Cytomegalovirus Ventriculoencephalitis after Unrelated Double Cord Blood Stem Cell Transplantation with an Alemtuzumab-containing Preparative Regimen for Philadelphia-positive Acute Lymphoblastic Leukemia

Despite the prophylaxis and preemptive strategies using potent antiviral agents, cytomegalovirus (CMV) remains a major infectious cause of morbidity and mortality in allogeneic stem cell transplantation (SCT) recipients. Delayed immune reconstitution after SCT, such as cord blood and T-cell depleted SCT with the use of alemtuzumab, has been associated with an increased frequency of CMV disease as well as CMV reactivation. CMV disease involving central nervous system is an unusual presentation in the setting of SCT. We report a case of CMV ventriculoencephalitis after unrelated double cord blood SCT with an alemtuzumab-containing preparative regimen for Philadelphia-positive acute lymphoblastic leukemia.     

Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation

The effect of suppression with antimicrobial agents of the intestinal microflora of paediatric bone marrow graft recipients on severe bacterial and fungal infections and on moderate to severe acute graft-versus-host disease was studied retrospectively. Data on 65 cases of bone marrow transplantation for either severe bone marrow failure or leukaemia, performed in a strict protective environment with either complete or selective gastrointestinal decontamination, were evaluated. All bone marrow grafts were from HLA-identical siblings and were not depleted of T-lymphocytes. Twenty percent of the recipients had one or more episodes of septicaemia during the granulocytopenic period after transplantation, mostly due to gram-positive bacteria. Only five children died due to infection, in each case caused by a microorganism originating from the endogenous flora. Complete gastrointestinal decontamination was superior to selective gastrointestinal decontamination in preventing infectious complications (p<0.001). The same was the case for the prevention of acute graft-versus-host disease of grade II or higher, which was observed in 7 of 40 (17.5 %) completely decontaminated children versus 9 of 18 (50 %) selectively decontaminated children evaluable for graft-versus-host disease (p<0.01). It is concluded that complete gastrointestinal decontamination in a strict protective environment is a feasible and very effective method for preventing severe infections and acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents; it resulted in a low transplantation-related mortality of 26 % and a good quality of survival in 69 % of the graft recipients.     

Cytomegalovirus and adenovirus infections and diseases among 75 paediatric unrelated allogeneic bone marrow transplant recipients

Viral infections remain a major complication of allogeneic bone marrow transplantation. A population of children who underwent unrelated allogeneic bone marrow transplantation in a single centre has been followed-up for viral infections and diseases. We describe the detection of cytomegalovirus (CMV) and adenovirus among 75 children transplanted between 1989 and 2000. CMV was detected among 22 patients (29%) and adenovirus among 19 patients (25%); they were associated with clinical diseases in 10 and 8 patients, respectively. Four patients had adenovirus and CMV coinfection. The obvious risk factor for CMV infection is seropositivity of the recipient prior to transplantation. Adenovirus is detected significantly more frequently when conditioning regimen includes anti-thymocyte or anti-lymphocyte globulin. Diseases associated with adenovirus have been correlated with a significantly higher mortality rate, stressing the need for the implementation of a systematic virological survey for this virus and for the evaluation of therapeutic protocols including new molecules.     

Host-specific interleukin-2-secreting donor T-cell precursors as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings.

BACKGROUND. Acute graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation from an HLA-identical sibling. There is no practical test before transplantation that gives sufficient information to predict the degree of allogeneic reactivity between HLA-identical siblings. METHODS. We determined the frequency with which host-specific interleukin-2-secreting donor T-cell precursors occurred in 16 consecutive pairs of HLA-identical siblings before they underwent marrow grafting. The results were correlated with the development of acute GVHD after transplantation. RESULTS. High frequencies of host-specific T-cell precursors (> or = 1 per 100,000) were detectable before transplantation in eight donors whose siblings later had severe (grade II or III) acute GVHD. Among the donors to eight patients with mild (grade 0 or 1) acute GVHD, low frequencies (< 1 per 100,000) were found. CONCLUSIONS. Analysis of the frequency of such cells before transplantation may be a useful predictor of severe acute GVHD in allogeneic bone marrow transplantation between HLA-identical siblings. It is possible that the patients at risk for serious acute GVHD after marrow grafting may benefit from some alternative form of immunosuppressive therapy.     

Persistence of host dendritic cells after transplantation is associated with graft-versus-host disease.

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in patients undergoing allogeneic bone marrow transplantation following either a conventional or reduced-intensity preparative regimen. In a murine model, inactivation of host dendritic cells (DCs) was associated with a significant reduction in acute GVHD, suggesting that host DCs may play an important role in the pathogenesis of acute GVHD. The role of host DCs in the development of GVHD following allogeneic stem cell transplantation in humans, however, is unclear. We examined DC chimerism in patients with various hematologic malignancies who underwent a reduced-intensity preparative regimen of extracorporeal photophoresis, pentostatin, and reduced-dose total body irradiation (n = 21) or a conventional preparative regimen of cyclophosphamide and total body irradiation (n = 3). Full donor hematopoietic reconstitution was demonstrated in 19 of 21 patients who underwent a reduced-intensity preparative regimen and in all patients who underwent a conventional preparative regimen. Grade 0 to I acute GVHD and limited or no chronic GVHD were observed in 18 patients who underwent a reduced-intensity regimen and 1 patient who underwent a conventional regimen who achieved full donor DC chimerism at day +100 posttransplantation. In contrast, grade II to IV acute GVHD and extensive chronic GVHD were observed in the 2 patients who underwent a conventional regimen and the 1 patient who underwent a reduced-intensity regimen who had host rather than donor DC chimerism. The persistence of host DCs at day +100 posttransplantation is correlated with the development of severe acute and chronic GVHD (P =.001). Host DCs may represent a therapeutic target for reducing GVHD in allogeneic bone marrow transplants.     

Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease.

Reduced-intensity allogeneic transplantations for myelodysplastic syndrome (MDS) patients have been limited by significant graft-versus-host disease (GVHD), treatment-related mortality, and disease relapse. We treated 18 MDS patients ineligible for standard allogeneic transplantation with a preparative regimen of photopheresis day -7 and -6, pentostatin 4 mg/m(2) by continuous infusion day -5 and -4, and total body irradiation 600 cGy in 3 fractions day -3 and -2, followed by allogeneic stem cell infusion from 6/6 or 5/6 HLA-matched related donors or 6/6 HLA-matched unrelated donors. GVHD prophylaxis consisted of cyclosporin A and a short course of methotrexate. The median age was 54 years (range, 30-70 years). Diagnoses included refractory anemia (n = 2), refractory anemia with ringed sideroblasts (n = 2), refractory anemia with excess blasts (n = 10), refractory anemia with excess blasts in transformation (n = 3), and chronic myelomonocytic leukemia (n = 1). Sixteen of 18 patients developed full donor chimerism with no day +100 transplant-related mortality. Grade II to IV acute GVHD and extensive chronic GVHD developed in 19% and 18% of patients, respectively. Disease relapse occurred in 2 patients. At a median follow-up of 14 months (range, 1-35 months), the 1-year failure-free and overall survival were 64% and 65%, respectively. Our photopheresis and pentostatin-based reduced-intensity preparative regimen for allogeneic bone marrow transplantation in high-risk MDS patients achieves successful donor engraftment and disease remission with less transplant toxicity and grade II to IV acute GVHD.     

CMV antigenemia following bone marrow transplantation: risk factors and outcomes.

Cytomegalovirus (CMV) infection remains a major problem in blood and bone marrow transplant (BMT) recipients. Recent efforts have been directed at prevention, early diagnosis, and treatment of CMV disease following BMT. Assay for CMV early antigen pp65 on circulating leukocytes has been shown to be sensitive, and specific in detecting early CMV infection. We examined the frequency, risk factors, and outcomes of a positive CMV antigen assay in 118 consecutive BMT patients. Forty-three (36%) of the 118 patients developed CMV antigenemia a median of 26 days post-BMT (range, -6 to 209 days). The incidence of antigenemia in autologous, related donor, and unrelated donor BMT recipients was 15%, 50%, and 48%, respectively (P < .01) and was lower in CMV-seronegative patients (19% versus 51% in seropositive patients; P < .01). Patients with grade II to IV acute graft-versus-host disease (GVHD) had 2.2 times the risk of antigenemia of patients with no or only limited GVHD (P = .03). Age at transplantation, underlying disease, CMV prophylaxis regimen, and GVHD prophylaxis regimen did not affect the risk of CMV antigenemia. Ten of the 43 antigenemic patients, all CMV-seropositive allogeneic BMT (alloBMT) recipients, developed CMV organ disease a median of 101 days (range, 28-283 daya) post-BMT. These data suggest that CMV-seropositive alloBMT patients are at highest risk for CMV antigenemia and for organ disease as well. CMV disease may occur before antigenemia is detectable in leukopenic patients and may also develop late post-BMT, even in patients still receiving antiviral prophylaxis. In high-risk groups, intensive surveillance continuing for more than 6 months after BMT may be indicated.     

Infectious complications in patients undergoing unrelated donor bone marrow transplantation: experience from a single institution

Objective   To analyze the incidence and characteristics of documented infections in patients with hematologic malignancies undergoing unrelated donor bone marrow transplantation (UD-BMT).
Methods   We studied the occurrence of infections in 22 patients with hematologic malignancies or severe aplastic anemia who underwent UD-BMT from April 1990 to December 2000. The median age was 26 years (range 13–46). Acyclovir–ganciclovir, co-trimoxazole, fluconazole–nystatin and ciprofloxacin were administered for anti-infectious prophylaxis.
Results   We registered 61 infectious episodes. During the early post-transplant period, there were eight clinically documented infections (CDIs), four cases of fever of unknown origin (FUO), seven cases of bacteremia, two cases of cytomegalovirus (CMV) antigenemia, and one case of CMV disease. In the intermediate period (days 30–100 after BMT), there were nine cases of CMV antigenemia, three bacterial infections, two fungal infections, one case of disseminated toxoplasmosis, and one case of FUO. In the late period (day 100 and later), we documented 13 viral infections, eight bacterial infections, one CDI, and one case of invasive aspergillosis. Infections contributed to death in 10 of 17 patients. Citrobacter bacteremia and sepsis of unknown origin were the main causes of infectious mortality in the early period. Infection was the main cause of death in six of seven patients in the late period.
Conclusion   A high incidence of life-threatening infections and infection-related mortality was observed. A high rate of CMV infection in the early period, and death caused by multiresistant Gram-negative microorganisms in the late period, were the main findings in this series.     

Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft

BACKGROUND: The treatment of chronic granulomatous disease with conventional allogeneic hematopoietic stem-cell transplantation carries a high risk of serious complications and death. We investigated the feasibility of stem-cell transplantation without ablation of the recipient's bone marrow. METHODS: Ten patients, five children and five adults, with chronic granulomatous disease underwent peripheral-blood stem-cell transplantation from an HLA-identical sibling. We used a nonmyeloablative conditioning regimen consisting of cyclophosphamide, fludarabine, and antithymocyte globulin. The allograft was depleted of T cells to reduce the risk of severe graft-versus-host disease. Donor lymphocytes were administered at intervals of 30 days or more after the transplantation to facilitate engraftment. RESULTS: After a median follow-up of 17 months (range, 8 to 26), the proportion of donor neutrophils in the circulation in 8 of the 10 patients was 33 to 100 percent, a level that can be expected to provide normal host defense; in 6 the proportion was 100 percent. In two patients, graft rejection occurred. Acute graft-versus-host disease (grade II, III, or IV) developed in three of the four adult patients with engraftment, one of whom subsequently had chronic graft-versus-host disease. None of the five children had grade II, III, or IV acute graft-versus-host disease. During the follow-up period, four serious infections occurred among the patients who had engraftment. Three of the 10 recipients died. Preexisting granulomatous lesions resolved in the patients in whom transplantation was successful. CONCLUSIONS: Nonmyeloablative conditioning followed by a T-cell-depleted hematopoietic stem-cell allograft is a feasible option for patients with chronic granulomatous disease, recurrent life-threatening infections, and an HLA-identical family donor.     

Adenovirus infection in hematopoietic stem cell transplantation: effect of ganciclovir and impact on survival.

Adenoviruses (ADV) are emerging as important causes of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In mainly non-T-cell depleted HSCT recipients, we analyzed the incidence of ADV infection, risk factors for infection, the effect of ganciclovir administered for prevention of cytomegalovirus (CMV), and the impact of ADV infection on survival. The overall incidence of ADV, irrespective of the method of detection, was 8.5% (450/5233) and 12.3% (43/348) after the first or second allogeneic HSCT, and 6.3% (78/1219) and 6.5% (5/77) after the first or second autologous HSCT, respectively. The most frequent sites of infection and disease were stool and gastrointestinal tract, respectively. Statistically significant risk factors associated with ADV infections among allogeneic recipients included younger age, grade II to IV graft-versus-host disease, year of transplantation, and a second allogeneic HSCT. Furthermore, allogeneic patients seronegative for CMV at transplantation and seropositive allogeneic patients who did not receive ganciclovir, either at engraftment or as pre-emptive therapy on CMV reactivation, were at higher risk of developing ADV infections compared with seropositive patients who received ganciclovir (odds ratio=1.8, 95% confidence interval (CI) 1.2 to 2.8, P=.005 and odds ratio=3.4, 95% CI 2.1 to 5.55, P<.0001, respectively). The hazard of overall mortality was higher in patients who contracted ADV compared with those who did not (hazard ratio 1.5, 95% CI 1.3 to 1.7, P<.0001). This study shows that ADV infections are associated with poor transplantation outcome in T-cell repleted HSCT recipients. Ganciclovir, given for CMV prevention, may have a protective effect. Controlled treatment and prevention studies are warranted.     

The risk of cytomegalovirus infection in non-myeloablative peripheral stem cell transplantation compared with conventional bone marrow transplantation

Non-myeloablative allogeneic peripheral stem cell transplantation (NST) is a novel therapeutic strategy for patients with hematologic malignancies. Whether non-myeloablative transplants are associated with increased risk of cytomegalovirus (CMV) infections is unknown. To clarify this issue, we compared the outcome of CMV infection following 24 allogeneic non-myeloablative peripheral blood stem cell transplants and 40 conventional bone marrow transplants (CBT). The NST regimen consisted (mg/kg). Twelve patients (50%) in the NST group and 17 (43%) in the CBT group developed positive antigenemia before day 100 (p=0.60). The time to the first appearance of positive antigenemia was not different between these two groups (p=0.40), and two groups showed similar initial and maximal antigenemia values (p=0.56 and p=0.68, respectively). Only one case of CMV colitis developed in the CBT group whereas CMV disease did not develop in the NST group. Although statistically insignificant, the treatment response against CMV antigenemia using ganciclovir was in favor of NST group. In conclusion, there was no difference in the risk of CMV infection between NST group and CBT group. Further prospective and controlled study is needed to clarify the impact of non-myeloablative procedure on the outcome of CMV infection.     

Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation.

Delayed immunologic recovery after allogeneic bone marrow transplantation (BMT) represents a major cause of morbidity and mortality that limits the overall success of the transplantation procedure. Recent clinical data suggest that a subset of donor dendritic cells may inhibit the graft-versus-tumor activity of donor T cells. We studied the immunoregulatory activity of donor dendritic cells in allogeneic BMT between major histocompatibility complex-disparate strains of mice. Bone marrow grafts enriched or depleted of CD11b- and CD11b+ dendritic cell subsets by immunomagnetic cell sorting were combined with small numbers of congenic splenic T cells. Recipients of CD11b-depleted bone marrow had significant posttransplantation expansion of donor spleen-derived CD4+ memory T cells compared with recipients of unmanipulated bone marrow. CD11b depletion enhanced the antitumor activity of the splenic donor T cells without producing significant graft-versus-host disease and resulted in long-term survival after a supralethal dose of T-cell leukemia administered after BMT. Expansion of donor spleen-derived T cells was proportional to the number of CD11b- dendritic cells in the bone marrow graft and was associated with increased levels of serum interferon-gamma. Thus, manipulating the content of donor antigen-presenting cells in allogeneic BMT is a novel strategy to activate donor memory T cells and enhance allogeneic graft-versus-leukemia effects with minimal graft-versus-host disease.     

Low incidence of transplantation-related acute complications in patients with chronic myeloid leukemia undergoing allogeneic stem cell transplantation with a low-dose (550 cGy) total body irradiation conditioning regimen.

Although allogeneic transplantation is a curative therapy for chronic myeloid leukemia (CML), treatment-related mortality is still a major cause of posttransplantation mortality, especially for patients older than 40 years. We investigated, in a phase II trial, the role of a low-dose (550 cGy) high-dose rate (35 cGy/min) single-exposure total body irradiation (TBI) conditioning regimen for allogeneic peripheral blood stem cell (PBSC) transplantation in patients with CML. Between June 1997 and August 2000, 30 adult patients with CML underwent cytokine-mobilized allogeneic PBSC transplantation from HLA-matched siblings following administration of cyclophosphamide (60 mg/kg per day intravenously on days -2 and -1) and single-dose TBI (550 cGy delivered at 30 cGy/min on day 0). Cyclosporine A alone was administered for prophylaxis against graft-versus-host disease (GVHD). Median patient age was 47 years (range, 21-63 years), with 23 patients (77%) older than 40 years. The preparative regimen was well tolerated. Grade 4 toxicities and oral mucositis were not observed. Graft failure did not occur. Severe acute GVHD was observed in 5 patients (17%). The median follow-up was 23 months (range, 6-39 months). Cytogenetic or hematologic relapse was detected in 3 patients (10%), 2 of whom subsequently entered remission following a taper of immunosuppression. Nonrelapse mortality occurred in 5 patients (17%), and the Kaplan-Meier estimate of survival at 2 years was 83% (95% confidence interval, 70%-97%). In summary, this low-dose TBI-based preparative regimen resulted in uniform donor engraftment, with markedly reduced organ toxicity and nonrelapse mortality, in this relatively older cohort of patients with CML.     

Cytology and histology of haemopoietic cell transplantation under the influence of ALS in mice. II. The effect of marrow from donors pretreated with antilymphocyte serum (ALS) on the recipient

Cytology and histology of recipients of allogeneic bone marrow were studied 13. 20, 24, 30 and 34 days after transplantation. The developing chronic secondary disease was characterized by increased numbers of myeloid cells, by lymphopenia and by erythroblastopenia in the bone marrow and the spleen. Erythroblastopenia together with lymphopenia and augmented myeloid cells also occurred in irradiated F₁-hybrids suffering from a chronic homologous disease. The latter model eliminated the following as a cause of erythroblastopenia in secondary disease: (1) host-versus-graft reaction against donor-type erythroblasts for immunogenetical reasons, and (2) graft-versus-host reaction against recipient-type erythroblasts since they had already been destroyed by irradiation. Treatment of the donor with ALS resulted in a suppression of homologous disease in F₁-hybrids with a cytology resembling that of recipients of syngeneic spleen cells. The same treatment only delayed the onset of chronic secondary disease in recipients of allogeneic bone marrow. These allogeneic recipients, in contrast to the F₁-hybrid recipients, died with the typical morphology of a chronic secondary disease.

In recipients of syngeneic bone marrow from donors treated with ALS, repopulation with lymphocytes was somewhat delayed and transient erythroblastosis in the spleen occurred 20 days after transplantation.

     

Cytomegalovirus infection after bone marrow transplantation in children

Cytomegalovirus (CMV) is a well-known cause of disease occurring after bone marrow transplantation (BMT). The manifestations of CMV range from asymptomatic infection, defined as active CMV replication in the blood in the absence of clinical manifestations or organ failure abnormalities, to CMV disease, characterized by CMV infection with clinical symptoms or organ function abnormalities. Diagnostic procedures to assess the viral load have improved greatly with the increased use of antigenemia, CMV DNA, and immediate early-messenger RNA. Many conditions concur in determining the risk of developing CMV reactivation or disease after bone marrow transplant with serologic status of donor and recipient, type of bone marrow transplant, presence of graft-versus-host disease being the most studied. However, time and quality of immune reconstitution seems to be the pivotal factors. Pneumonia and gastrointestinal involvement are the most frequently documented clinical pictures with late-onset CMV reactivation or disease representing a new challenge. CMV prophylaxis or pre-emptive therapy adopted during the last few years in allogeneic BMT recipients has changed the natural history of the disease, reducing the risk of CMV disease, CMV-associated death, transplant-related mortality, and has prolonged the period at risk. Specific studies on children are lacking, however, the clinical pictures and features seems to be similar both in children and adults.     

Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia

Chemoradiotherapy and transplantation of bone marrow from matched sibling donors have been useful for the treatment of acute lymphoblastic leukemia in patients with a poor prognosis but are not available to some two thirds of patients who do not have a matched allogeneic donor. We undertook this study to compare autologous and allogeneic marrow transplantation in the treatment of such cases. We treated 91 patients with high-dose chemoradiotherapy and followed them for 1.4 to 5 years. Forty-six patients with an HLA-matched donor received allogeneic marrow, and 45 patients without a matched donor received their own marrow taken during remission and purged of leukemic cells with use of monoclonal antibodies. Bone marrow engraftment occurred earlier in patients who received autologous marrow. Recipients of autologous marrow had shorter hospital courses, with significantly fewer peritransplantation deaths than recipients of allogeneic marrow. Post-transplantation relapse of leukemia was the most frequent cause of treatment failure; relapses occurred in an estimated 37 percent of patients with allogeneic grafts in whom graft-versus-host disease developed, 75 percent of patients with allogeneic grafts in whom graft-versus-host disease did not develop, and 79 percent of patients who received autologous grafts. The interval before relapse was significantly shorter in the autologous-marrow group than in the allogeneic-marrow group. Recipients of autologous and allogeneic marrow whose first pretransplantation remissions were short (less than 18 months) had eventual outcomes similar to those whose first remissions were longer than 18 months. Patients with a first remission lasting less than 18 months had an outcome better than that expected with chemotherapy alone. The fractions of "cured" patients were estimated to be 20 percent in the autologous-marrow group and 27 percent in the allogeneic-marrow group--not a significant difference, but because of the limited statistical power of the study, the question of long-term disease-free survival must still be considered open.     

Strong Donor Mononuclear Cell Reactivity for Herpes Simplex Virus (HSV) Antigen in HSV Immune Donors Combined with Recipient Seropositivity for HSV is Associated with Acute Graft-versus-Host Disease

Prior to bone marrow transplantation (BMT) titres of IgG antibodies for cytomegalovirus (CMV), herpes simplex virus (HSV) and varicella zoster virus (VZV) were analysed in 51 donors and recipients of allogeneic bone marrow. Donor mononuclear cells from peripheral blood and bone marrow cells were stimulated with antigen prepared from CMV, HSV and VZV. High IgG titres for HSV in the recipient were associated with grade II-III acute graft-versus-host disease (GVHD) (P = 0.05). Furthermore, the combination of positive IgG titre for HSV antibodies in the recipient, and strong donor blood mononuclear cell reactivity to HSV antigen in HSV immune donors, significantly increased the incidence of grade II-III acute GVHD (P = 0.04). The data suggest that HSV immune donor mononuclear cells may initiate a GVH reaction.     

Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation

BACKGROUND: Since allogeneic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematologic cancers, we sought to induce analogous graft-versus-tumor effects in patients with metastatic renal-cell carcinoma by means of nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. METHODS: Nineteen consecutive patients with refractory metastatic renal-cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of a peripheral-blood stem-cell allograft from an HLA-identical sibling or a sibling with a mismatch of a single HLA antigen. Cyclosporine, used to prevent graft-versus-host disease, was withdrawn early in patients with mixed T-cell chimerism or disease progression. Patients with no response received up to three infusions of donor lymphocytes. RESULTS: At the time of the last follow-up, 9 of the 19 patients were alive 287 to 831 days after transplantation (median follow-up, 402 days). Two had died of transplantation-related causes, and eight from progressive disease. In 10 patients (53 percent) metastatic disease regressed; 3 had a complete response, and 7 had a partial response. The patients who had a complete response remained in remission 27, 25, and 16 months after transplantation. Regression of metastases was delayed, occurring a median of 129 days after transplantation, and often followed the withdrawal of cyclosporine and the establishment of complete donor-T-cell chimerism. These results are consistent with a graft-versus-tumor effect. CONCLUSIONS: Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy.     

Nonmyeloablative conditioning with busulfan before matched littermate bone marrow transplantation results in reversal of the disease phenotype in canine leukocyte adhesion deficiency.

Leukocyte adhesion deficiency (LAD)-1, a primary immunodeficiency disease caused by molecular defects in the leukocyte integrin CD18 molecule, is characterized by recurrent, life-threatening bacterial infections. Myeloablative hematopoietic stem cell transplantation is the only curative treatment for LAD-1. Recently, canine LAD (CLAD) has been shown to be a valuable animal model for the preclinical testing of nonmyeloablative transplantation regimens for the treatment of children with LAD-1. To develop new allogeneic transplantation approaches for LAD-1, we assessed a nonmyeloablative conditioning regimen consisting of busulfan as a single agent before matched littermate allogeneic bone marrow transplantation in CLAD. Three CLAD dogs received busulfan 10 mg/kg intravenously before infusion of matched littermate bone marrow, and all dogs received posttransplantation immunosuppression with cyclosporin A and mycophenolate mofetil. Initially, all 3 dogs became mixed chimeras, and levels of donor chimerism sufficient to reverse the CLAD phenotype persisted in 2 animals. The third dog maintained donor microchimerism with an attenuated CLAD phenotype. These 3 dogs have all been followed up for at least 1 year after transplantation. These results indicate that a nonmyeloablative conditioning regimen with chemotherapy alone is capable of generating stable mixed chimerism and reversal of the disease phenotype in CLAD.     

Idiopathic pneumonia syndrome after allogeneic bone marrow transplantation in mice. Role of pretransplant radiation conditioning.

Idiopathic pneumonia syndrome (IPS) is a significant clinical problem encountered among patients treated with bone marrow transplantation (BMT). IPS is identified as an inflammatory lung disease characterized by diffuse interstitial pneumonitis and alveolitis leading to interstitial fibrosis in the absence of an identifiable infectious agent. In an earlier study we characterized a murine model of IPS following allogeneic BMT that exhibits several features of human IPS. In this report we show that the lung represents a unique target of post-BMT disease in this model. The kinetics of developing lung disease were found to be markedly different from the kinetics of graft-versus-host disease in other tissues such as liver, colon, ear, skin, and tongue. Mice transplanted by our standard protocol with T-cell-depleted semiallogeneic donor bone marrow plus donor spleen cells in the absence of pretransplant radiation conditioning did not develop lung inflammation or fibrosis characteristic of IPS. Pretransplant radiation conditioning in the absence of BMT also failed to cause IPS, demonstrating an important role for radiation conditioning in the development of BMT-related IPS. The occurrence of lung disease post-BMT was found to be dependent on radiation conditioning in a dose-dependent manner. Finally, thoracic irradiation alone was demonstrated to be sufficient in causing IPS in mice transplanted with bone marrow plus spleen cells, albeit with reduced severity. Based on these findings, we conclude that pretransplant radiation conditioning plays an important role in the development of IPS following allogeneic BMT.