Allogeneic Marrow Transplant Patients Research Articles

Allogeneic marrow transplantation in patients with severe systemic sclerosis: Resolution of dermal fibrosis

To evaluate the safety and efficacy of allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning in patients with severe systemic sclerosis (SSc). Eligibility criteria for the study included SSc patients with features indicative of a poor prognosis. The myeloablative conditioning regimen included busulfan, cyclophosphamide, and antithymocyte globulin. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate. Bone marrow was transplanted from HLA-identical siblings. Two patients with diffuse cutaneous SSc and lung involvement who were refractory to conventional immunosuppressive treatment were enrolled in the study. In patient 1, there were no complications related to the conditioning regimen, and GVHD did not develop after transplantation. At 5 years after HCT, there was nearly complete resolution of the scleroderma and marked improvement in physical functioning. Internal organ function improved (lung) or remained stable. On examination of serial skin biopsy samples, there was resolution of the dermal fibrosis. Patient 2 experienced skin toxicity from the conditioning regimen and hypertensive crisis that was likely related to high-dose corticosteroids given for treatment of GVHD. Although this patient experienced an improvement in scleroderma and overall functioning, a fatal opportunistic infection developed 17 months after HCT. Allogeneic HCT may result in sustained remission of SSc. GVHD and opportunistic infections are the major risks associated with allogeneic HCT for SSc, as for allogeneic HCT in general.

Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long‐term follow‐up

A total of 81 severe aplastic anaemia patients, aged 2-63 years, received human leucocyte antigen-matched related marrow grafts after cyclophosphamide + antithymocyte globulin followed by postgrafting methotrexate + cyclosporin. Median follow-up was 9.2 years. Ninety-six per cent of patients had sustained engraftment, 24% developed acute graft-versus-host disease (GVHD), grade II in all but two patients, and 26% developed chronic GVHD; all surviving patients eventually responded to immunosuppressive therapy. Six patients developed cancer: one fatal lymphoma and five carcinomas (all five patients are now free of cancer). Survival was 88%. The regimen appeared well tolerated and effective in heavily pretreated patients with aplastic anaemia.

Obliterative Bronchiolitis Complicating Bone Marrow Transplantation

Respiratory complications of bone marrow transplantation comprise the majority of its morbidity and mortality. Obstructive airways disease is the most common noninfectious respiratory complication, usually indicative of obliterative bronchiolitis (OB), which occurs in 9% of allogeneic marrow transplant patients. OB is rarely seen after autologous transplant because chronic graft versus host disease (GVH), the most commonly identified risk factor, does not occur in this setting. Alloreactive immunity is likely the cause, with donor type 2 T-helper (TH2) lymphocytes the primary mediators. OB presents at 6 to 12 months post-transplant with cough and dyspnea. Results of investigations include relatively normal or hyperinflated chest radiographs; thickened, dilated airways; and mosaic attenuation on high-resolution computed tomography (HRCT), and fixed airflow obstruction, hyperinflation, and gas trapping on physiological testing. Bronchoscopy and lavage are performed primarily to exclude infections. Transbronchial biopsy is often nondiagnostic, but because the clinical diagnosis is generally sufficient, surgical biopsy is not usually recommended. Histology reveals lymphocytic bronchiolitis, concentric bronchiolar fibrosis, and bronchiolar obliteration. Corticosteroids remain the mainstay of treatment, which is usually required for 3 to 9 months. Response is generally poor, with mortality between 40 and 100%, and lung function infrequently improves. Stabilization with permanent respiratory impairment is common. Early detection and prompt immunosuppression may improve outcomes.

Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations.

Human herpesvirus 6 (HHV-6) DNA levels in peripheral blood mononuclear cells were prospectively evaluated in 20 cytomegalovirus-seronegative allogeneic marrow transplant patients and in 10 healthy control subjects. Blood and saliva specimens obtained weekly for 3 months after transplant were evaluated by quantitative HHV-6 polymerase chain reaction. One of 20 patients experienced primary HHV-6 infection after marrow transplant (seroconversion, HHV-6 viremia, skin rash); 18 of 20 had increased peripheral blood mononuclear cell HHV-6 DNA levels consistent with asymptomatic reactivations, and 1 patient experienced a reactivation-associated skin rash. Genotyping revealed HHV-6 variant B DNA in all cases. Therapy with acyclovir or intravenous immunoglobulin was not correlated with lower HHV-6 DNA levels. Thus, asymptomatic HHV-6 reactivations appear to be common following allogeneic marrow transplantation. Among HHV-6-seronegative and viral DNA-negative patients, primary HHV-6 infection can ensue in association with self-limited clinical symptoms, including diffuse maculopapular rash.

Excellent long-term survival after allogeneic marrow transplantation in patients with severe aplastic anemia.

Between 1982 and 1996, 20 patients (10 male, 10 female) with severe aplastic anemia (SAA) with a median age of 25 years (17-37 years), received grafts from an HLA-identical sibling (n = 17), HLA-identical unrelated donor (n = 2) or identical twin (n = 1). The median time from diagnosis to marrow transplantation (BMT) was 15 months (range 1-96 months). More than half of the patients had received more than 10 units of red blood cells or platelet transfusions prior to BMT. Pretransplant immunosuppression consisted of cyclophosphamide (CY) alone (n = 10), CY in combination with total body irradiation (n = 8), and CY and antithymocyte globulin (n = 2). For graft-versus-host disease (GVHD) prophylaxis methotrexate (MTX) alone (n = 9) or MTX with cyclosporin A (n = 10) were given. One patient died on day 18 after marrow grafting due to infection; all other patients had complete and sustained engraftment (95%). Eight patients developed acute GVHD (42%), nine patients chronic GVHD (53%) including four with extensive disease manifestation. One patient experienced a secondary malignancy 11 years after BMT. Eighteen patients followed for a median of 9.45 years (0.42-14.7 years) have sustained hematological reconstitution and are alive and well with a Karnofsky performance score of at least 90%. Thus, excellent long-term survival and low morbidity make allogeneic or syngeneic BMT the treatment of choice for younger patients with severe aplastic anemia.

Long-term leukemia-free survival after allogeneic marrow transplantation in patients with acute myelogenous leukemia

Long-term leukemia-free survival after allogeneic marrow transplantation in patients with acute myelogenous leukemia

Long-term leukemia-free survival after allogeneic marrow transplantation in patients with acute myelogenous leukemia

Between February 1982 and April 1995, 62 patients (37 male, 25 female) with acute myelogenous leukemia (AML) with a median age of 32 years (19-51 years) received allogeneic marrow grafts from an HLA-identical sibling (n=60) or an HLA-mismatched family member (n=2). At the time of transplant, 35 patients were in first complete remission (CR), five in second CR, eight were primary refractory, eight were in untreated relapse and six in refractory relapse. The FAB subtypes were as follows: M1 (n=17), M2 (n=13), M3 (n=6), M4 (n=19), M5 (n=6), M6 (n=1). For conditioning most patients were given total body irradiation combined with cyclophosphamide (CY, n=50) or CY and busulfan (n=9). For graft-versus-host disease prophylaxis patients received cyclosporin A (CSA) and methotrexate (MTX) (n=32), MTX alone (n=12), CSA and methylprednisone (n=5), or CSA alone (n=13). As of April 1995, probability of leukemia-free survival projected at 10 years after BMT was 60% for patients transplanted in first CR compared with 10% for patients transplanted beyond first CR. Transplant-related mortality was 11% after BMT in first CR and 39% after BMT beyond first CR. Probability of relapse projected at 10 years after BMT is 32% for patients who received transplants in first CR and 81% for patients who received transplants beyond first CR. Thus, high-dose chemo/radiotherapy followed by allogeneic marrow infusion has a high curative potential for patients with AML who receive transplants in first CR and offers the chance of long-term disease-free survival for some patients with advanced disease.

Cytomegalovirus surveillance and prevention in allogeneic bone marrow transplantation: Examination of a preemptive plan of ganciclovir therapy

Forty-two cytomegalovirus (CMV)-seropositive allogeneic marrow transplant patients or recipients of CMV-seropositive marrow allografts were entered into a surveillance program to detect and treat CMV infection during the first 120 days posttransplant. CMV infection was detected at a mean time of day 50 in 21/37 (58%) patients who had surveillance cultures. Twelve of 42 (28%) received preemptive ganciclovir treatment for virus isolated from blood (9 patients) or from bronchoalveolar lavage fluid (3 patients), and all had no CMV-associated sequelae. CMV disease was diagnosed in 5 patients (4 with pneumonia), 1 with gastroenteritis) who did not have positive cultures until the onset of their disease. CMV-related mortality was 4/42 (10%). Patients who earlier manifested lung injury or diffuse alveolar hemorrhage (DAH) were significantly predisposed to subsequent CMV pneumonia (P = 0.0013, Fisher's exact test) at a median onset of day 42. Restricted prophylactic use of ganciclovir in such patients may be indicated. Fifty percent of all patients never required ganciclovir during the surveillance period. When compared to a universal prophylaxis program of ganciclovir for the prevention of CMV disease, the use of ganciclovir in a preemptive strategy could avoid unnecessary therapy for a substantial number of patients and earn significant cost-savings.

Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation

Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation

Conditioning for Allogeneic Marrow Transplantation in Patients With Lymphohematopoietic Malignancies Without the Use of Total Body Irradiation

VIDENCE THAT INFUSION of syngeneic spleen or E marrow cells could protect mice and guinea pigs from lethal doses of irradiation' led Thomas et a1 to perform studies on total body irradiation (TBI) and marrow transplantation in dogs and eventually in human^.^-^ TBI was chosen because irradiation could be delivered expeditiously, did not generate metabolites that might interfere with the function of transplanted cells, had a powerful antileukemic effect, and reached privileged sites, such as the central nervous system, where drugs might not penetrate. Furthermore, irradiation was profoundly immunosuppressive as shown in murine and canine models. The latter effect was of particular importance because in the clinical situation identical (syngeneic) twin donors were only infrequently available and, therefore, for the vast majority of patients allogeneic tissue barriers would have to be overcome. In the early 1970s, following the observation that two patients prepared with TBI alone developed a recurrence of leukemia posttransplant in donor-derived cells, cyclophosphamide (Cy) was added to TBI in an attempt to increase leukemic cell kill. Early studies showed that allogeneic marrow transplantation, generally from a genotypically HLA-identical sibling, after TBI and Cy conditioning cured 10% to 15% of patients with endstage acute leukemia.6 Since then further improvement in the outcome of such patients has largely resulted from the performance of transplantation earlier in the disease c o u r ~ e ~ ~ and the application of more sophisticated supportive care measures, including prevention and treatment of graft-versus-host disease (GVHD).'-12

Phase I/II trial of recombinant human granulocyte-macrophage colony- stimulating factor following allogeneic bone marrow transplantation

Forty-seven patients with hematologic neoplasia received recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) by daily 2-hour infusion following allogeneic bone marrow transplantation from HLA-identical sibling donors in a phase I-II dose-escalation trial. Dose levels ranged from 30 to 500 micrograms/m2/d. At doses at or below 250 micrograms/m2/d, toxicity felt to be caused by rhGM-CSF was negligible. However, three of five patients treated with 500 micrograms/m2/d had unacceptable side effects caused by rhGM-CSF. Two different graft-versus-host disease (GVHD) prophylactic regimens were administered. Twenty-seven evaluable patients were administered regimens that did not contain methotrexate (MTX) (Group I) and reached an absolute neutrophil count of 1,000/microL by a median of day 14. In contrast, 18 patients who received GVHD prophylactic regimens containing MTX (Group II) reached an absolute neutrophil count of 1,000/microL on a median of day 20. Patients in Group I had fewer febrile days and, of those discharged, had shorter initial hospitalizations than patients in Group II. The overall incidence of severe acute GVHD (grade 2 or greater) in the rhGM-CSF-treated patients was 28% and was similar to that in historical “good risk” patients who did not receive rhGM-CSF. These preliminary data suggest rhGM-CSF is unlikely to exacerbate GVHD in HLA-identical sibling donor transplants and indicate the need for randomized trials of rhGM-CSF in allogeneic marrow transplant patients.

Phase I/II Trial of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor Following Allogeneic Bone Marrow Transplantation

Forty-seven patients with hematologic neoplasia received recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) by daily 2-hour infusion following allogeneic bone marrow transplantation from HLA-identical sibling donors in a phase I-II dose-escalation trial. Dose levels ranged from 30 to 500 micrograms/m2/d. At doses at or below 250 micrograms/m2/d, toxicity felt to be caused by rhGM-CSF was negligible. However, three of five patients treated with 500 micrograms/m2/d had unacceptable side effects caused by rhGM-CSF. Two different graft-versus-host disease (GVHD) prophylactic regimens were administered. Twenty-seven evaluable patients were administered regimens that did not contain methotrexate (MTX) (Group I) and reached an absolute neutrophil count of 1,000/microL by a median of day 14. In contrast, 18 patients who received GVHD prophylactic regimens containing MTX (Group II) reached an absolute neutrophil count of 1,000/microL on a median of day 20. Patients in Group I had fewer febrile days and, of those discharged, had shorter initial hospitalizations than patients in Group II. The overall incidence of severe acute GVHD (grade 2 or greater) in the rhGM-CSF-treated patients was 28% and was similar to that in historical "good risk" patients who did not receive rhGM-CSF. These preliminary data suggest rhGM-CSF is unlikely to exacerbate GVHD in HLA-identical sibling donor transplants and indicate the need for randomized trials of rhGM-CSF in allogeneic marrow transplant patients.

Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens

A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.

Allogeneic Marrow Transplantation in Patients With Chronic Myeloid Leukemia in the Chronic Phase: A Randomized Trial of Two Irradiation Regimens

AbstractA randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.

Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens [see comments

A randomized trial of 12.0 Gy versus 15.75 Gy of total body irradiation (TBI) was performed in patients with acute myeloid leukemia undergoing allogeneic marrow transplantation while in first complete remission. All patients received 120 mg/kg cyclophosphamide followed by TBI and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease (GVHD). Thirty-four patients received 2.0-Gy fractions of irradiation daily for 6 days and 37 received 2.25-Gy fractions daily for 7 days. The 3-year actuarial probabilities for relapse-free survival were 0.58 for the patients who received 12.0 Gy and 0.59 for those who received 15.75 Gy. The 3-year probabilities of relapse were 0.35 for the 12.0 Gy group and 0.12 for the 15.75 Gy group (P = .06). The 3-year probabilities of transplant-related mortality were 0.12 and 0.32, respectively (P = .04). The probability of moderate to severe acute GVHD was 0.21 for the 12.0 Gy group and 0.48 for the 15.75 Gy group (P = .02). Patients exposed to the higher irradiation dose received less immunoprophylaxis against, and had a higher incidence of, acute GVHD. The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.

Allogeneic Marrow Transplantation in Patients With Acute Myeloid Leukemia in First Remission: A Randomized Trial of Two Irradiation Regimens

Abstract A randomized trial of 12.0 Gy versus 15.75 Gy of total body irradiation (TBI) was performed in patients with acute myeloid leukemia undergoing allogeneic marrow transplantation while in first complete remission. All patients received 120 mg/kg cyclophosphamide followed by TBI and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease (GVHD). Thirty-four patients received 2.0-Gy fractions of irradiation daily for 6 days and 37 received 2.25-Gy fractions daily for 7 days. The 3-year actuarial probabilities for relapse-free survival were 0.58 for the patients who received 12.0 Gy and 0.59 for those who received 15.75 Gy. The 3-year probabilities of relapse were 0.35 for the 12.0 Gy group and 0.12 for the 15.75 Gy group (P = .06). The 3-year probabilities of transplant-related mortality were 0.12 and 0.32, respectively (P = .04). The probability of moderate to severe acute GVHD was 0.21 for the 12.0 Gy group and 0.48 for the 15.75 Gy group (P = .02). Patients exposed to the higher irradiation dose received less immunoprophylaxis against, and had a higher incidence of, acute GVHD. The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.

Cytomegalovirus pneumonitis occurring after allogeneic bone marrow transplantation: A study of 106 recipients.

We have followed 106 recipients of allogeneic bone marrow transplantation (BMT), and observed 47 episodes of interstitial pneumonitis (IP) in 37 patients. Cytomegalovirus (CMV) pneumonitis was seen in 18 episodes in 18 patients, of whom 10 patients were diagnosed by bronchoalveolar lavage (BAL), 7 patients by autopsy, and 1 patient by sputum culture. There was one varicella-zoster virus pneumonitis diagnosed by autopsy. However, we could find no apparent etiology of pneumonitis in the other 18 patients. The median interval between BMT and episodes of IP was 74 days (range, 23-578 days) for CMV pneumonitis, and 180 days (range, 41-428 days) for idiopathic pneumonitis (p less than 0.05). BAL was more sensitive than transbronchial lung biopsy in the diagnosis of CMV pneumonitis, and CD4/CD8 ratio in BAL fluid was inverted in all episodes of CMV pneumonitis. Computed tomography (CT) scans were performed in 31 episodes in 26 patients, and all scans revealed abnormalities. CT scans were more sensitive than routine chest X-rays against micro- or small-nodular patterns, air bronchogram, and air alveologram (p less than 0.05). CT scan and arterial blood gas analysis were most useful and necessary in approaching the problem of pneumonitis in allogeneic marrow transplant patients. Based on these findings, when CMV pneumonitis is suspected, it is recommended to perform BAL for the final diagnosis of CMV pneumonitis.

A PROSPECTIVE STUDY OF UNEXPLAINED NAUSEA AND VOMITING AFTER MARROW TRANSPLANTATION

We prospectively studied patients with enigmatic nausea and vomiting after allogeneic marrow transplantation to define the causes of this syndrome. Fifty consecutive episodes of persistent vomiting were investigated using physical examination and laboratory tests, endoscopic biopsies and brushings, and clinical follow-up for four weeks. Potential causes of vomiting were identified in 39 of the 50 cases (78%). Fifteen cases had gastrointestinal infections (mainly herpesviruses), 13 had unsuspected acute intestinal graft-versus-host disease (GVHD), 8 had intestinal infection plus acute GVHD, and 3 had other causes (subdural hematomas, bacteremia, and encephalitis). In the remaining 11 cases, no cause of vomiting was found. Endoscopy was necessary for diagnosis in 36 cases and required a combination of methods: routine histology, cytology, viral culture, and immunohistology using monoclonal antibodies to cytomegalovirus (CMV) and herpes simplex virus type 1. Patients with unexplained vomiting or intestinal GVHD had significant improvement of nausea and vomiting over the four-week observation period, but those with CMV did not (P = .01). We conclude that most allogeneic marrow transplant patients with enigmatic nausea and vomiting have gastrointestinal herpesvirus infections, acute GVHD, or both. Untreated CMV infections and persistent GVHD are associated with protracted vomiting in these patients.

Results of allogeneic marrow transplantation in patients transplanted for leukemia: A five year follow-up

Results of allogeneic marrow transplantation in patients transplanted for leukemia: A five year follow-up

Allogeneic marrow transplantation from HLA-identical siblings in the acute leukemias: Baltimore experience.

Allogeneic bone marrow transplantation in the treatment of acute leukemia has shown remarkable therapeutic progress in recent years. Long-term remissions and possible eure rates of 50% or higher have been obtained by a number of centers in acute nonlymphocytic leukemia (ANL), particularily when patients were transplanted in their first remission [1–9]. Most reported series of allogeneic marrow transplantation in acute lymphocytic leukemia (ALL) performed in the second remission have shown long-term disease-free survival of 20%–30%. Data for patients in their third and subsequent remissions are less good [10–14]. The recent report from the Memorial Sloan Kettering group [15] and the Baltimore group [16] has shown a therapeutic improvement over the previously reported series of ALL transplanted in their second remission. In the present communication, we wish to update our results of allogeneic marrow transplantation in patients with ANL and ALL who received marrow grafts from genotypically HLA-identical siblings.KeywordsAcute Lymphocytic LeukemiaMarrow TransplantationCentral Nervous System LeukemiaPhoblastic LeukemiaAllogeneic Marrow TransplantationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.