Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.

A phase I study was designed to evaluate the toxicity of escalating doses of gemcitabine along with fixed-dose paclitaxel in patients heavily pretreated with chemotherapy or radiotherapy. All patients had no prior therapy with the study drugs and possessed both adequate performance and end organ function. Eighteen patients were entered in the study. Characteristics included a median age of 66 years (range, 41 to 77) and stage IV disease in all patients; there were six patients with colon cancer, two with bladder cancer, three with non-small-cell lung cancer, two with esophageal cancer, three with pancreatic cancer, and two with cancer of unknown primary. Paclitaxel (150 mg/m2 over 3 hours) was given on day 1 and gemcitabine (800, 900, and 1,000 mg/m2 over 15 minutes) was given in three separate dose-escalating cohorts (1-3) on days 1 and 8. The treatment cycled every 21 days. The dose-limiting toxicity (DLT) proved to be neutropenia. All nonhematologic toxicities were mild and included gastrointestinal (nausea, vomiting, and diarrhea), dermatologic (rash), and neurologic (paresthesias) disturbances along with transient elevations of liver function tests. The combination of gemcitabine and paclitaxel seems to be well tolerated, and the recommended starting dose for a phase II study, in pretreated patients using a day 1/day 8 treatment schedule, should be 900 mg/m2 for gemcitabine (days 1 and 8) along with 150 mg/m2 for paclitaxel (day 1).

Pure red cell aplasia due to parvovirus B19 in a patient treated with rituximab.

Rituximab is a chimeric monoclonal antibody directed against CD20 and used in the treatment of B-cell non-Hodgkin's lymphoma. Due to its ability to deplete B lymphocytes, rituximab can interfere with humoral immunity, causing it to be suppressed for several months after treatment. The reported case depicts a serious consequence of this effect of rituximab therapy: pure red cell aplasia resulting from chronic parvovirus B19 infection. The point of interest in this case is not only the association between rituximab therapy and pure red cell aplasia, but the diagnostic and therapeutic utility of the knowledge of parvovirus B19 as the likely etiologic link between the two. Given the known efficacy of intravenous immunoglobulin (IVIg) in the treatment of chronic parvovirus B19 infection, this therapy can cure some of these patients and successfully render most others transfusion-independent until recovery of their own humoral immune system.

Diagnostic and clinical implications of lineage fidelity in acute leukemia patients undergoing allogeneic stem cell transplantation.

We report on a series of five acute leukemia patients who have undergone allogeneic bone marrow transplantation. Initially, these patients were classified as having biphenotypic leukemia; however, subsequent developments in the perception of what constitutes lineage fidelity has resulted in controversy regarding the diagnosis. Flow cytometry and non-random cytogenetic results have had a major impact on redefining the concept of biphenotypic disease. In this report we review the diagnostic dilemma associated with defining acute leukemia lineage fidelity as diagnostic techniques evolve. While our unique focus on the treatment of biphenotypic leukemia patients represents a small population, we verify the single most promising therapy where otherwise the diagnosis is dismal.

Mobilization of peripheral blood stem cells in high-risk breast cancer patients using G-CSF after standard dose docetaxel.

Chemotherapy, in addition to recombinant growth factors, has been effective in mobilizing stem cells. Unfortunately, the use of chemotherapy for this purpose has resulted in profound myelosuppression and increased morbidity. Docetaxel, the single most active agent in the treatment of advanced breast cancer, was evaluated for its potential to mobilize stem cells when given at conventional doses followed by granulocyte colony-stimulating factor (G-CSF). Sixteen high-risk breast cancer patients were mobilized with a regimen consisting of docetaxel (100 mg/m2) followed by daily G-CSF (10 microg/kg), beginning 72 h after the docetaxel, and continuing until completion of the apheresis. The median white blood cell count (WBC) nadir was 1,000/microl (range 500 to 4000/microl ) occurring a median of 6 days (range 4 to 9 days) after the docetaxel. No patient experienced a neutropenic febrile episode due to the mobilization regimen. The median time interval for initiating the apheresis was 8 days (range 6 to 11 days) following the docetaxel. The median number of apheresis was 2 (range 1 to 3) in each patient. Stem cell recovery as measured by the CD34 cell count x 10(6)/kg was a median of 5.2 (range 1.4 to 15.1). A significant correlation was found between CFU-GM, BFU-E, and CFU-GEMM/kg and CD34 cells/kg (r = 0.891, 0.945, and 0.749, respectively, p < 0.001). When our results were compared to a matched cohort receiving G-CSF alone, the docetaxel group demonstrated a superior CD34 cells/kg yield (p = <0.001). Following myeloablative chemotherapy consisting of thiotepa and cyclophosphamide with or without carboplatinum, the hematopoetic recovery determined by an absolute neutrophil count (ANC) of greater than 500/microl and an unsupported platelet count of > or =20,000/microl for 48 h, was a median of 10 days (range 9 to 14 days) and 10 days (range 8 to 30 days), respectively. The results demonstrate that conventional dose docetaxel, combined with G-CSF, is an effective mobilization regimen with minimal toxicity in high-risk breast cancer patients.

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group.

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

Dose-intensive chemotherapy for breast cancer with brain metastases: a case series.

Most clinical trials using dose-intensive chemotherapy exclude patients with brain metastases. This exclusion was based on anecdotal experience reflecting high treatment-related mortality. We analyzed the outcome of 11 patients with metastatic breast cancer who had brain metastases, diagnosed either before or during high-dose chemotherapy. In three patients, the death was attributed to non-central nervous system (CNS) regimen-related toxicity. Five patients died as a results of non-CNS disease progression. One patient died as a result of both CNS and non-CNS disease progression. Two patients are alive without disease progression with follow-up of 13.4 and 7.3 months, respectively. Of the five patients who have survived 1 year, four have hormone receptor expression and continued on antihormone therapy after high-dose therapy. These results are the first to show that breast cancer patients having brain metastases who receive high-dose chemotherapy do not experience more treatment-related complications or treatment failure as a result of the metastatic CNS disease. To this end, exclusion of these patients from high-dose therapy trials, especially those with expression of hormone receptors, needs to be reevaluated.

The transfusion needs of an autologous bone marrow transplant patient with IgA deficiency.

BACKGROUND: Transfusion management of the patient who is undergoing a marrow or peripheral blood stem and progenitor cell transplantation is often challenging. The situation is further complicated when the patient is IgA deficient with circulating anti-IgA. CASE REPORT: This report describes an approach to transfusion therapy primarily using red cells washed by automated techniques and cryopreserved autologous plateletpheresis components. Additional platelet support was provided with manually washed allogeneic plateletpheresis components. Autologous fresh-frozen plasma was collected concurrently, and IgA-deficient allogeneic units were ordered and kept in storage, but they were not needed during transplantation. The patient experienced no transfusion sequelae as a result of the IgA deficiency. CONCLUSION: With this approach, the transfusion needs of an IgA-deficient patient were adequately met during bone marrow transplantation.

The use of partially HLA-mismatched donors for allogeneic transplantation in patients with mucopolysaccharidosis-I.

Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.

CML blast crisis resulting in biliary obstruction following BMT.

Allogeneic BMT is the treatment of choice for various hematologic malignancies. Despite careful patient scrutiny, a large number of patients experience significant morbidity and mortality due to procedure-related toxicity. Hepatobiliary toxicity presenting as biliary cholestasis, due to the preparative regimen (ie venoocclusive disease), supportive pharmaceuticals, and/or GVHD have been implicated. We report a unique cause of cholestasis in a patient undergoing BMT for CML. The cholestasis was found to be secondary to relapsed leukemia, which resulted in a granulocytic sarcoma obstructing the biliary ductal system.

Impact of obesity on allogeneic stem cell transplant patients: a matched case-controlled study.

PURPOSE: To determine the impact of obesity on survival after high-dose therapy followed by allogeneic stem cell transplant in adults and children with various malignancies as well as metabolic disorders. PATIENTS AND METHODS: A matched case-controlled evaluation of 322 allogeneic patients from a single institution with a median follow-up of 296 and 120 days among nonobese and obese patients, respectively, was conducted between April 1983 and June 1995 at the University of Kentucky. The overall survival distributions among subsets defined as either obese or nonobese were measured. RESULTS: The overall survival among the nonobese and obese was 35% and 20%, respectively (P = 0.0045). When patients were separated by age, the adult patients maintained this difference, while the children did not. When patients were stratified according to donor status, both the histocompatible and the nonhistocompatible adults had an inferior outcome among obese patients. The difference, however, was significant only among the histocompatible group (P = 0.0007). Causes of deaths were insignificantly distributed among both relapse as well as nonrelapse mechanisms. CONCLUSION: Adult obese patients undergoing high-dose chemotherapy with stem cell rescue have a more adverse outcome. Both relapse and nonrelapse causes are responsible for the different outcome between obese and nonobese groups.

Treatment of leukemia with partially matched related bone marrow transplantation.

The results of partially matched related donor (PMRD) marrow transplantation for 82 patients with leukemia are reported, including 45 who received two antigen disparate grafts. Following intensive radiochemotherapy, patients received grafts which were partially depleted of T cells by the monoclonal antibody T10B9 and complement. Actuarial probability of engraftment was 86% (95% CI = 78-93%). The median day to engraftment was similar among recipients of grafts disparate at one, two or three antigen loci. The incidence of severe (grades III and IV) acute graft-versus-host disease and extensive chronic graft-versus-host disease was 13% and 6%, respectively. The probability of disease-free survival for the entire cohort of patients is 31% at 3 years. Age < or = 30 years, early or intermediate stage disease and a graft disparate at one or two loci predicted longer disease-free survival in multivariant analysis. Moreover, 47% of patients receiving PMRD grafts disparate at two loci who had both these favorable pretransplant characteristics were alive and free of disease 3 years after transplantation. We believe that the utilization of PMRDs, especially those with two antigen disparate grafts, can extend allogeneic transplantation to additional leukemic patients lacking a histocompatible donor, with acceptable results.

The safety of injecting insulin through clothing.

OBJECTIVE: Many of the "antiseptic" practices recommended by health care professionals for insulin injection have been successfully challenged as unnecessary. Since people with diabetes have long been observed to inject their insulin through their clothing, this study was undertaken to determine the safety and perceived benefits of administering insulin by this "rogue" technique. RESEARCH DESIGN AND METHODS: Fifty people with insulin-treated diabetes were randomized into a 20-week single-blinded prospective crossover study comparing the conventional subcutaneous injection technique (with skin preparation) to an experimental injection technique through clothing. Skin assessment, glycated hemoglobin levels, and leukocyte count were determined before randomization, at 10 weeks (before crossover), and again at 20 weeks (at completion). The participants injected through a single layer of fabric, which ranged from nylon to denim. Problems, benefits, type of clothing, and other comments were recorded by the subjects in an injection log. RESULTS: Forty-two (84%) subjects completed the study. The mean age was 41 years (range, 23-63 years), 50% were women, 86% were Caucasian, and 80% had type I diabetes. The mean duration of diabetes was 14 years (range, 1-33 years). Fifty-one percent had > 16 years of education. The demographic characteristics of the dropouts were similar to those who completed the study. Over the 20-week period approximately 13,720 injections were performed by participants. None of the subjects experienced erythema, induration, or abscess at injection sites. Neither the glycated hemoglobin levels nor the leukocyte counts differed between the conventional and experimental regimens. During the injection-through-clothing phase of the study, only minor problems, such as blood stains on clothing and bruising, were recorded in the logbooks. However, subjects reported that injection through clothing offered benefits such as convenience and saving time. CONCLUSIONS: It is safe and convenient to inject insulin through clothing.

Hyperkalemia associated with cyclosporine (CsA) use in bone marrow transplantation.

Two adult leukemia patients underwent allogeneic bone marrow transplantation and received cyclosporine (CsA) as part of their immunosuppressive therapy. Despite adequate kidney function, both patients developed hyperkalemia. Cyclosporine was the only pharmaceutical agent to which this electrolyte abnormality could be attributed. Although the mechanism of the hyperkalemia is unclear, it seems to be related to an aldosterone-resistant state. Cyclosporine-induced hyperkalemia is a relatively common occurrence; however, there is only a single 'case report' addressing this phenomenon in bone marrow transplantation patients. We propose both mechanisms and methods of managing CsA-associated hyperkalemia in allogeneic transplantation patients.

Allogeneic bone marrow transplantation with T cell-depleted partially matched related donors for advanced acute lymphoblastic leukemia in children and adults: a comparative matched cohort study.

Allogeneic BMT provides the best treatment currently available for long-term disease-free survival in patients with recurrent ALL. Historically, partially matched related donors provided the opportunity for treatment to a greater number of patients than matched related donors at the expense of decreased overall survival. In this study we compare the results in recurrent ALL patients transplanted with either HLA identical sibling bone marrow or partially matched related bone marrow. Thirty-two patients with relapsed ALL received partially matched bone marrows from a relative with one to three HLA, A, B and Dr antigen mismatches. Bone marrow was partially T cell-depleted with murine T10B9.1A-31 moAb. Sixteen patients with relapsed ALL received HLA-matched sibling bone marrows. All partially matched patients received additional GVHD prophylaxis with methylprednisolone in addition to anti-CD5 immunotoxin and/or CYA. All matched patients in addition to methylprednisolone received MTX and/or CYA. We observed no difference in disease-free survival between patients transplanted with partially matched bone marrow (median follow-up 1252 days, range 778-2035 days) vs those transplanted with HLA-matched bone marrow (median follow-up 1472 days, range 1165-2800 days; P = 0.48). Median survival for all patients is 38% (95% CI 24-52%) at 6 years. Patients transplanted in remission had a significant increase in disease-free survival when compared to those in relapse (P = 0.007). Our data suggest that partially matched BMTs from related donors are a comparable alternative to fully matched transplants in patients with ALL.

Lymphocyte infusion for delayed extramedullary relapse of acute leukemia following bone marrow transplantation.

We report a case of extramedullary relapse of acute myelogenous leukemia twelve years after allogeneic bone marrow transplantation. Due to the localized nature of the relapse, we were able to eliminate a majority of the tumor burden, utilizing local irradiation. Destined with eventual systemic leukemia relapse, further therapy utilizing donor lymphocytes was given at a time of minimal disease burden. The patient remains in a state of complete remission.

Acute tumor lysis syndrome in hematologic malignancies.

Acute tumor lysis syndrome (ATLS) represents one of the most urgent of all oncologic treatment related complications. This is due not only to its broad impact on organ dysfunction, but also to its relative ease of prevention and treatment when aware of its potential threat. Despite anecdotal experiences of ATLS in settings outside the use of chemotherapy, the majority of patients susceptible to ATLS can be predicted using clinical as well as laboratory parameters and prophylaxis can prevent this potentially lethal consequence of otherwise successful cancer therapeutics. This review article will attempt to bring the critical aspects involving ATLS together in order to delineate the pathophysiology as well as treatment of this generally avoidable entity.