Busulfan Conditioning Regimen Research Articles

Matched‐related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research

We report outcomes after myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)-matched sibling donors in 67 patients with sickle cell disease transplanted between 1989 and 2002. The most common indications for transplantation were stroke and recurrent vaso-occlusive crisis in 38% and 37% of patients respectively. The median age at transplantation was 10 years and 67% of patients had received >10 red blood cell transfusions before HCT. Twenty-seven percent of patients had a poor performance score at transplantation. Ninety-four percent received busulfan and cyclophosphamide-containing conditioning regimens and bone marrow was the predominant source of donor cells. Most patients achieved haematopoietic recovery and no deaths occurred during the early post-transplant period. Rates of acute and chronic graft-versus-host disease were 10% and 22% respectively. Sixty-four of 67 patients are alive with 5-year probabilities of disease-free and overall survival of 85% and 97% respectively. Nine patients had graft failure with recovery of sickle erythropoiesis, eight of who had recurrent sickle-related events. This report confirms and extends earlier reports that HCT from HLA-matched related donors offers a very high survival rate, with few transplant-related complications and the elimination of sickle-related complications in the majority of patients who undergo this therapy.

Intravenous Busulfan

An intravenous formulation of busulfan, a cytotoxic bifunctional alkylating agent, has been developed to replace oral busulfan as a conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) in pediatric patients. Doses of intravenous busulfan based on actual bodyweight, but not age, reduce inter- and intraindividual variability in exposure. In a study of intravenous busulfan as a conditioning treatment prior to allogeneic or autologous HSCT, the majority of pediatric patients, who received one of five bodyweight-based doses, achieved busulfan area under the plasma concentration-time curve (AUC) values within the targeted therapeutic range. Although mean busulfan clearance values were highly variable between bodyweight strata, exposure was not affected, with no significant differences between bodyweight groups in mean AUC values. The achievement of therapeutic AUC values with intravenous busulfan resulted in a high rate of sustained engraftment, low transplant-related mortality, and promising survival outcomes post-transplant. Intravenous busulfan was considered to be well tolerated, in the particular context of HSCT, and no failure of HSCT due to organ toxicity was reported. Nonhematologic adverse events commonly associated with busulfan conditioning regimens were frequent, but generally of mild to moderate severity. The intravenous busulfan regimen was frequently associated with elevated liver enzymes, but hepatic veno-occlusive disease (HVOD) was infrequent, of mild to moderate severity, and resolved within 10 days of diagnosis. Unlike oral busulfan, intravenous busulfan does not appear to be associated with severe HVOD or death due to organ toxicity.

Granulocytic sarcoma with pulmonary involvement

A 42-year-old man presented with a 6-month history of cough, weight loss, and progressive dyspnea. His white blood count was 7,000/ml, 24% of which were found to be blasts on the peripheral blood film. A bone marrow examination revealed 20% of the cells to be immature, blast-like forms (See Image 1). The morphology of these cells was thought to be most consistent with acute myeloid leukemia (FAB M1/M2). Cytogenetic analysis revealed an 8;21 translocation. A computed tomography scan of the chest demonstrated a mass in the right hilum extending to the mediastinum and compressing the bronchi in the right middle and right lower lobes (See Image 2). A bronchoscopy was performed, and the morphologic appearance of the transbronchial biopsy specimen was initially felt to be most consistent with small cell carcinoma (See Image 3). However, subsequent special stains of this specimen were positive for myeloperoxidase (See Image 4), thereby establishing the diagnosis of a granulocytic sarcoma. The cells in the lung biopsy were also found to be CD34 positive, thereby providing further confirmation of this diagnosis. The lung mass was first treated with local radiotherapy (200 cGy 2), resulting in a rapid clinical improvement. The patient next received given combination chemotherapy that led to a complete hematologic remission along with a further decrease in the size of the lung mass. Finally, after two courses of consolidation therapy followed by a conditioning regimen of busulfan and cytoxan, an autologous bone marrow transplant was performed. The patient remains in complete remission at this time, now 2 months post transplantation. Granulocytic sarcoma is an extramedullary solid tumor composed of immature myeloid cells. It may occur in conjunction with myeloid leukemia or as an isolated phenomenon, and it can involve any organ. When it is initially found, a granulocytic sarcoma can be misdiagnosed as a malignant lymphoma. As in this case, granulocytic sarcoma is often associated with an 8;21 translocation. Pulmonary involvement by granulocytic sarcoma is rather uncommon and may indicate a relatively poor prognosis.

Favorable response of pediatric stem cell recipients to human protein C concentrate substitution for veno‐occlusive disease

Plasminogen activator inhibitor 1 is known to be elevated in patients with hepatic VOD after intensive chemotherapy. To re-establish endogenous fibrinolysis and to inhibit thrombin formation, we used non-APC (zymogen) to normalize PAI-1 levels. As a consequence of thrombin formation inhibition and the consecutive inhibition of the coagulation cascade, this treatment is expected to reduce the elevated D-dimer level. Six pediatric stem cell recipients with moderate or severe VOD after busulfan or total body irradiation conditioning regimen are reported here who were therapy-refractory to defibrotide or rt-PA therapy. All patients had low levels of PC activity (16-39%). The administration of PC (60-240 IU/kg) led to a rapid and sustained rise in PC activity (target level >80%) with near normalization of prothrombin and partial thromboplastin time in all patients. Elevated PAI-1 levels declined. Five of the six patients showed a good clinical response with prompt resolution of clinical, sonographic, and laboratory signs of hepatic blood flow obstruction, while one patient with severe VOD, as well as concomitant liver GVHD and CMV disease, had a slow but detectable response to PC therapy. All patients survived.

Busulfan/melphalan is an effective and well tolerated conditioning regimen for pediatric AML and MDS patients receiving a matched sibling BMT

Background: Allogeneic transplant results in the best outcomes for pediatric patients with myeloid malignancies and matched sibling donors (MRD). Improvements in supportive care, prophylaxis of infections, and treatment of GvHD has decreased non-relapse related morbidity and mortality. Conditioning regimens without TBI would be expected to result in less long term toxicity, but may not be as effective in preventing relapse. We report results of allogeneic MRD transplantation after a busulfan (Bu) and melphalan (Mel) conditioning regimen for a group of 36 pediatric patients transplanted at a single center.

Prognostic Models for Predicting Outcomes after Autologous Stem Cell Transplantation (ASCT) in Patients with Relapsed or Refractory Hodgkin's Disease: How Predictive Are They?.

Multiple prognostic models for patients with advanced Hodgkin's disease have been developed in an effort to identify high-risk individuals for ASCT and predict outcomes of high dose therapy and transplant. The utility of four of these models was examined in a cohort of patients transplanted in our program between 1993 and 2005. A total of 113 patients with relapsed or refractory Hodgkin's disease received ASCT. Forty-five patients received a conditioning regimen of busulfan, melphalan, and thiotepa (BuMelTT) whereas 68 patients received other standard conditioning regimens (SCR) including Cy/TBI/VP (23), CBV (39), and other (6). Median age is 34.5 years for BuMelTT and 34.0 years for SCR patients. Ninety-eight percent of patients receiving BuMelTT had at least two or more prior regimens compared with 86% SCR patients. Eighty-seven percent of BuMelTT and 93% of SCR patients had chemosensitive disease prior to transplant. Median followup is 113 weeks for BuMelTT patients versus 201 weeks for SCR patients. To date 37% of the BuMelTT and 56% of SCR patients have relapsed (p<0.05) with a median time to relapse of 30 and 36 weeks (p=NS) respectively. Statistically significant factors differentiating the BuMelTT and SCR groups included median followup post-ASCT, total percent relapse after transplant, death after transplant, relapse in prior radiation field, and stage at salvage therapy pre-ASCT. Median OS, EFS, and RFS have not yet been reached for BuMelTT patients compared with 439 (p=0.03), 67 (p=NS), and 74 (p=NS) weeks for the SCR patients. TRM was five percent in both groups at five years. We investigated the predictive value of four prognostic models on the entire group, BuMelTT and SCR cohorts. Models evaluated included Roswell Park (RPCI), Memorial Sloan-Kettering, German Hodgkin's Study Group, and Southwestern Oncology Group (SWOG). Each of these models has identified three negative prognostic indicators on the basis of multivariate analysis. Patients who had 0 or 1 factor were considered good risk and those that had 2 or 3 factors poor risk. Only the SWOG model (>2 prior regimens, relapse in previous radiation field, extranodal disease) was predictive for OS for the entire group (p<0.01) and for the BuMelTT (p=0.05) and SCR (p<0.01) cohorts. The SWOG model was also able to differentiate EFS between good and poor risk patients for the entire group (p=0.02) and SCR group (p=0.05) but not for the BuMelTT cohort. None of the models could differentiate between good and poor risk patients with regard to RFS. When good and poor risk were defined as 0 factors versus 1 to 3 factors, the RPCI model (chemotherapy-resistant disease, poor performance status, and 3 or more chemotherapy regimens prior to transplant) was predictive of OS (p=0.02) and EFS (p=0.02) but only for the BuMelTT cohort. These results suggest that BuMelTT may improve long-term outcomes in patients with advanced Hodgkin's disease. The prognostic models evaluated had limited utility in our patient cohort with only the SWOG model being predictive of outcome. Large multi-institutional studies are needed to improve prognostic models for transplantation in advanced Hodgkin's disease.

Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia

We evaluated the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 43 patients with chronic myelomonocytic leukemia. Patients were classified according to the French-American-British and World Health Organization classifications, as well as the International Prognostic Scoring System and the M.D. Anderson prognostic score. Comorbidity scores were assessed by using an HCT-specific comorbidity index. Patients were aged 1 to 66 years (median, 48 years). Twenty-one patients received transplants from related donors (18 HLA-identical siblings and 3 HLA-nonidentical family members), and 22 received transplants from unrelated donors (18 HLA matched and 4 HLA nonidentical). Several busulfan or total body irradiation-based conditioning regimens were used. Sustained engraftment was achieved in 41 patients. Eighteen are alive at 1.9 to 14.1 years, for an estimated relapse-free survival of 41% at 4 years. Ten patients have relapsed, thus leading to a cumulative incidence of 23% at 4 years. Risk category by International Prognostic Scoring System, World Health Organization, M.D. Anderson prognostic score, or proliferative/dysplastic status had no statistically significant association with outcomes. However, patients with higher comorbidity scores had worse overall survival than patients with lower scores ( P = .01). There was a trend for a higher relapse incidence among patients at higher risk by the M.D. Anderson prognostic score. The data suggest that patients with few or no comorbidities and those who undergo transplantation earlier in the disease course have the highest probability of successful outcome after allogeneic HCT.

Keratinocyte Dysplasia in Hematopoietic Stem Cell Transplant Recipients in the Day 28 to 84 Post Transplant Period.

Severe keratinocyte dysplasia (SKD) has been reported in the early post‐transplant period of hematopoietic stem cell transplant (HCST) patients, with a frequency as high as 47.4%. In the period less than 3 weeks post‐transplant it was associated with cyclophosphamide conditioning. The purpose of our study was to determine the prevalence of SKD in a later post‐transplant period, from 28 days to 84 days, and study the possible causes. The 2003 slide file (227 slides) of Seattle Cancer Care Alliance was examined for skin biopsies from patients who had undergone HCST. Twenty‐two cases (9.7%) showed SKD. A control group of 22 biopsies matched for days post‐transplant and age were selected from the remaining 205 biopsies. SKD was associated with a busulfan conditioning regimen, 72.7% in the SKD group and 36.3% in the control group (p = 0.016). SKD was not associated with cyclophosphamide (p = 0.174), fludarabin (p = 0.263) or total body irradiation (p = 0.50). Although active GVHD (grade 2 or 3) was more commonly seen in SKD group (45.5%) than the control group (22.2%), it did not show significant difference (p = 0.052). Our study showed that SKD developed in 9.7% of the skin biopsies from days 28 to 84 post‐transplant, and was associated with busulfan conditioning regimen.

The Efficacy and Long-Term Toxicity of Intravenous Busulfan and Cyclophosphamide Conditioning Regimen for Stem Cell Transplantation in Advanced Lymphoma.

Background: Although busulfan (Bu) in combination with cyclosphosphamide (Cy) is a commonly used conditioning regimen for the treatment of patients with hematologic diseases, its toxicity profile when administered intravenously (IV) as well as efficacy remains unclear, especially in the setting of autologous transplant for lymphoma.Objective: To determine toxicity and the efficacy of the IV Bu/Cy conditioning regimen in patients who underwent autologous peripheral stem cell transplantation (APSCT) for the treatment of lymphoma.Methods: A retrospective analysis was performed in 37 patients (21 male; 16 female) who underwent APSCT and received IV Bu/Cy regimen between January 2000 and May 2004.Results: The median age was 50 years old (range: 20–68). Forty-seven percent of the patients were heavily pretreated (≥ 3 previous treatment, range 2–5). The distribution of lymphoma was: diffuse large B-cell lymphoma (DLBCL, 23), follicular lymphoma (8), mantle cell lymphoma (MCL, 5), and T-cell lymphoma (1). All patients received IV busulfan 3.2 mg/kg and cyclophosphamide 120 mg/kg, and were evaluable for toxicity. The patients engrafted (ANC ≥ 500 μ/l) at a median of 11 days (range: 9–14), and sustained platelet count (≥ 20,000 μ/l) at a median of 11 days (range: 8–42). The most common toxicities encountered were grade 1–2 including nausea, vomiting, stomatitis, esophagitis, and diarrhea. Grade 3–4 toxicities included hepatic veno-occlusive disease (HVOD, n=2), SIADH (n=1), and atrial fibrillation (n=2). Treatment related mortality (TRM) was seen in 3 patients due to HVOD (n=2) and septic shock (n=1). Twenty patients are still alive and 18 have no evidence of disease progression, with a median follow up of 17 months (range: 2–54 months). Kaplan-Meir actuarial OS at 24 months was 55.3% with a 47.3% DFS. Median event-free survival was 24 months (range 2–52).Conclusions: IV Bu/Cy is a well-tolerated conditioning regimen with acceptable TRM, when compared with other regimens in heavily pretreated patients. The risk for HVOD is low. Further prospective trials are necessary to evaluate the role of Bu/Cy regimen in autologous stem cell transplant for lymphoma.

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): A phase I study of the pediatric blood and marrow transplant consortium

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): A phase I study of the pediatric blood and marrow transplant consortium

Philadelphia chromosome-negative engraftment after autologous transplantation with granulocyte-macrophage colony-stimulating factor for chronic myeloid leukemia

Autologous bone marrow transplantation (BMT) has not been curative in chronic myeloid leukemia (CML), because of the inability to purge CML from the autograft and the absence of the allogeneic T cell-mediated antileukemic activity. However, recent advances demonstrate that normal progenitors can be selected from CML marrows by a variety of techniques, including isolation by their small size. Furthermore, we found that myeloid growth factors have a potent antileukemic effect against CML progenitors in vitro by inducing their terminal differentiation. Based on these data, we initiated a trial of autologous BMT in patients with high-risk CML. Autografts were processed in an attempt to enrich for normal progenitors, first by isolating small cells by counterflow centrifugal elutriation and then incubating them in granulocyte-macrophage colony-stimulating factor (GM-CSF) for 72 hours. After a conditioning regimen of busulfan and cyclophosphamide, all patients received GM-CSF daily for 2 months. The median age of the 13 patients in the trial was 45 years (range 17-56 years). The median duration of disease before BMT was 24 months (range 13-72 months). Eight patients were in chronic phase (CP), and five were in accelerated phase (AP). All patients failed to achieve a cytogenetic response to interferon-alpha and were 100% Philadelphia chromosome (Ph)+ before BMT. There were three transplant-related deaths, all AP patients. All of the remaining 10 patients engrafted with some degree of Ph- hematopoiesis; despite high-risk features, nine patients engrafted 100% Ph-. All patients relapsed cytogenetically at a median of 6 months (range 4-22 months). These results demonstrate that autologous BMT can consistently induce complete Ph- engraftment in CP patients. GM-CSF appears to produce a clinical antileukemic effect against CML after autologous BMT. Biol Blood Marrow Transplant 1999;5(6):394-9.

Pneumatosis Cystoides Intestinalis with Abdominal Free Air in a 2-Year-Old Girl after Allogeneic Bone Marrow Transplantation

A 2-year-old girl with acute lymphoblastic leukemia (ALL) showing a t(4;11)(q21;q23) karyotype underwent allogeneic bone marrow transplantation (BMT) with the conditioning regimen of L-PAM (70 mg/m2/d for 3 days), busulfan (140 mg/m2/d for 2 days), and total body irradiation (12 Gy). On day 57, the patient developed pneumatosis cystoides intestinalis (PCI) when she received cyclosporin A and corticosteroids for graft-versus-host disease (GVHD), Because of the presence of massive abdominal free air and the suspicion of peritonitis, she underwent surgical intervention, which, however, revealed neither intestinal perforation nor peritoneal infection. She recovered from PCI in 10 days with nasogastric suction, fasting, and systemic broad-spectrum antibiotics. PCI with massive abdominal free air after BMT should be manageable by conservative therapy alone.

Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

AbstractFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

#670 Hematopoietic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and etoposide for children with acute myelogenous leukemia (AML)

Sandier, E. S.; Hagg, R. K.*; Mustafa, M.*; Wall, D. A.; Gamis, A.; Kamani, N. R.* Author Information

Bone marrow transplantation in 26 patients with Wiskott-Aldrich syndrome from a single center

We retrospectively analyzed the outcome of bone marrow transplantation (BMT) performed in 26 patients with Wiskott- Aldrich syndrome (WAS) in one center. Twenty-eight transplantation procedures were performed. Ten unselected patients received unmanipulated marrow from a donor with genetically identical human leukocyte antigen (HLA). Eight patients were cured and survive 1.5 to 16.5 years after BMT. One patient successfully received a T-cell-depleted marrow from a matched unrelated donor. Sixteen patients were selected to receive a related HLA partially incompatible BMT because of the occurrence of life-threatening complications from the WAS (i.e., refractory thrombocytopenia, autoimmunity including vasculitis and sepsis). All but one received T-cell-depleted marrow after a conditioning regimen of busulfan and cyclophosphamide. One patient had two BMTs. Engraftment occurred in 12 of 17 attempts. The addition of monoclonal antibodies to lymphocyte function-associated antigen-1 and CD2 molecules appeared to improve engraftment. Six patients were long-term survivors, whereas others died of viral infections (n = 7), among which Epstein-Barr virus-induced B-lymphocyte proliferative disorder was predominant. Delay in development of full T- and B-cell functions accounted for severe infectious complications. These results confirm the excellent outcome of HLA genetically identical BMT in WAS, whereas BMT from HLA partially incompatible donors should be strictly restricted to patients with severe complications of WAS. (J P EDIATR 1996;129:238-44)

Peripheral blood progenitor cell transplantation in 118 patients with hematological malignancies: analysis of factors affecting the rate of engraftment.

We retrospectively studied the factors affecting the rate of hematopoietic reconstitution (HR) in 118 patients with hematological malignancies who underwent peripheral blood progenitor cell (PBPC) transplantation at a single institution. The patients received a median number of 6.6 x 10(8) nucleated cells/kg corresponding to 9.5 x 10(4) (0.5-578) CFU-GM/kg and 6.8 x 10(6) (0.2-161) CD34-positive cells/kg. The median number of days to reach 500 polymorphonuclear cells/mm3 and 50,000 platelets/mm3 was 12.5 (6-93) and 14.5 (6-440) days, respectively. No patient died from infection during the aplastic phase. By multivariate analysis, we found that the dose of CFU-GM infused was the only factor that significantly affects the HR rate (p < 0.0001). Moreover, patients with acute myelogenous leukemia or those transplanted after busulfan or total-body irradiation conditioning regimens had a slower engraftment (p < 0.08). These results could lead to identifying patients who need growth factors posttransplantation and/or the reinfusion of "back-up" marrow together with PBPC.

Megakaryocyte colony stimulating activity in allogeneic bone marrow recipients prepared with busulfan and cyclophosphamide

Increased megakaryocyte colony stimulating activity (MK-CSA) has been reported after total body irradiation (TBI) for bone marrow transplant (BMT). We studied the effect of a busulfan (Bu) and cyclophosphamide (Cy) marrow transplant conditioning regimen, without radiation, on MK-CSA production. Initial screening of MK-CSA was done on previously collected and banked sera from 14 BMT patients. MK-CSA was expressed as the ability to stimulate growth of megakaryocyte progenitors (CFU-MK) in standard plasma clot cultures. In the initial samples, MK-CSA peaked at day 7. This preliminary data led to a prospective study of MK-CSA and clinical parameters in seven allogeneic recipients. MK-CSA activity increased from day -7 pre-transplant (2.9 +/- 1.7 CFU-MK/10(5) NATD, mean +/- SD) to day 0 (10.3 +/- 4.7 CFU-MK) and peaked by day 9 post-transplant (20.6 +/- 6.4 CFU-MK). MK-CSA activity decreased in all seven patients by day 21 at which time five of seven patients studied had recovery of platelet counts to greater than 100 x 10(9)/l. MK-CSA activity rose rapidly in both groups of sera after the initiation of this non-irradiation, BMT preparative regimen. High MK-CSA levels, early after transplant, may contribute to the rapid platelet recovery in some patients.

Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation.

The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac, bladder, renal, pulmonary, hepatic, CNS, stomatic, and gastrointestinal) according to a recently developed RRT scale. A set of patient, disease, and treatment parameters (age, sex, diagnosis, Eastern Cooperative Oncology Group [ECOG] score, preconditioning liver function tests [LFT], prior chemotherapy exposure, disease status, graft-versus-host disease [GVHD] prophylaxis, antimicrobial agent use, hematologic recovery, and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%, respectively) but were rarely serious (9% and 1% grades II to IV, respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven), pulmonary (two), bladder (two), and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis, only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%, with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.

Immunoglobulin G Subclass Deficiency and Pneumococcal Infection After Allogeneic Bone Marrow Transplantation

Serum immunoglobulin (Ig) G subclass levels were measured in a radial immunodiffusion assay in 25 leukemic patients before and after allogenic bone marrow transplantation. All patients received a conditioning regimen of busulfan and cyclophosphamide followed by infusion of marrow from an HLA-identical sibling. Intravenous infusions of a commercial Ig preparation were administered every 2 weeks until day 120 posttransplant. Nine patients developed pneumococcal infections at 6 months or greater posttransplant. Infection was associated with low levels or the absence of detectable serum IgG2 and IgG4. At the time of infection, 4 of 7 patients evaluated had undetectable IgG2, while 5 of 7 had undetectable levels of IgG4. After infection, none of the 8 patients evaluated had detectable levels of IgG2, and only 2 of 8 had detectable levels of IgG4. In contrast, all 16 patients without pneumococcal infection had IgG2 levels of 102 mg/dL or greater, and IgG4 levels of 20 mg/dL or greater. It appears that IgG2 and IgG4 subclass deficiencies after allogenic bone marrow transplantation contribute to susceptibility to pneumococcal infection. After pneumococcal infection, IgG2 and IgG4 levels remain low for a prolonged period and patients remain susceptible to infection by encapsulated organisms.