identified. We conclude that older patients with lymphoma should be carefully evaluated prior to being accepted for HDC programs. Older patients with breast cancer may tolerate this procedure well. There is a trend towards cardiac toxicity in patients with a past history of low ejection fraction, although seemingly poor cardiac risk patients may fare well with HDC if carefully selected with the aid of a thorough cardiac evaluation. Bone Marrow Transplantation (2000) 25, 885–894.

Myelodysplasia and acute leukemia following high-dose chemotherapy and autologous bone marrow or peripheral blood stem cell transplantation.

Therapy-related myelodysplastic syndrome (t-MDS)/ acute myeloid leukemia (t-AML) has been reported after autologous bone marrow or peripheral blood stem cell transplantation (ABMT/PBSCT) for various malignancies. We retrospectively reviewed all adult ABMT/PBSCT cases performed at the University of Chicago Medical Center from 1985 to 1997 in order to determine the incidence of therapy-related leukemia. Among 649 patients, seven (1.1%) developed therapy-related acute lymphoblastic leukemia (one patient) or t-MDS/t-AML (six patients). Of these seven, primary malignancies included one case of breast carcinoma, five cases of Hodgkin’s disease (HD) and one case of non-Hodgkin’s lymphoma (NHL). Disease-specific incidences for therapy-related leukemia occurring after ABMT/PBSCT were one in 354 (0.3%) for breast carcinoma, five in 79 (6.3%) for HD and one in 103 (1%) for NHL. The median latency periods for the development of therapy-related leukemia from the time of initial diagnosis and of ABMT/PBSCT were 5.5 and 1.5 years, respectively, for the combined HD and NHL group of patients and 4.4 and 2.8 years, respectively, for the one breast carcinoma patient. All seven patients had clonal cytogenetic abnormalities, and five had recurring abnormalities typical of myeloid disorders. Given the similar latency period observed in patients treated with conventional chemotherapy alone, our findings support the hypothesis that therapy-related leukemia after ABMT/PBSCT likely results from pre-transplant therapy. Early detection of therapy-related leukemia is therefore critical to exclude these patients from undergoing ABMT/PBSCT.

A Pilot Study of Prophylactic Aerosolized Amphotericin B In Patients at Risk for Prolonged Neutropenia

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.

Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome

BackgroundEzatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.Results54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.ConclusionPhase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.Trial RegistrationClinicaltrials.gov: NCT00035867

Modulation of vinblastine resistance with cyclosporine: A phase I study

Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine.

High dose chemotherapy and stem cell rescue for aggressive non-Hodgkin's lymphoma: Pattern of failure and implications for involved-field radiotherapy

PURPOSE To evaluate the pattern of failure and outcome of patients with aggressive non-Hodgkins lymphoma (NHL) undergoing high-dose chemotherapy (HDCT) and autologous stem cell rescue (SCR) with an emphasis on the role of adjuvant involved-field radiotherapy (IFRT). METHOD AND MATERIALS Fifty-three adult patients with aggressive NHL (46 intermediate-and 7 high-grade) underwent HDCT with SCR. All patients underwent induction chemotherapy prior to high dose intensification. Seven (13.2%) received IFRT to 10 disease sites either prior to or following HDCT. Indication included symptomatic or bulky disease, persistent disease, or to consolidate a complete response (CR). Sites of relapse were designated as old (involved prior to HDCT) or new (previously uninvolved). Median followup was 20.1 months (range, 1.2-69.3 months). RESULTS The 4-year actuarial progression-free (PFS) and cause-specific (CSS) survivals of the entire group were 30.0 and 50.2%, respectively. Excluding toxic deaths, 24 patients (52.2%) relapsed. Sixteen (34.7%) failed in old and 15 (32.6%) in new sites. Patients treated with IFRT had a lower rate of relapse in old sites (0 vs. 41%) (p = 0.04) than patients treated with HDCT alone. Of the 141 sites present prior to induction, 127 (90.1%) were amenable to IFRT. Excluding irradiated sites, the overall 4-year local control (LC) of all amenable sites was 61.1%. Amenable sites failing to achieve a CR to induction had a poorer LC (32.0 vs. 95.1%) (p < 0.0001) than sites in CR. The 4-year LC of sites failing to achieve a CR to HDCT was 29.4%. Adjuvant IFRT improved the 4-year LC of all sites (100 vs. 61.1%) (p = 0.05), persistent sites following induction (100 vs. 32.0%) (p = 0.01) and persistent sites following HDCT (100 vs. 29.4%) (p = 0.01). Adjuvant IFRT was not associated with any untoward acute or late toxicity. CONCLUSIONS The predominant site of relapse in patients with aggressive NHL undergoing HDCT and SCR is in sites of disease present prior to HDCT. However, the risk of relapse of prior disease sites varies greatly depending upon their response to chemotherapy. Sites at greatest risk are those failing to achieve a CR to induction regardless of their response to HDCT. IFRT is capable of reducing the high risk of relapse in these sites, the majority of which are amenable to IFRT. These results demonstrate a rationale for and possible benefit to IFRT in patients with aggressive NHL undergoing HDCT and SCR.

High-dose chemotherapy consolidation with autologous stem cell rescue in metastatic breast cancer: a 10-year experience.

One hundred women with metastatic breast cancer (MBC) underwent high-dose chemotherapy with autologous stem cell rescue at our institution beginning in 1986. The patients underwent induction chemotherapy from June 1986 to December 1993. Patients who showed stable or responsive disease underwent HDC with cyclophosphamide (CY) at 7.5 g/m2 and thiotepa (TPA) at 675 mg/m2 or the same doses of CY and TPA with carmustine at 450 mg/m2. The source of stem cell rescue was either BM alone, BM and G-CSF-mobilized peripheral blood progenitor cells (PBPC) or PBPC alone if patients had BM involvement with MBC. With a median follow-up of 62 months (range 1–109 months), median survival from reinfusion was 16 months with a 5-year survival of 19 ± 4%. The median event-free survival (EFS) was 8 months with a 5-year EFS of 11 ± 3%. Patients achieving a complete response to induction therapy showed a higher 5-year EFS from reinfusion of 31 ± 8% in contrast to 3 ± 3% (P = 0.006) for patients who achieved a partial response to induction therapy prior to HDC. Marrow involvement or source of stem cell rescue did not affect outcome. Our mature results confirm that high-dose chemotherapy with autologous stem cell rescue can confer a prolonged DFS in a subset of women with MBC. However, the high rate of relapse remains a universally disturbing problem in this patient population.

Immunocytochemistry and flow cytometry evaluation of human megakaryocytes in fresh samples and cultures of CD34+ cells.

Adhering platelets on the cell surface can give misleading results when doing flow cytometry analysis of platelet/megakaryocyte-specific glycoprotein (GP) antigens to enumerate megakaryocytes (MK) in mobilized peripheral blood (PB), apheresis products, or normal bone marrow (BM). For adequate quantification and characterization of human MK, we examined samples with parallel flow cytometry and immunocytochemistry. MK expression of GP IIb/IIIa (CD41a), GP Ib (CD42b), GP IIIa (CD61), CD45, CD33, and CD11b, and their light scatter properties were evaluated. Fresh samples of low density mononuclear cells (MNC) or purified CD34+ cells contained 10-45% of platelet-coated cells. Platelet-coated cells decreased dramatically after several days of incubation in a serum-free medium supplemented with stem cell factor, IL-3, IL-6, and/or GM-CSF. Between d 9-12, flow cytometry detected a distinct CD41a+ MK population, 8.3 +/- 1.3% in BM CD34 cell cultures (n = 7) and 13.1 +/- 2.1% in PB CD34 cell cultures (n = 14), comparable to immunocytochemistry data (7.8 +/- 1.9% and 16.4 +/- 2.6%, respectively). CD41a stained a higher proportion of MK than CD42b or CD61, while CD42b+ or CD61+ cells contained more morphologically mature MK than CD41a+ cells in cultures containing aplastic serum. When fluorescence emission of CD41a was plotted against forward-light scatter (FSC), subpopulations of small and large MK were observed. Such subpopulations overlapped in CD41a intensity and side-light scatter (SSC) property. Most MK co-expressed CD45 (98.8% positive) but not CD33 (80.7% negative) or CD11b (88.9% negative). Our data indicate that flow cytometry can be used effectively to identify MK. However, caution should be taken with samples containing adherent platelets.