CD34 augmentation improves allogeneic T cell-depleted bone marrow engraftment.

T cell depletion (TCD) performed by elutriation has decreased the incidence of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation (BMT). However, as with all forms of TCD, patients may experience graft failure (10%), delayed engraftment, and mixed chimerism. Because 66%-75% of the CD34+ cells coseparate with the small lymphocytes, which are removed by elutriation, we designed a phase I trial in HLA-identical siblings to determine if the readdition of these previously lost small CD34+ cells would improve elutriation's engraftment kinetics. CD34+ cells were isolated from the small cell fraction of 10 consecutive donor grafts and infused into the recipients along with the TCD graft. The positively selected product had a mean T cell content of 1.2 x 10(5)/kg and was 80% CD34+, doubling the CD34+ content of the graft. All patients engrafted promptly with a median time to 500 neutrophils/mm3, untransfused 50,000 platelets/mm3, and discharge from the hospital of 19 (range 10-25), 24 (14-52), and 24 (18-29) days, respectively. Acute GvHD occurred in 2 patients, and no patient had chronic GvHD. Augmenting stem cell dose may be an efficient and safe alternative for overcoming TCD-associated delayed engraftment and graft failure, rather than increasing immunosuppression.

Lichenoid graft-vs-host disease in an autologous bone marrow transplant recipient.

BACKGROUND: Graft-vs-host disease (GVHD) represents one of the major complications of allogeneic bone marrow transplantation (BMT) but is less common in autologous BMT. Following autologous BMT, chronic GVHD has been reported in only four patients, all of whom had a self-limited sclerodermoid form. Lichenoid chronic GVHD has not been previously reported in an autologous BMT patient. OBSERVATIONS: Mucosal and cutaneous lichenoid lesions and histologic findings compatible with chronic lichenoid GVHD developed in a patient 35 days after autologous BMT was performed. The onset of clinical lesions at 35 days after BMT is not incongruent with the diagnosis of chronic lichenoid GVHD (rather than a graft-vs-host reaction) and may have been augmented by cyclosporin A in a manner similar to animal model experiments. CONCLUSION: All forms of GVHD can and do occur following autologous BMT.

The role of autologous hematopoietic stem cell transplantation in hematologic malignancy.

Supraintensive cytoreductive therapy with hematopoietic stem cell rescue (HSCR) is able to provide curative therapy in a number of hematologic malignancies. Allogeneic HSCR is limited to less than 50% of patients because of the absence of related or unrelated compatible donors. Autologous HSCR is a viable alternative to allogeneic HSCR and is applicable to a greater number of patients. In addition, because of the absence of graft-versus-host disease, it is applicable to older patients. Although the relapse of malignancy is higher following autologous compared with allogeneic marrow, the disease-free survival for autologous HSCR is often equal to or greater than that seen following allogeneic HSCR. A number of posttransplantation immunological based therapies have shown promise for further decreasing the relapse rate following autologous HSCR.

The eye in bone marrow transplantation. VI. Retinal complications.

OBJECTIVE: To evaluate the posterior segment ocular complications of patients undergoing bone marrow transplantation (BMT). DESIGN: Retrospective analysis. SETTING: Academic ophthalmology department at a tertiary care hospital with a BMT unit. PATIENTS: Patients undergoing BMT were seen by an ophthalmologist for clinical care and enrolled in a long-term follow-up study, during which they were seen 6 and 12 months after the transplantation and annually thereafter. RESULTS: Of 397 patients undergoing BMT, 51 (12.8%) developed posterior segment complications. Fourteen patients (3.5%) developed hemorrhagic complications with either intraretinal and/or vitreous hemorrhages and 17 patients (4.3%) developed cotton-wool spots in the fundus of both eyes. Eleven patients (2.8%) had bilateral optic disc edema, with eight cases attributed to the toxic effects of cyclosporine and three to other causes. Two patients (0.5%) developed serious retinal detachments. Eight patients (2.0%) developed infectious retinitis and/or endophthalmitis. Fungal infections with Candida or Aspergillus usually occurred within 120 days after BMT, while viral infections with herpes zoster or cytomegalovirus and parasitic infections with Toxoplasma occurred later. Intraocular lymphoma occurred in one patient (0.2%). CONCLUSION: Severe, potentially vision-threatening, posterior segment complications following BMT occur due to a variety of causes.

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.

Lichenoid chronic graft-vs-host disease occurring in a dermatomal distribution.

BACKGROUND: Chronic graft-vs-host disease (GVHD) is a late complication of allogeneic bone marrow transplantation and is associated with high morbidity and mortality. While the pathogenesis of chronic GVHD is not fully understood, several observations and studies suggest that viral infections may play a role. We describe two patients who developed linear lichenoid chronic GVHD. The dermatomal distribution of their lesions suggests an association with herpes zoster virus infection. OBSERVATIONS: Two allogeneic bone marrow transplantation patients developed violaceous papules in a dermatomal distribution. Histologic examination of these lesions revealed dyskeratosis, vacuolar changes in the basal layer, and a mild perivascular and interstitial infiltrate, diagnostic of lichenoid chronic GVHD. CONCLUSIONS: The linear distribution of our patients' lichenoid chronic GVHD is unique and may represent an association with herpes zoster virus infection, providing further support for a role for viral infections in the pathogenesis of chronic GVHD.

Cyclosporine-induced graft-versus-host disease after autologous bone marrow transplantation for acute myeloid leukemia.

Rodents given cyclosporine (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have received autologous bone marrow transplantation (ABMT) with untreated marrow for lymphoma or acute myeloid leukemia (AML). Our study was designed to determine whether CSP administration is associated with appearance of autologous GVHD in patients with AML receiving ABMT with 4-hydroperoxycyclophosphamide (4HC)-purged marrow and whether there was a dose-dependent effect of CSP on development of the syndrome. Thirty-three patients with AML (18 in first remission [CR1], 10 in CR2, and 5 in CR3) received intravenous CSP, beginning on the day of ABMT, after a preparative regimen of busulfan and cyclophosphamide and ABMT with 4HC-treated marrow. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. In the first phase of this study, groups of patients received CSP dosages of either 1 mg/kg/day (7 patients), 2.5 mg/kg/day (8 patients), or 3.75 mg/kg/day (6 patients) for 28 days. Sixteen of the 21 patients (76%) developed cutaneous histopathologic grade 2 GVHD at a median of 34 days (range, 14-49) after ABMT, and cutaneous manifestation were present at time of positive biopsy in 11 of the 16 patients. There was no apparent difference in frequency, time to onset, or duration of GVHD among the three CSP dosage groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of busulfan/cyclophosphamide preparative regimens.

Bone marrow transplantation (BMT) preparative regimens consisting of busulfan (Bu) and cyclophosphamide (Cy) were developed as an alternative to preparative regimens based on total body irradiation (TBI). Animal studies demonstrated that Bu had a high level of myeloablative and antileukemic activity, but little immunosuppressive effect. In contrast, Cy was sufficiently immunosuppressive to allow allogeneic marrow engraftment in animal systems. In both animals and humans, the combination of Bu and Cy results in effective eradication of the host's bone marrow and suppression of the immune response, thus allowing engraftment by either allogeneic or autologous marrow. A number of BMT preparative regimens have been developed for use in leukemic patients. These regimens differ primarily in the myeloablative agent used (Bu or TBI) and the dose of Cy. Although few comparative studies have been conducted, BuCy regimens appear to be similar in efficacy to those containing Cy and TBI. In addition to its use in leukemic patients, BuCy BMT preparative regimens also have been used in patients with nonmalignant lymphohematopoietic disorders or other malignant diseases.

Busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation for marrow transplantation in chronic myelogenous leukemia--a review.

Allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML) offers the only significant chance of cure for this disease. About 50% of patients transplanted in the 1980s appear to be cured and with subsequent advances, it is suggested that more patients transplanted in the 1990s will be cured. Cyclophosphamide (Cy) (120 mg/kg) followed by fractionated total body irradiation (TBI) (Cy2/TBI) has been usually employed in preparation for BMT. Alternative regimens of Busulfan (Bu) (16 mg/kg) and Cy (120 mg/kg) (Bu/Cy2) or Bu (16 mg/kg) and Cy (200 mg/kg) (Bu/Cy4) have more recently been employed. At least three studies of Bu/Cy2 or Bu/Cy4 have given encouraging results. Two ongoing randomized studies of Bu/Cy2 versus Cy2/TBI have shown no difference in the event free survival (EFS). In addition, two ongoing randomized studies of Bu/Cy4 versus Cy (200 mg/kg) plus TBI (Cy4/TBI) show no significant differences in EFS. It appears that Bu/Cy regimens are as effective as Cy/TBI regimens. The choice of one regimen over the other depends on matters other than therapeutic efficacy.

Autologous graft-vs-host disease: mechanisms and potential therapeutic effect.

Administration of the immunosuppressive drug cyclosporine (CsA) after autologous or syngeneic bone marrow transplantation (BMT) elicits an autoimmune syndrome with pathology identical to graft-vs-host disease (GVHD). This syndrome can be induced both in man and in rats and is associated with the development of cytolytic autoreactive T cells that recognize MHC class II determinants. Studies in a rat model suggest that there are two essential components necessary for the induction of an autologous/syngeneic GVHD and include the inhibition of thymic dependent clonal deletion of autoreactive T lymphocytes by CsA and the elimination of a peripheral regulatory mechanism by the preparative regimen. The absence of peripheral autoregulation creates a permissive environment for the activation of the autoreactive T cells. Based on our understanding of the immunobiology of this autoimmune syndrome, we have utilized the induction of autologous/syngeneic GVHD in an attempt to provide an antitumor therapeutic effect after autologous BMT. Interim analyses of our clinical trials suggest that this approach is quite promising.

Impaired erythropoietin response to anemia after bone marrow transplantation.

Delayed erythroid recovery is common after bone marrow transplantation (BMT), with some patients continuing to require red blood cell (RBC) transfusion support for as long as 1 year. While the etiology is multifactorial, inadequate stimulation of erythroid progenitors by the erythroid growth factor, erythropoietin, may play a role. In this study, the erythropoietin response to anemia of 70 consecutive patients undergoing BMT at the Johns Hopkins Oncology Center was compared with the erythropoietin response in uncomplicated iron deficiency anemia. Erythropoietin levels were elevated for the degree of anemia early after BMT; however, at the time of marrow recovery, erythropoietin levels were significantly suppressed in both allogeneic and autologous BMT patients compared with the iron-deficient patients. Patients with acute graft-versus-host disease (GVHD) had a more marked suppression of the erythropoietin response to anemia. In the patients who remained anemic for extended periods of time (up to 12 months after BMT), an inadequate erythropoietin response to anemia persisted. Delayed erythroid recovery after BMT is associated with inadequate erythropoietin levels. Therefore, recombinant human erythropoietin may be useful in the treatment of the anemia associated with both autologous and allogeneic BMT.

Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation.

Busulfan (BU) is a widely used myeloablative and antineoplastic agent in clinical bone marrow transplantation (BMT). The lower incidence of BU-associated toxicities and lower therapeutic effectiveness in young children given BU doses based on body weight (ie, 16 mg/kg) is associated with altered pharmacokinetics of BU; the area under the curve (AUC) of BU concentration versus time is significantly less in these patients than those observed in older children and adults. To optimize BU dosage in young BMT recipients, we developed a dosage regimen based on body surface area (BSA) and determined BU pharmacokinetics and BU-associated toxicities. Seven children (median age, 3.9 years, range, 1.1 to 5.7) undergoing allogeneic or autologous BMT for leukemia received 40 mg/m2/dose BU every 6 hours for 16 doses; BU concentrations were measured in the plasma, and AUCs were determined for each patient after the first and 13th doses. Expressed as a function of body weight, the median BU dosage was 26.4 mg/kg (range, 24.3 to 28.2), a 60% increase over the BU dosage based on body weight. Four patients developed mucositis, and one of them also developed nonfatal hepatic veno-occlusive disease (VOD). No patients receiving 40 mg/m2 BU developed neurotoxicity (eg, seizures) or interstitial pneumonitis. Prompt and sustained engraftment was observed in the allogeneic BMT recipients, and late graft failure was not seen. The mean BU AUCs were 1,105 mumol/L.min (range, 790 to 2,080) after the first dose and 1,022 mumol/L.min (range, 632 to 1,860) after the 13th dose of BU, comparable to the AUCs in adults given 16 mg/kg of BU. These studies suggest that, in young children, BSA-based dosing of BU (40 mg/m2) provides drug exposures (AUCs) closer to adult values with acceptable toxicities and may improve therapeutic effects.

Autologous graft-versus-host disease: a novel approach for antitumor immunotherapy.

Autologous bone marrow transplantation (BMT) is a therapeutic option for the treatment of lymphohematopoietic malignancies and solid tumors. Despite the intensive cytoreductive therapy, however, the rates of tumor recurrence after autologous BMT remain unacceptably high. Current studies suggest that the administration of cyclosporine (CsA) disrupts the reconstitution of self-tolerance following autologous BMT leading to the induction of an autoimmune graft-versus-host disease (GVHD). Studies in a rat tumor model and preliminary clinical trials suggest that this autoimmune or autologous GVHD provides a significant antitumor effect. Moreover, the antitumor effect of autologous GVHD can be enhanced by administration of gamma-interferon, which upregulates the antigen recognized by the autoreactive effector cells of autologous GVHD. These studies indicate that the induction of an autoimmune GVHD after autologous BMT may be a promising immunotherapeutic approach for treatment of certain neoplastic diseases.

Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing autologous bone marrow transplantation for acute myeloid leukemia.

Cutaneous graft-versus-host disease (GVHD) has been reported after administration of cyclosporine (CSP) after autologous bone marrow transplantation (ABMT) with unpurged marrow in patients with lymphoma. To determine whether GVHD can be induced after ABMT with chemopurged marrow in acute myeloid leukemia (AML), we administered intravenous CSP for 28 days (beginning on the day of ABMT) to 19 patients with AML (12 in first remission [CR1], six in CR2, and one in CR3) who received busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) and ABMT with 4-hydroperoxycyclophosphamide (4HC)-treated marrow. In this dose-escalation trial, CSP daily doses were 1 mg/kg in seven patients, 2.5 mg/kg in eight patients, or 3.75 mg/kg in four patients. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. Overall, 15 of 19 patients (79%) had cutaneous histopathologic grade 2 GVHD at a median of 33 days (range, 14 to 49) after ABMT; in 10, cutaneous manifestations were present at time of positive biopsy. The frequency, time to onset, and duration of GVHD were similar among the three CSP dosage groups. No patients had hepatic or gastrointestinal dysfunction attributable to GVHD or required specific therapy for GVHD. Positive biopsies for GVHD were seen in seven of eight patients who received full-course, full-dose CSP and 8 of 11 patients who had CSP discontinued or dosage reduced because of renal insufficiency. Three patients (one with positive biopsy) died with ABMT-related complications. Seven patients (four CR1, three CR2) relapsed with AML at a median of 411 days (range, 178 to 549) after ABMT; six of seven had positive biopsies for cutaneous GVHD. Nine patients (seven CR1, one CR2, and one CR3) are alive without relapse at a median of 501+ days (range, 252+ to 811+) after ABMT; eight of nine had cutaneous GVHD. Short-course CSP can induce autologous GVHD in recipients of chemopurged marrow autografts for AML, but randomized prospective trials are needed to determine whether this immunologic reaction is associated with alterations in leukemic relapse rate and disease-free survival after ABMT in AML.

Relapse of leukemia after bone marrow transplantation: effect of second myeloablative therapy.

Twenty-three patients with recurrent leukemia after bone marrow transplantation (BMT) underwent a second myeloablative therapy followed by second transplant between June 1977 and April 1991. Patients had either acute lymphocytic leukemia (n = 4), acute myelogenous leukemia (n = 7) or chronic myelogenous leukemia (n = 12). The median age was 29 years and the median interval between first and second BMT was 22.6 months. The second preparative therapy consisted of cyclophosphamide (200 mg/kg) and total body irradiation (1200 cGy) in nine patients and busulfan (16 mg/kg) and cyclophosphamide (120-200 mg/kg) with or without etoposide (30-60 mg/kg) in 14 patients. The same sibling donor (three syngeneic, 20 allogeneic) was used for both transplants. All patients demonstrated prompt neutrophil recovery (median 21 days) with donor-derived hematopoiesis documented in 16 of 16 evaluable patients. With a median follow-up of 24 months after second BMT, the survival, event-free survival and probability of remaining in remission at 26 months are 47%, 38% and 76% respectively. Outcome was best in patients with chronic myelogenous leukemia (7/12 survivors) and worst in patients with acute leukemia (2/11 survivors). Thus, the data would suggest that (1) selected patients with recurrent leukemia after BMT can still be cured with myeloablative therapy and second BMT, and (2) further improvements in outcome will be dependent upon the reduction of regimen-related toxicity.

Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation.

Growth was assessed during the first and second years following bone marrow transplantation (BMT) in 47 children treated by either busulfan plus cyclophosphamide (BU/CY) (n = 24) or cyclophosphamide plus fractionated total body irradiation (CY/TBI) (n = 23). Before transplant, the median height was only 0.2 SD below age- and sex-adjusted means (range, -2.5 to +3.0). Height was greater than 2.0 SD below normal in only three patients (6%). The pretransplant heights were comparable in the BU/CY and CY/TBI groups (-0.1 v -0.6 SD, P = .35). Following transplant, median 1- and 2-year heights were 0.7 and 0.9 SD below normal, respectively. Growth rates were 2.2 SD and 1.4 SD below normal during the first and second years, respectively. Growth rates were greater than 2.0 SD below normal in 24 of 47 (51%) at 1 year and in 12 of 31 (39%) at 2 years after transplant. Growth rates in patients treated with BU/CY were comparable to those treated with CY/TBI during both years: -2.5 versus -1.7 SD during the first year (P = .19, Wilcoxon), and -1.5 versus -1.1 SD during the second year (P = .61). Growth rates during the second year correlated with growth rates during the first year (r = .36, P = .046). Growth rates during the first year were lower in patients who had been given prior cranial irradiation, those who were near pubertal age at the time of transplant, and those who were transplanted for a disease other than acute lymphoblastic leukemia (ALL). During the second year, poor rates of growth were associated only with the use of corticosteroids after transplant.