Jonathan C. Yau

Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support

We have used high-dose therapy followed by randomization to receive or not receive autologous bone marrow infusion in 58 stage IV breast cancer patients (all were estrogen receptor-negative [ER-] or primary hormonal refractory). Patients received a median of four courses of induction chemotherapy and if stable or responding received two courses of intensive therapy with cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 180 mg/m2 (CVP). The complete remission (CR) rate after completion of the induction and intensive phases was 55%. Median progression-free interval from induction is 57 weeks with a projected 2-year progression-free survival of approximately 25%. Six of seven patients followed for greater than 2 years are still progression-free. Three favorable features predicted for improved progression-free survival are the following: (1) absent liver involvement, (2) absent soft tissue involvement, and (3) less than or equal to two disease sites (P values of .001, .013, and .048, respectively). Hormonal and menopausal status did not predict for progression-free survival. Major toxicities were infectious secondary to neutropenia, with a 93% incidence of fever and a 38% incidence of sepsis. The treatment-related mortality rate was 9%, with three infectious, one coronary, and one late hemorrhage-related death of unknown cause. Longer follow-up is still needed to truly evaluate the possibility of long-term disease-free survival, but further studies of this approach to high-dose intensification in poor prognostic groups of stage IV breast cancer appear warranted.

Factors predicting long‐term survival for metastatic breast cancer patients treated with high‐dose chemotherapy and bone marrow support

Background. Poor prognosis of Stage IV breast cancer patients have at best a 10% 3‐year survival rate with conventional chemotherapy. Dose‐intensive chemotherapy improved survival rates for some of these patients.

A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer.

To further improve the effect of high-dose chemotherapy in the treatment of locally advanced and metastatic breast cancer, we sought to develop a second active high-dose noncross-resistant regimen to use in tandem with our customary high-dose regimen of cyclophosphamide, etoposide, and cisplatin (CVP). We performed a phase II trial of high-dose mitoxantrone 30 mg/m2, etoposide 200 mg/m2 every 12 hours x 6, and thiotepa 250 mg/m2 x 3 days (MVT) in 31 patients with heavily pretreated metastatic breast cancer and one with locally advanced chemotherapy-refractory breast cancer. These patients were ineligible for high-dose CVP chemotherapy because of the amount of prior treatment and poor-response status. Of the 32 patients, 14 responded to cycle 1, did not experience any grade 4 toxicity, and received a second cycle of MVT. Overall, seven of 31 patients achieved a complete response (CR; 23%). Four of the 14, who were partial responders to the first cycle, achieved a CR after the second cycle. The overall response rate was 19 of 31 (61%) with an overall median freedom from progression of 4 to 5 months and an overall median survival of 9 months. Toxicity consisted primarily of mucositis (grade 3 or 4 in 69%). The results indicate that high-dose MVT produces significant activity, even in heavily pretreated patients. Administration of a second cycle of high-dose therapy with MVT increased the CR rate, and the morbidity and mortality from the second cycle were not greater than that for the first cycle. Because of the high incidence of grade 3 or 4 mucositis with this regimen, we are currently completing a follow-up study of high-dose mitoxantrone and thiotepa alone.

Immune recovery following allogeneic bone marrow transplantation

A total of 144 evaluations of cell surface markers and cellular immune functions were carried out in 57 patients undergoing allogeneic bone marrow transplantation for acute leukemia in remission and relapse and for aplastic anemia. The periods tested were pretransplant, and 1-3, 4-6, 7-12 and more than 12 months posttransplant. The determination consisted of lymphocyte counts; lymphocyte surface marking using OKT3, OKT4, and OKT8 antibodies; and determination of adherent cells, lysozymes and antibody dependent cellular cytotoxicity (ADCC) against chicken red blood cells, human red blood cells, and CEM cells. Natural killer cells were determined against K562 target cells. Lymphoblastic responses were tested after stimulation with pokeweed mitogen (PWM), concanavalin-A (Con-A), and phytohemagglutinin (PHA). We found that the progression in the leukemic state (first remission, second remission, and relapse), prior to transplantation was paralleled by a decrease in T4 lymphocytes (976/microliter +/- 462; 411/microliter +/- 222; 372/microliter +/- 419; P = .04). There was a lack of helper cells and an inverted T4:T8 ratio beyond one year posttransplant independent of graft-versus-host disease status. Lymphocyte functions persisted to be depressed for more than one year. We found a direct correlation of T4 helper cells and an inverse correlation of T8 suppressor cells with lymphoblastic responses to mitogens. It is hoped that the longitudinal evaluations of immune functions after allogeneic bone marrow transplantation, and the characterization of the immune defects seen may lead to better immunorestorative treatments.

Randomized placebo‐controlled trial of granulocyte‐macrophage colony‐stimulating‐factor support for dose‐intensive cyclophosphamide, etoposide, and cisplatin

This is a double‐blind randomized placebo‐controlled trial to evaluate the efficacy and safety of granulocyte‐macrophage colony‐stimulating‐factor (GM‐CSF) after dose‐intensive cyclophosphamide, etoposide, and cisplatin (DICEP). Fifty‐six patients with lymphoma or breast carcinoma were randomized to receive GM‐CSF 250 μg/m2 or placebo subcutaneously (SC) every 12 hr after each course of DICEP until recovery of absolute neutrophil count (ANC) of 1.5 × 109/L. Each patient was to receive three courses of DICEP. There were 28 patients in each group. The median duration of ANC below 0.5 × 109/L was 10 versus 12 days for Course 1 (P = 0.010), 10 versus 12 days for Courses 2 (P = 0.248), and 16.5 versus 15 days for Course 3 (P = 0.126); platelet counts below 20 × 109/L was 4 versus 4 days for Course 1 (P = 0.586), 8.5 versus 7 days for Course 2 (P = 0.013), and 23.5 versus 10.5 days for Course 3 (P = 0.104); hospitalization for patients readmitted with cytopenic fever were 4 versus 8 days for Course 1 (P = 0.035); 7 versus 6 days for Course 2 (P = 0.692); and 8 versus 12 days for Course 3 (P = 0.884) in the GM‐CSF and placebo group, respectively. GM‐CSF significantly shortens the duration of neutropenia and readmission only during the first course of DICEP. There was a delay in platelet recovery and an increase in transfusion requirement during subsequent courses in the GM‐CSF group. The result cautions the routine use of lineage specific hematopoietic growth factors in supporting repeated cycles of dose‐intensive chemotherapy.

Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of philadelphia chromosome‐negative cells in chronic myelogenous leukemia

Fifteen patients with Philadelphia chromosome (Ph)‐positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha‐interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 × 108 nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP‐16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph‐positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph‐positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph‐positive marrows, and in all 4 patients infused with Ph‐mosaic marrows (mixture of diploid and Ph‐positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha‐interferon therapy became sensitive to alpha‐interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph‐positive CML and reinduced disease sensitivity to alpha‐interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.

A comparative randomized trial of vinca alkaloids in patients with metastatic breast carcinoma

The therapeutic efficacy of vincristine, vinblastine, and vindesine were evaluated in a prospective randomized trial in patients with metastatic breast carcinoma. All patients were refractory to doxorubicincontaining chemotherapy. Vincristine was administered at 0.4 mg/M2/I/day by continuous infusion (CI), vinblastine at 1.7 mg/M2/I/day by CI, and vindesine at 1.2 mg/M2/I/day by CI or intermittent bolus (IB) over 5 days. The courses were administered at 2‐week intervals for vincristine and 3‐week intervals for vinblastine and vindesine. Ninety‐nine patients were evaluable for response. The 15 patients treated with vincristine had no objective response. Of 23 patients treated with vinblastine, there were 2 complete responses (9%) and 5 partial responses (22%). Of 31 patients treated with CI vindesine, there were 6 partial responses (19%). Of 30 patients treated with IB vindesine, there were 5 partial responses (17%). The median duration of disease control was 13 weeks (range, 8–140 +) for vinblastine, 18 weeks (range, 8–34) for CI vindesine, and 20 weeks (range, 12–47) for IB vindesine. These data illustrate that vinblastine (CI) and vindesine (CI or IB) have significant antitumor activity in patients with refractory metastatic breast carcinoma and that vincristine has no antitumor activity in similar patients.

Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation

Abstract: Cytomegalovirus (CMV) infection is one of the most common causes of morbidity and mortality after allogeneic marrow transplantation. We studied 14 consecutive CMV‐seropositive patients adding ganciclovir (2.5 mg/kg i.v. every 8 hours for 7 days prior to transplant and 6 mg/kg three times a week after neutrophils became > 0.5 times 109/1 and the patients were platelet transfusion‐independent until d 70) to our previous prophylaxis regimen which consisted of intravenous immunoglobulin and acyclovir. The result was compared with 30 consecutive patients whom we studied with our previous regimen. The addition of ganciclovir did not cause any extra toxicities. The incidence of interstitial pneumonitis and cumulative probability of CMV excretion in the first 100 d post‐transplantation was significantly reduced (p = 0.038 and p = 0.035 respectively). The result shows that addition of ganciclovir significantly decreased the incidence of CMV infection in the early post‐transplantation period.

Second bone marrow transplants for relapsed leukemia

Seventeen patients who had a relapse at a median of 9 months after marrow transplant (14 allogeneic and three syngeneic) received second transplants. Eight patients were in remission when transplanted. Of the nine patients with active disease at the time of transplant, six had complete remissions, and one converted from blastic to chronic phase of chronic myelogenous leukemia. The median survival was 9 months (95% confidence interval, 4 to 17 months). Four patients died within 100 days of transplantation, and three were disease‐free. Ten patients died after 100 days, all except two of disease relapse. Five patients had remissions that were greater than 12 months and longer than the remission after their first transplant (inversions). Three patients remain alive and disease‐free at 37+, 55+, and 61+ months, the former two despite remissions of less than 1 year after their first transplant. Second transplants with a different cytoreductive regimen can eradicate disease resistant to prior myeloablative treatment; some patients may benefit from second transplants, even if the first transplant only achieves a short remission.

Longitudinal study of cyclosporine and lipids in patients undergoing bone marrow transplantation

The metabolic effects of intravenous cyclosporine on lipids and lipoproteins were studied in 29 allogeneic bone marrow recipients compared with 13 autologous bone marrow patients not requiring cyclosporine therapy. Patients were monitored continuously from 5 days prior to 27 days following transplantation; cyclosporine treatment was initiated 4 days before transplantation. Fasting lipid and lipoprotein levels were measured in serial blood samples throughout the study period. Nutritional supplementation, conditioning regimens and concomitant medications were not significantly different between groups. Furthermore, no significant differences in age, weight, lipid, or lipoprotein levels were found at baseline between the patient groups. Cholesterol, triglyceride, low‐density lipoprotein cholesterol, and very low‐density lipoprotein cholesterol levels remained unchanged in autologous patients. As compared with baseline values, plasma total cholesterol increased by an average of 26 percent in allogeneic transplantation patients receiving cyclosporine. Similarly, the ratio of low‐density lipoprotein to high‐density lipoprotein cholesterol was fourfold greater in those patients treated with cyclosporine compared to the autologous group. We conclude that cyclosporine appears to elevate cholesterol levels. Neither acute graft vs host disease nor changes in hepatic function could explain the differences in plasma cholesterol levels between groups.