Outpatient-based bone marrow transplantation for hematologic malignancies: cost saving or cost shifting?

PURPOSE: To determine whether a shift in care from an inpatient-based to an outpatient-based bone marrow transplantation (BMT) program decreased charges to payers without increasing clinical complications or out-of-pocket costs to patients. PATIENTS AND METHODS: This nonrandomized prospective cohort study compared clinical and economic outcomes for 132 consecutive BMT patients with hematologic malignancies who received either inpatient- or outpatient-based BMT care. RESULTS: Seventeen of 132 BMT patients underwent outpatient-based BMT. Compared with the inpatient-based group, the outpatient-based group had a markedly lower mean number of inpatient hospital days (22 v 47; P <.001) and decreased mean inpatient facility charges ($61,059 less per patient; P <.0001) but had higher mean outpatient facility charges ($49,732 higher; P <. 0001). Total professional fees were similar for the groups. The mean total charge to payers was only 7% less ($12,652; P =.21) for outpatient-based BMT than for inpatient-based BMT, but total charge was 34% less for outpatient compared with inpatient BMT ($54,240; P = 0.056) in a subset of patients who had a standard rather than high risk of treatment failure. There was no significant difference between groups in out-of-pocket costs for transportation, lodging, meals, home nursing, household assistance, child care, medication expenses, or unreimbursed medical bills. There also was no significant difference between groups in reported income lost, involuntary unemployment, or months of disability. The two groups had similar rates of major complications, including death, significant acute graft-versus-host disease, and veno-occlusive disease of the liver. CONCLUSION: Increased use of outpatient-based BMT should produce substantial cost savings for payers without adverse effects on patients for those patients who do not have a high risk of treatment failure.

Phase I trial of intravenous cyclosporine to induce graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if graft-versus-host disease (GVHD), which is associated with an antitumor effect, could be induced in women with advanced breast cancer by treatment with cyclosporine (CSA) following reinfusion of purged autologous marrow after treatment with high-dose chemotherapy and defined the toxicities of this approach. PATIENTS AND METHODS: Fifty-one women with advanced breast cancer responding to therapy were treated with escalating doses of CSA (1.0, 2.5, or 3.75 mg/kg/d) for 28 days following high-dose chemotherapy and autologous bone marrow transplantation and monitored for induction of GVHD and toxicity of therapy. RESULTS: GVHD was induced in a dose-dependent fashion in 14%, 68%, and 92% of patients at each dose level, respectively, a median of 15 days following autologous marrow reinfusion. GVHD was clinically mild and limited to skin. Toxicity was acceptable, with two deaths within 50 days of marrow reinfusion. Statistically significant increases in maximum creatinine and bilirubin levels were seen at all dose levels when compared with similarly treated historic controls who did not receive CSA. Time to last platelet transfusion was significantly delayed in patients treated at the highest dose. CONCLUSION: GVHD can be safely induced by treatment with CSA in women with advanced breast cancer who are receiving high-dose alkylating agents and autologous bone marrow transplantation. The toxicity of this approach is acceptable. Evidence of antitumor efficacy awaits further investigation.

Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if interferon gamma (IFN-gamma) could augment cyclosporine (CSA)-induced graft-versus-host disease (GVHD) following autologous bone marrow transplant in women with metastatic breast cancer and defined the toxicities of this therapy. PATIENTS AND METHODS: Thirty-six women with advanced breast cancer were treated with CSA 2.5 mg/kg daily for 28 days and IFN-gamma 0.025 mg/m2 subcutaneously (SC) every other day, days 7 to 28 following autologous bone marrow transplantation and monitored for induction and severity of GVHD and toxicity of therapy. RESULTS: GVHD was induced in 56% of patients. The severity of GVHD was greater than in a historic control population treated with CSA alone. Stage III rash was seen in 36% of patients, compared with 3% in the historic control population. Fourteen of 36 patients required therapy with topical corticosteroids and two of 36 required systemic treatment. Only three of 31 historic controls needed topical corticosteroids and no patient was treated systemically. There was no severe visceral GVHD. Hematopoietic recovery was not delayed. There were three toxic deaths. CONCLUSION: CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Impact of age on outcome of patients with cancer undergoing autologous bone marrow transplant.

PURPOSE: We examined the impact of age on outcomes in patients with cancer undergoing autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: All 506 adult patients who underwent ABMT at the Johns Hopkins Oncology Center between January 1987 and January 1994 were studied. A total of 405 patients were aged 18 to 49 years and 101 were aged > or = 50. The effect of age and other prognostic variables on transplant-related mortality (TRM), relapse, and event-free survival rates were analyzed. RESULTS: Patients aged > or = 50 years has a 2.24-fold increased risk of TRM. Although relapse rates were not different based on age, the increased TRM rate resulted in a slight decrease in overall event-free survival in the older patients. Causes of death were not different by age and were mainly related to preparative regimen toxicity. Length of hospital stay and hospitalization costs were not increased in the older patients. CONCLUSION: While the TRM rate was higher in older patients, relapse rates were not increased. Nearly 25% of older patients were expected to be cured of the disease. These data support the use of ABMT in eligible older patients, at least up to the age of 65.

Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin's disease.

Five patients with acute myelocytic leukemia (AML) after combined modality therapy for Hodgkin's disease (HD) were treated with cyclophosphamide and busulfan followed by bone marrow transplantation (BMT). Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide. Two patients died of complications of acute graft-v-host disease (GVHD) despite prophylaxis with either low-dose cyclophosphamide or cyclosporine. The remaining three patients were alive and disease-free 382, 617, and 620 days after transplant. These initial results are encouraging and more patients with treatment-related AML need to be evaluated with both allogeneic and autologous BMT to fully elucidate the potentially curative role of this intensive therapy in an otherwise fatal hematologic malignancy.

Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

PURPOSE: Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS: Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS: Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS: The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

Advances in the treatment of graft-versus-host disease.

Graft-versus-host disease (GVHD) is a complicated disease whose treatment requires an equally multifaceted approach. Recipient conditioning, donor T cell activation, and end stage effectors all may be potential targets for treatment. Many drugs used in the past are returning to the forefront for investigation. Some of the newer nucleoside analogs that are in various stages of development, such as fludarabine and pentostatin, are showing promising activity in GVHD.

Recognition of dementia among medical patients.

To determine how accurately dementia was diagnosed among medical inpatients, we compared the judgments of medical interns with diagnoses based on standard criteria. Fifty-seven interns rendered opinions regarding the presence of dementia in 380 medical inpatients who were simultaneously examined by physician-investigators applying criteria derived from DSM III. The sensitivity and specificity of diagnosis by interns were 79% and 80%, respectively. Patients who were misdiagnosed as demented were less likely to be high school graduates than their correctly classified nondemented counterparts, and those with unrecognized dementia were more likely to be younger than 65 years than patients whose dementia was recognized by house staff. It is concluded that misdiagnosis is related to age and educational status and that attention to these factors may improve diagnostic accuracy.

Separation of rat bone marrow cells by counterflow centrifugal elutriation: a model for studying the effects of lymphocyte depletion.

We have developed a simple three flow-rate, fixed rotor speed, counterflow centrifugal elutriation (CCE) procedure that permits the isolation of an engraftable lymphocyte-depleted (greater than 98%) fraction from ACI rat bone marrow. The different cell fractions were characterized by morphology, alloreactivity in mixed lymphocyte culture and limiting dilution analysis, colony-forming capacity, and their capacity to reconstitute hematopoiesis and effect a graft-versus-host reaction in lethally irradiated allogeneic hosts. After CCE fractionation of ACI rat marrow, transplantation of the lymphocyte-depleted marrow fraction resulted in sustained engraftment without evidence of clinical or histologic acute graft-versus-host disease (GVHD). CCE fractionation of rat bone marrow may be a useful preclinical model for studying lympho-hematopoietic and immune reconstitution after transplantation with lymphocyte-depleted donor marrow, as well as for studying the role of lymphocyte subpopulations on engraftment, acute GVHD, and leukemia relapse in syngeneic and allogeneic bone marrow transplantation.

Management of graft-versus-host disease.

The increasing number of allogeneic stem cell transplants, particularly those involving donors other than HLA-identical siblings, has made the management of acute and chronic graft-versus-host disease (GVHD) a continuing problem for transplant experts. There have been improvements in the prevention of acute GVHD with cyclosporine- and FK506-based combination therapies, as well as lymphocyte depletion. However, fewer than 50% of patients have durable improvement after initial treatment. FK506 and mycophenolate mofetil (MMF) are promising salvage therapies in steroid-resistant GVHD, as are the anti-cytokine antibodies and the purine nucleoside analog, pentostatin. The incidence of chronic GVHD has unfortunately not decreased, despite advances in treatment of acute GVHD. Treatment of chronic GVHD involves treatment of the underlying immunologic process and supportive therapies. Initial therapy has tended to be cyclosporine and prednisone. Refractory patients have hope with combination MMF and FK506, etretinate, plaquenil, and nonpharmacologic approaches, such as PUVA. Supportive care is an integral part of chronic GVHD management with emphasis on infection control and symptom control. Death in chronic GVHD is still largely attributable to infection. The progress in therapies for GVHD has been encouraging, but the future of GVHD management lies in a better understanding of its pathogenesis.

Reappraisal of histologic features of the acute cutaneous graft-versus-host reaction based on an allogeneic rodent model.

We employed a rat model of complete major histocompatibility complex-mismatched allogeneic bone marrow transplantation to better characterize the histologic expression of the acute cutaneous graft-versus-host reaction (GVHR), compared with changes due to the preparative regimen. Cyclosporin A abolished the development of this GVHR. Low levels of dyskeratotic cells were present in all groups (allogeneic and syngeneic transplants with and without cyclosporin A) and, alone, were insufficient to diagnose a cutaneous GVHR. A consistent histologic feature of the GVHR was significant lymphoid infiltration of the dermis. The pattern of cytotoxic folliculitis involved follicular epithelium above the entry of sebaceous glands. Immunostain for major histocompatibility complex class II, IA, and IE antigens revealed that dendritic cells within the follicle were limited to this upper region and that lower follicular epithelium did not upregulate expression with evolution of the GVHR. Based on this model, we conclude 1) that the diagnostic scheme for the acute cutaneous GVHR should include lymphoid infiltration of the dermis, 2) that the preparative regimen (including total body irradiation) induces persistent low levels of dyskeratotic cells (two to three cells/linear mm of epidermis), and 3) that the pattern of follicular involvement may relate to the distribution of dendritic cells and to an inability of lower follicular epithelium to upregulate major histocompatibility complex class II antigens.

Clinical, laboratory, and histopathologic indicators of the development of progressive acute graft-versus-host disease.

Graft-versus-host disease (GvHD) is the major cause of morbidity and mortality following bone marrow transplantation (BMT). The goal of this study of 69 cyclosporin-treated, allogeneic BMT patients was to identify early clinical, laboratory, or histopathologic indicators of the development of progressive, fatal GvHD. Peak values within 100 d of allogeneic BMT for total bilirubin, stool volume in a day, clinical stage of cutaneous GvHD (based on extent of rash), and overall clinical stage of GvHD (based on a combination of graft-versus-host reactions in the skin, liver, and gastrointestinal tract) were most useful (p less than 0.05, by logistic regression) in identifying those patients with clinically progressive and fatal GvHD. Peak values for each of these parameters were reached an average of 40 d or less after BMT. Each unit increase in peak clinical stage of rash (e.g., stage 2 versus stage 3) was associated with an odds ratio incremental risk of 5.8 for clinical progression of GvHD, and each tenfold increase in peak total bilirubin (e.g., 2 mg/dl versus 20 mg/dl) or stool output in a day (e.g., 100 cm3/d versus 1000 cm3/d) was associated with an incremental risk of 8.4 and 10.6, respectively, for a fatal outcome from GvHD. Number of exocytosed lymphocytes and dyskeratotic epidermal keratinocytes (DEK) per linear millimeter of epidermis, the presence of follicular involvement, and the degree of dermal perivascular lymphocytic infiltration in 121 skin biopsy specimens were not associated with the development of progressive or fatal GvHD. Pretransplant total body irradiation was associated (p = 0.03, by Mann-Whitney U testing) with an increased number of DEK in skin biopsy specimens taken less than 20 d after BMT. This study demonstrates that monitoring of total bilirubin, stool output, extent of rash, and overall clinical stage of GvHD is most useful during the first 40 d after BMT in formulating the prognosis of early acute GvHD in allogeneic BMT patients receiving cyclosporin.

Cutaneous graft-versus-host reaction lacks evidence of cutaneous cytomegalovirus by the immunoperoxidase technique.

Sixty skin biopsy specimens from 21 bone-marrow transplant patients were evaluated for the presence of cytomegalovirus (CMV) using two monoclonal antibodies to early and late antigens. Each patient had at least one biopsy showing an acute graft-versus-host reaction (GVHR), grade 2, and one positive culture for CMV from blood, bone marrow or urine. In no case could CMV antigens be identified in biopsies showing an acute or chronic cutaneous GVHR or in any other of the skin biopsies obtained from these patients. While CMV may play a role in immunologic events culminating in graft-versus-host disease (GVHD), this immunoperoxidase study did not reveal evidence of viral antigens in tissue displaying features of cutaneous GVHR.

Acute graft-versus-host disease: clinical characteristics in the cyclosporine era.

Graft-versus-host disease (GVHD) remains the major problem in allogeneic bone marrow transplantation. GVHD has limited the use of this technique to HLA-matched donor recipient pairs. Thus, only a quarter of patients who ultimately may have benefited from bone marrow transplantation are currently eligible. Even in matched patient recipient pairs, GVHD accounts for approximately 40% of the deaths following allogeneic bone marrow transplants. One of the major challenges for transplantation is to derive better strategies to prevent and treat GVHD while retaining the allogeneic benefit of graft-versus-leukemia. Current pharmacologic approaches have used cyclosporine, usually in combination with other drugs. More experimental approaches have removed lymphocytes from the marrow grafts. With either approach, maintaining the anti-leukemic benefit of an allogeneic transplant (i.e., immunologic attack of the leukemia resulting in a lower relapse rate), will need to be maintained if that approach will ultimately prove to be useful.

Unusual case of acute leukemia. Coexisting acute leukemia and pernicious anemia.

Acute nonlymphocytic leukemia developed in a 57-year-old woman following adjuvant therapy with melphalan for ovarian carcinoma. Maturation of differentiating marrow myeloid and erythroid precursors was megaloblastic. The serum vitamin B12 level was low, and Schilling test revealed vitamin B12 malabsorption correctable with intrinsic factor. Megaloblastic maturation of the marrow cells was converted to normoblastic following treatment with vitamin B12 and folic acid. However, blast cells persisted in the marrow, and cytogenetic analysis revealed aneuploidy and trisomy 18. In contrast to the marrow blast cells, there was a decline in circulating blast cells following vitamin replacement, suggesting that these cells were capable of maturation but required vitamin B12 for this purpose.

Long-term survivors of small cell carcinoma of the lung.

Small cell carcinoma of the lung has been shown to be exquisitely responsive to chemotherapy. Unfortunately, these responses are often short in duration and long-term disease-free survival is infrequent. This review of the records of all patients with small cell carcinoma of the lung treated on protocol at The Johns Hopkins Oncology Center from 1973 to 1982 showed that 25 of 225 (11.1 percent) survived two years or longer. Patients with limited disease (20 of 94) and patients with a complete response (15 of 72) had greater two-year survival than those with extensive disease (five of 131) or partial remission (eight of 104). However, 18 of the 25 long-term survivors eventually had relapses, and relapse occurred as late as eight years after diagnosis. This study further emphasizes the impressive discrepancy between the rate and magnitude of the initial response and ultimate survival in patients with small cell carcinoma of the lung.

Treatment and prevention of acute graft-versus-host disease with thalidomide in a rat model.

We have investigated the immunosuppressive effects of thalidomide (Thal) in a bone marrow transplant (BMT) model for graft-versus-host disease (GVHD). Lewis rats received RT1-incompatible marrow transplants from ACI rats after total-body irradiation. Twenty-two of twenty-three rats with established severe acute GVHD were successfully treated with Thal. Thal was given for therapy by gavage at 50 mg/kg/day or 100 mg/kg/day for 40 days after GVHD was clinically and histologically present. Fourteen of twenty-two received prophylaxis successfully with Thal at a dose of 50 mg/kg/day or 100 mg/kg/day. Acute GVHD did not develop after the drug was stopped. Three animals treated for severe GVHD later developed chronic GVHD. Chimerism was shown by permanent acceptance of ACI skin grafts and rejection of third-party skin grafts. Lymphocytes from Thal-treated animals likewise did not respond to Lewis or ACI cells in mixed lymphocyte culture but responded to third-party BN lymphocytes. Thal appears to be a potent new agent for therapy and prophylaxis of GVHD.

Denuded bowel after recovery from graft-versus-host disease.

Graft-versus-host disease (GVHD) is a common complication of bone marrow transplantation and often involves the gastrointestinal system. It is unclear whether there can be severe enough damage by GVHD to permanently injure the bowel and thereby prevent mucosal regeneration. We describe a patient who had successful treatment of GVHD, but who had such severe scarring of the bowel mucosa that the colonic epithelium could not regenerate even 50 days after biopsy-demonstrated resolution of GVHD. Surveillance cultures and histological analysis indicate that this denudation was not caused by infection or continued GVHD. This is an important observation with implications for monitoring response to GVHD therapy and using rectal biopsy to evaluate GVHD.

Pulmonary hemorrhage as a cause of death in allogeneic bone marrow recipients with severe acute graft-versus-host disease.

Acute graft-versus-host disease (GVHD) has recently been associated with endothelial cell injury. The potential clinical significance was explored here in an autopsy review. Thirty-seven allogeneic bone marrow recipients were identified in the autopsy files at The Johns Hopkins Hospital with no evidence of systemic infection. Forty-one percent (15/37) of these patients were found to have extensive recent pulmonary hemorrhage at autopsy which was thought to have led to terminal respiratory failure and death. The 37 patients were divided into 2 groups: those with significant acute GVHD (stage 2 or greater) and those without GVHD (stage 0 or 1). Fifty-nine percent (10/17) of the patients with significant acute GVHD died of acute respiratory failure due to recent pulmonary hemorrhage as opposed to 25% (5/20) of those without acute GVHD (P = 0.032, Fisher's exact test). Terminal pulmonary hemorrhage was also associated with preparation for BMT, with 67% (12/18) of those prepared with total body irradiation (TBI) having pulmonary hemorrhage as opposed to 15% (3/19) of those prepared with chemotherapy using Busulphan (P = 0.002). There was no significant difference in posttransplant survival, engraftment, or final platelet count between the patients stratified by GVHD or preparative protocol. The data support a strong association between significant acute GVHD and terminal hemorrhage, as well a possible association between TBI and pulmonary hemorrhage. Analysis of variance demonstrates that GVHD and TBI are independently associated with increased pulmonary hemorrhage (P < 0.01 for GVHD, P < 0.001 for TBI). We propose that GVHD contributes to terminal pulmonary hemorrhage by injuring the endothelium. However, this association could also be a secondary effect, i.e., toxicity from therapy for GVHD, or an abnormality in cytokines or growth factors. The pathogenic relationship between significant GVHD and terminal hemorrhage is discussed briefly.