Age does not adversely influence outcomes among patients older than 60 years who undergo allogeneic hematopoietic stem cell transplant for AML and myelodysplastic syndrome.

Allogeneic hematopoietic stem cell transplant (AHSCT) outcomes data of older AML/myelodysplastic syndrome (MDS) patients are limited. We retrospectively evaluated consecutive patients ⩾60 years old with AML/MDS who underwent AHSCT between January 2005 and December 2014. The primary objectives were to determine nonrelapse mortality (NRM), relapse, relapse-free survival (RFS) and overall survival (OS) at 1 year post AHSCT. A total of 159 patients underwent AHSCT with a median age of 64 (range, 60-75) years. Of these, 103 patients (65%) had AML and 56 patients (35%) had MDS. At 1 year post AHSCT, grade III-IV acute GvHD and chronic GvHD occurred in 20.8% (95% confidence interval (CI), 14.9-27.5%) and 54.1% (95% CI, 46.0-61.5%) of patients, respectively. NRM, RFS, relapse rate and OS at 1 year post AHSCT were 25.3% (95% CI, 18.8-32.3%), 53.3% (95% CI, 46.1-61.7%), 21.4% (95% CI, 15.4-28.1%) and 56.4% (95% CI, 49.2-54.7%), respectively. High disease risk index was associated with poor RFS, OS and higher relapse rate (P<0.03), whereas non-thymoglobulin-based GvHD prophylaxis, higher comorbidity index (⩾3) and MDS were associated with higher NRM (P<0.03). Importantly, age did not have an adverse effect on NRM, relapse, RFS and OS. AHSCT was well tolerated. Hence, older age alone should not be considered a contraindication to AHSCT.

Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic hematopoietic cell transplantation (HCT) causing significant morbidity and mortality. The kidneys are not considered a target organ for cGVHD in humans, although animal models show renal damage. Renal involvement in patients with cGVHD, presenting as nephrotic syndrome (NS), has rarely been reported in patients who received allogeneic transplantation. Herein we describe, by far, the largest series of nine patients with NS associated with cGVHD, including two patients who received a reduced-intensity regimen. Pathological features of membranous nephropathy were the most common finding on renal biopsy. The clinical course of the NS was temporally associated with the classical features of cGVHD in all but one of the nine cases. The clinicopathologic features of NS in our series as well as reports in the literature demonstrate an immunopathologic process typical of antibody-mediated damage consistent with cGVHD. Treatment directed against antibody-mediated damage, such as anti-B-cell antibody may play an important role in ameliorating NS associated with cGVHD.

Intensive combined modality therapy for limited-stage small-cell lung cancer.

BACKGROUND: Conventional-dose chemotherapy for small-cell lung cancer has resulted in high response rates but rarely in a cure. The addition of thoracic radiotherapy (chemoradiotherapy) has improved survival for patients having limited disease, resulting in a median survival of 14-18 months. Previous trials evaluating high-dose chemotherapy and autologous bone marrow transplantation have demonstrated enhanced complete response rates without documenting overall survival benefit. PURPOSE: The purpose of this phase II trial was to determine the disease-free and overall survival, toxic effects, and relapse patterns in patients with limited small-cell lung cancer who were in partial or complete response to first-line conventional-dose chemotherapy and then received intensive systemic combined modality therapy. METHODS: Adults with stage III small-cell lung cancer who had achieved at least a partial response to conventional-dose induction chemotherapy were treated with high-dose cyclophosphamide, cisplatin, and carmustine combined with autologous bone marrow transplantation. Cumulative doses of the three drugs were 5625, 165, and 480 mg/m2, respectively. After recovery, patients received thoracic radiotherapy (50-60 Gy in 25-30 fractions over 5-6 weeks) and cranial radiotherapy (30 Gy in 15 fractions during 3 weeks). RESULTS: Of 19 patients in the study, six had achieved complete response, eight had a greater than 90% reduction in tumor size, and five had a 50%-90% reduction in tumor size. After high-dose therapy, 15 of the 19 were in complete response. Overall, median time to treatment failure after high-dose therapy was 12 months. Overall survival was 73% (95% confidence interval [CI] = 42%-89%) at 1 year and 53% (95% CI = 22%-77%) at 2 years. Of the 14 patients in or near complete response before high-dose therapy, 10 remain disease free with no further chemotherapy a median of 15 (4-69+) months after therapy. Actuarial 2-year disease-free survival is 57% (95% CI = 20%-82%). One patient died of Candida sepsis. Morbidity was low, and most patients returned to full-time work. With the exception of herpes zoster, there were no complications more than 3 months after high-dose therapy. CONCLUSIONS: The majority of the patients in this study are experiencing prolonged and unmaintained disease-free survival. Our findings suggest that patients in or near complete response before high-dose therapy have the most favorable prognosis. IMPLICATIONS: A randomized comparison between this approach and conventional-dose therapy is planned to define the utility of dose intensification with autologous bone marrow transplantation in the treatment of patients with limited-stage small-cell lung cancer who are in or near complete response.

Prognostic factors for treatment outcome in autotransplantation of intermediate-grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide.

PURPOSE: We examined a consecutive series of 78 patients with non-Hodgkin's lymphoma treated on prospective protocols with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) plus autotransplantation to determine prognostic factors for time to treatment failure. PATIENTS AND METHODS: Patients with relapsed, refractory, or poor-risk intermediate- and high-grade non-Hodgkin's lymphoma were treated with CBV with autologous marrow or peripheral-blood progenitor cell support. Patient characteristics before transplantation were examined in univariate analyses by the log-rank test and simultaneously in a Cox proportional hazards regression analysis. A best-predictive model was determined from those variables significant (P < .10) in the univariate test. RESULTS: In univariate analysis, intermediate-grade and immunoblastic lymphoma, responsiveness to pretransplant salvage chemotherapy, and transplantation after primary therapy (first complete response [CR] or partial response [PR]) were associated with prolonged time to treatment failure. In proportional hazards multiple regression analysis, intermediate-grade and immunoblastic histology, responsive disease, and autotransplantation in first CR or PR were positive prognostic factors, and these characteristics are the basis of the best-predictive model for prolonged time to failure. Actuarial 3-year failure-free survival of patients with stable or responding disease at autotransplant was 54%. CONCLUSION: CBV is an effective conditioning regimen in intermediate-grade and immunoblastic non-Hodgkin's lymphoma. Patients with these histologies transplanted while responding to primary therapy, or those with stable disease or disease responding to salvage therapy at the time of autotransplant, are most likely to benefit. Patients with lymphoblastic lymphoma or diffuse undifferentiated lymphoma did poorly with CBV and should be offered alternative therapy.

Double dose-intensive chemotherapy with autologous marrow and peripheral-blood progenitor-cell support for metastatic breast cancer: a feasibility study.

PURPOSE: Twenty-seven percent of responding metastatic breast cancer patients remain progression-free a median 29 months following one intensification course of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). European investigators report high complete response (CR) rates with melphalan for breast cancer. This trial studied the feasibility of two tandem high-dose intensification therapies in an attempt to optimize disease response and duration. PATIENTS AND METHODS: Women with at least partial responses (PRs) to induction therapy received melphalan (140 to 180 mg/m2), followed 24 hours later by chemotherapy and granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral-blood progenitor cells (PBPCs) and subsequent G-CSF until WBC recovery. The women were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. RESULTS: Twenty women were assessable. Fourteen (70%) required admission for fever (10% infection) or mucositis (35%) after melphalan (median stay, 5 days). Median days of absolute neutrophil count (ANC) less than 500/microL and platelet count less than 20,000/microL were 6 and 5.5, respectively. Patients received CTCb 25 days after starting melphalan and had a hospital stay of 25 days. After CTCb, median days of ANC less than 500/microL and platelet count less than 20,000/microL were 11.5 and 24, respectively. Grade 3 toxicities included venoocclusive disease (VOD) (10%), mucositis (45%), and infection (20%). Toxicities were reversible without mortality. CONCLUSION: With mobilized PBPCs and growth factors, double dose-intensive chemotherapy is feasible with acceptable toxicity. When compared with trials using marrow alone, these supportive adjuncts decrease sepsis and organ toxicity. The concepts of dose and dose-intensity may now be more effectively and safely studied in chemosensitive tumors, including breast cancer.

Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer.

PURPOSE: With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS). METHODS: From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS. RESULTS: The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066). CONCLUSION: We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.

Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

BACKGROUND: Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS: Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS: Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION: These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.

PURPOSE: The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS: Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS: Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

Dose-intensive therapy for limited-stage small-cell lung cancer: long-term outcome.

PURPOSE: To determine progression-free survival (PFS) and overall long-term survival for limited-stage small-cell lung cancer (SCLC) patients aged 60 years or younger who respond to first-line chemotherapy followed by high-dose combination alkylating agents (cyclophosphamide 5,625 mg/m(2), cisplatin 165 mg/m(2), and carmustine 480 mg/m(2)) with hematologic stem-cell support and chest and prophylactic cranial radiotherapy. PATIENTS AND METHODS: Patients were selected on the basis of their continued response to first-line therapy, their relative lack of significant comorbidity, and their ability to obtain financial clearance. RESULTS: Of 36 patients with stage III SCLC, nine patients (25%) had achieved a complete response (CR), 20 had achieved a near-CR, and seven had achieved a partial response before undergoing high-dose therapy. Toxicity included three deaths (8%). For all patients, the median PFS was 21 months. The 2- and 5-year survival rates after dose intensification were 53% (95% confidence interval [CI], 39% to 72%), and 41% (95% CI, 28% to 61%). Of the 29 patients who were in or near CR before undergoing high-dose therapy, 14 remain continuously progression-free a median of 61 months (range, 40 to 139 months) after high-dose therapy. Actuarial 2- and 5-year PFS rates were 57% (95% CI, 41% to 79%) and 53% (95% CI, 38% to 76%). By multivariate analysis, short intensive induction chemotherapy was associated with favorable outcome (P <.05). CONCLUSION: Use of high-dose systemic therapy with intensive local-regional radiotherapy was associated with manageable treatment-related morbidity and mortality. Patients who were in or near CR before intensification are enjoying an unmaintained 5-year PFS rate of 53%. Late complications were infrequent, and most patients returned to full-time work and activity. A randomized comparison of this approach and conventional-dose therapy should define the use of dose intensification with hematopoietic support in patients with responding limited-stage SCLC.

Hepatic venoocclusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.

Retrospective review of 291 solid tumor and lymphoma patients undergoing autologous bone marrow transplantation (BMT) was performed to determine the influence of pretransplant characteristics and preparative regimen to the development of hepatic venoocclusive disease (VOD). Twelve patients (4.1%) developed a clinical syndrome of right upper quadrant (RUQ) tenderness or hepatomegaly, jaundice, and ascites, with or without encephalopathy, within 40 days of marrow reinfusion. Evidence of metastatic liver disease was the only pretransplant characteristic predictive for VOD (P = .0002). Sex, age, histology, hepatitis B serology, and elevated liver function tests were not predictive. No individual preparative agent had a significant effect on the development of VOD. However, a single 2-hour infusion of carmustine (BCNU) (greater than or equal to 450 mg/m2) led to an increased incidence of VOD when compared with the same dose administered in a fractionated schedule (P = .0258) when given with two other chemotherapeutic agents. Seven of eight autopsy specimens confirmed the clinical diagnosis of VOD. The four patients in whom clinical VOD resolved had lower median peak bilirubins (7.3 v 15.9 mg/dL), lower median peak creatinines (2.1 v 4.1 mg/dL), and relatively quick engraftment of neutrophils (mean, 18.7 days). One of the four patients in whom VOD resolved had other grade 4 (life-threatening) toxicities in contrast to eight of eight who succumbed. In summary, VOD is an uncommon complication in autotransplantation of solid tumors and lymphomas. Our data suggest caution in selecting patients with known metastatic liver disease and consideration of a fractionated BCNU schedule especially in combination with other alkylating agents.

A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: no improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin.

PURPOSE: Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration. METHODS: Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. RESULTS: Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively. CONCLUSION: Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.

High-dose multimodality therapy with autologous stem-cell support for stage IIIB breast carcinoma.

PURPOSE: Women with locally unresectable and inflammatory breast carcinoma (IBC) have an approximately 30% 5-year disease-free survival (DFS) rate with conventional multimodality therapy. A short but dose-intensive multimodality phase II trial was designed in an attempt to improve outcome in stage IIIB disease. Mastectomy was performed after high-dose therapy to evaluate pathologic response to treatment. METHODS: Women with newly diagnosed disease received four 2-week cycles of doxorubicin 90 mg/m2 with granulocyte colony-stimulating factor (G-CSF), followed by cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) with marrow and peripheral-blood progenitor cell (PBPC) support. Local therapy consisted of mastectomy and radiotherapy. Tamoxifen (5 years) was begun if the patient was estrogen receptor-positive (ER+). RESULTS: Fifty women (46 stage IIIB [91% IBC], four stage IIIA) entered the study and 47 are assessable. Ten had mastectomy before any systemic therapy (seven with pathologic IBC, three with residual tumor after mastectomy). Eighty percent received full-dose doxorubicin with 60% on schedule. Clinical response rates to induction were 15% complete response (CR), 5% very good partial response (VGPR), 59% partial response (PR), and 21% minor response (MR)/stable disease (SD). Mastectomy after CTCb in 37 patients showed a 14% pathologic CR rate, 29% microscopic foci in breast and/or axilla, and 57% gross tumor. Fifteen (32%) patients have relapsed (median, 17 months post-CTCb). The 30-month DFS is estimated at 64%. For those in pathologic CR, with microscopic, or with gross disease remaining after CTCb, the 30-month DFS is estimated at 100%, 70%, and 38%, respectively. Those with zero, one to three, or > or = four positive nodes at axillary dissection had a median DFS of 31, 18, and 13 months, respectively. CONCLUSION: This short but dose-intensive multimodality approach for stage IIIB breast carcinoma is feasible with encouraging results to date.

Repetitive cycles of cyclophosphamide, thiotepa, and carboplatin intensification with peripheral-blood progenitor cells and filgrastim in advanced breast cancer patients.

PURPOSE: As an alternative to single-cycle cyclophosphamide, thiotepa, and carboplatin (CTCb) intensification, we evaluated the feasibility of administering one-quarter dose CTCb for four cycles with peripheral-blood progenitor-cell (PBPC) and filgrastim (granulocyte colony-stimulating factor [G-CSF]) in advanced-stage breast cancer patients. PATIENTS AND METHODS: From June 1992 to August 1993, 20 stage IIIB (n = 7) and IV (n = 13) breast cancer patients received 78 cycles of induction with doxorubicin 90 mg/m2 by intravenous (IV) bolus with G-CSF 5 microg/kg/d by subcutaneous injection (SC) repeated every 14 to 21 days for four cycles. PBPC were collected by 2-hour single-blood volume leukapheresis on 2 consecutive days at the time of hematologic recovery from each cycle of doxorubicin. Eighteen patients received 61 cycles of intensification with cyclophosphamide 1,500 mg/m2, thiotepa 125 mg/m2, and carboplatin 200 mg/m2 by IV continuous infusion with G-CSF 10 microg/kg/d SC and PBPC support repeated every 21 to 42 days for four cycles. RESULTS: Twelve of 20 patients (60%) completed all four planned cycles of doxorubicin induction followed by four cycles of one-quarter dose CTCb intensification. Statistically significantly decreases in the yield of mononuclear cells (MNC) (median slope per day, -0.032; P = .03), granulocyte-macrophage colony-forming unit (CFU-GM) (median slope per day, -0.57; P = .0008), and burst-forming unit-erythroid (BFU-E) (median slope per day, -1.18; P = .006) were observed over the course of the eight leukaphereses. Of 18 patients who began CTCb, 12 (67%) completed four cycles. Six patients were removed from study during intensification: two for progressive disease (PD), one refused further treatment, and three for dose-limiting hematologic toxicity. A fourth patient fulfilled the criteria for dose-limiting hematologic toxicity after cycle 4. The toxicity of the multiple cycle CTCb intensification regimen consisted of grade IV leukopenia, grade IV thrombocytopenia, and febrile neutropenia in 100%, 100%, and 26% of cycles, respectively. The median duration of each CTCb cycle was 24 days (range, 18 to 63), and the median duration of an absolute neutrophil count (ANC) < or = 500/microL and platelet count < or = 20,000/microL during each cycle was 6 days (range, 2 to 15) and 4 days (range, 0 to 38), respectively. CONCLUSION: It is feasible to administer repetitive cycles of one-quarter dose CTCb intensification with PBPC and G-CSF. Additional studies are required to determine whether multiple cycles of CTCb intensification might offer a therapeutic advantage over a single high-dose cycle.

Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.

Low-dose antithymocyte globulin enhanced the efficacy of tacrolimus and mycophenolate for GVHD prophylaxis in recipients of unrelated SCT.

We performed a retrospective analysis of the outcome of 197 consecutive unrelated donor transplant recipients who received GVHD prophylaxis either TM regimen (tacrolimus and mycophenolate) (121 patients) or TM/ATG-G regimen (TM with low-dose antithymocyte globulin (ATG) of 4.5 mg/kg, ATG-G, Genzyme) (76 patients). Cumulative incidences of grade II-IV acute GVHD for the TM and TM/ATG-G cohorts were 49% and 61% (P=0.11) and grade III-IV acute GVHD for the TM and TM/ATG-G cohorts were 27% and 14% (P=0.02), respectively. There was no difference in the incidence of relapse or disease progression between TM and TM/ATG-G-16% and 23% (P=0.64). TM/ATG-G cohort had lower incidence of non-relapse mortality (NRM; 37% vs 20%, P=0.01), chronic GVHD (56% vs 43%, P<0.001) and more favorable global chronic GVHD severity (P<0.001). Univariate analyses showed improved OS and PFS of patients who received TM/ATG-G. Multivariate analysis confirmed TM/ATG-G had a favorable influence on OS (P=0.05) but not on PFS (P=0.07). We concluded that low-dose ATG of 4.5 mg/kg given in conjunction with TM improved GVHD prophylaxis without increased risk of relapse. Lower NRM, lower incidence and severity of chronic GVHD could potentially improve survival.

Low blood lymphocyte count at 30 days post transplant predicts worse acute GVHD and survival but not relapse in a large retrospective cohort.

Multiple reports have shown that low absolute lymphocyte count at day 30 (ALC30) after allogeneic hematopoietic SCT (AHSCT) is associated with higher risk of disease relapse and worse OS. However, these reports included heterogeneous populations with different grafts and GVHD prophylaxis. Therefore, we retrospectively evaluated the association of ALC30 with transplant outcomes in a cohort of 381 consecutive patients who underwent AHSCT between 2005 and 2010 and received T-replete PBSC grafts and Tacrolimus/Mycophenolate combination as GVHD prophylaxis. Median follow-up was 57 months. Lower ALC30 (⩽400 × 10(6)/L) was associated with lower OS and increased nonrelapse mortality (NRM) for the whole cohort as well as for recipients of SD and UD grafts separately. Lower ALC30 was associated with more severe acute GVHD (aGVHD; III-IV) for the entire cohort as well as for the SD and UD groups. No association was found between lower ALC30 and relapse. Pretransplant factors associated with lower ALC30 were: unrelated donors; HLA mismatch; older donors; lower recipient age; and lower CD34+ cell dose. In this large retrospective study, ALC30⩽400 × 10(6)/L was associated with worse OS, increased NRM and severe aGVHD.

Clinical protocol. Purging of autologous stem cell sources with bcl-x(s) adenovirus for women undergoing high-dose chemotherapy for stage IV breast carcinoma.

High-dose chemotherapy (HDCT) and autologous bone marrow transplantation (BMT) is frequently used to treat patients with metastatic cancer including breast cancer and neuroblastoma. However, the bone marrow of such patients is often contaminated with tumor cells. Recently, we have found that a recombinant adenovirus vector that contains a bcl-x, minigene (a dominant negative inhibitor of the bcl-2 family), called the bcl-x(s) adenovirus, is lethal to cancer cells derived from epithelial tissues, but not to normal human hematopoietic cells. To determine the mechanism, by which this virus spares normal hematopoietic cells, we isolated normal mouse hematopoietic stem cells and infected them with an adenovirus that contains a beta-galactosidase minigene. Such cells do not express beta-galactosidase, indicating that hematopoietic stem cells do not express transgene encoded by adenovirus vectors based upon the RSV-AD5 vector system. When breast cancer cells mixed with hematopoietic cells were infected with the bcl-x(s) adenovirus, cancer cells were selectively killed by the suicide adenoviruses. Hematopoietic cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. We therefore propose to initiate a phase I clinical trial to test the safety of this virus in women with breast cancer undergoing high does chemotherapy and autologous BMT.

High-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy: analysis by age.

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose ifosfamide/carboplatin/etoposide with autologous hematopoietic stem cell support: safety and future directions.

Agents with broad cytotoxic activity, steep linear log dose-response relationships, relative non-cross-resistance, and nonoverlapping nonhematologic toxicities can be combined to create new high-dose combination regimens. We have previously reported phase I dose-escalation studies of ifosfamide, carboplatin, and the combination of the two. Etoposide has reported synergism with these alkylators and produces mucositis as its dose-limiting toxicity. The current study was designed to define the maximum tolerated doses of high-dose combination ifosfamide/carboplatin/etoposide (ICE), with stem cell support for amelioration of hematologic toxicity. Forty-eight adults with advanced malignancy received ICE chemotherapy by 96-hour continuous infusion. Initially, etoposide was added to fixed-dose ifosfamide and carboplatin, then the maximum tolerated dose of etoposide was fixed while doses of the alkylators were individually escalated. Autologous marrow, with or without peripheral blood progenitor cells, was reinfused 3 days after completing chemotherapy. The maximum tolerated doses of ifosfamide, carboplatin, and etoposide were identified as 16 g/m2, 1.8 g/m2, and 1.2 g/m2, respectively. Mortality was 4%. Patients who had prior cisplatin exposure were at increased risk for renal toxicity. If serum creatinine levels (monitored twice daily) rose sharply during chemotherapy, ifosfamide and carboplatin were immediately stopped. Severe multiorgan toxicity developed in the few patients who experienced early renal toxicity. Early stopping enhanced the safety of this regimen. Interpatient differences in chemotherapy drug metabolism or reduced renal clearance may predispose individuals to severe toxicity by increasing overall drug exposure. It was concluded that the ICE regimen is well tolerated and warrants further exploration as treatment of patients with small cell lung cancer, ovarian and germ cell carcinomas, and lymphomas in phase II trials.