Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors

Human herpesvirus 6 (HHV-6) infection was studied in 82 bone marrow transplant (BMT) recipients (72 allogeneic, 10 autologous). All recipients and 30 donors were seropositive for HHV-6 antibody at the time of bone marrow transplantation. Thirty-one recipients (37.8%) had HHV-6 viremia 2-4 weeks after transplantation. The incidence of HHV-6 viremia was significantly higher among allogeneic BMT recipients than in autologous BMT recipients (P=.011). Therefore, the following analyses of allogeneic BMT recipients were carried out (n=72). Geometric mean antibody titers (log(10)) were significantly higher in recipients without viremia than in those with viremia (1.84+/-0.39 vs. 1.61+/-0.42; P=.022). Logistic regression analysis demonstrated that leukemia or lymphoma is an independent risk factor (P=.031) for HHV-6 viremia. Rash occurring within 1 month after transplantation was observed in 17 (54.8%) of 31 recipients with HHV-6 viremia but in only 8 (19.5%) of 41 recipients without HHV-6 viremia (P=.001).     

Transfusion of bone marrow red cells during bone marrow harvests

Large volumes of bone marrow may be required for certain types of autologous bone marrow transplants. The present study was done to determine whether red cells obtained during a bone marrow harvest would be useful in reducing homologous transfusion requirements. A group of patients receiving standard transfusion support during the harvest (group 1) was compared to a group that received processed bone marrow red cells (PBMRBC) (group 2). Using the Cobe 2991 cell processor, 90% of the harvested bone marrow red cells were extracted and transfused during the procedure. Group 2 received a median of 1500 ml of blood processed from the bone marrow or 413 ml (volume of marrow processed x hematocrit) of red cells. Infusion of the PBMRBC reduced the homologous transfusion requirement from 6.5 units to 3.0 units (p = 0.02). In addition, group 1 had a 20% decrease in hematocrit following transfusion compared to the pre-harvest hematocrit, as opposed to an 8% decrease in group 2 (p = 0.02). This study indicates that PBMRBC can reduce the homologous transfusion requirements during an autologous bone marrow harvest.     

Early and late elevation of plasma atrial and brain natriuretic peptides in patients after bone marrow transplantation

Clinical usefulness of bone marrow transplantation (BMT) remains limited by myocardial damage during the post-transplantation period. Measurements of plasma atrial and brain natriuretic peptides (ANP, BNP) during the acute post-transplantation period could serve to monitor cardiac complications since these peptides are known to increase in heart failure depending on its severity. We prospectively analyzed ANP and BNP levels from 14 days before to 100 days after BMT in 46 consecutive patients undergoing allogeneic (n=42) and autologous (n=4) transplantation. Cardiac performance was assessed by echocardiography and radionuclide ventriculography. BNP and ANP levels of the patients on admission (baseline: day-14) were 16.3+/-13.3 pg/ml and 14.4+/-8.8 pg/ml, respectively. There were two different types of changes in the BNP and ANP levels. The 21 patients in group I showed dual peaks of elevation on day 1 (BNP=164.4+/-136.0 pg/ml, P<0.01; ANP=44.5+/-35.4 pg/ml, NS) and day 14 (BNP=233.9+/-106.2 pg/ml, P<0.01; ANP=142.7+/-154.6 pg/ml, P<0.05), whereas the remaining 25 patients in group II had a single peak on day 1 (BNP=124.5+/-124.9 pg/ml, P<0.05; ANP=45.2+/-42.4 pg/ml, NS). The left ventricular ejection fraction on day 63 was unchanged in both groups of patients from the baselines. The time to peak filling rate, a parameter of diastolic function in the radionuclide ventriculography, was significantly prolonged in group I patients (by 30+/-53%), whereas unaffected in group II patients. These results suggest that plasma BNP monitoring for 2 weeks after BMT may be useful for early detection of patients at high risk for cardiac dysfunction in the post-transplantation period.     

CFU-GM content of bone marrow graft correlates with time to hematologic reconstitution following autologous bone marrow transplantation with 4- hydroperoxycyclophosphamide-purged bone marrow

Autologous bone marrow transplants (BMTs) can repopulate the hematologic system of patients treated with marrow-ablative chemotherapy and/or radiotherapy. However, treatment of the bone marrow graft to eliminate residual tumor cells prior to reinfusion can delay the return of peripheral blood elements, presumably from damage to or loss of hematopoietic stem cells responsible for hematologic recovery. To develop a model predictive of hematologic recovery, we studied the progenitor cell contents of 4-hydroperoxycyclophosphamide (100 micrograms/mL)-purged bone marrow grafts of 40 consecutive patients undergoing autologous BMT at this center. Granulocyte-macrophage colonies (CFU-GM) were grown from all grafts after treatment with this chemotherapeutic agent, but erythroid (BFU-E) and mixed (CFU-GEMM) colonies were grown from only 44% and 33% of the grafts respectively. The recovery of CFU-GM after purging ranged from 0.07% to 23%. The logarithm of CFU-GM content of the treated grafts was linearly correlated with the time to recovery of peripheral blood leukocytes (r = -0.80), neutrophils (r = -0.79), reticulocytes (r = -0.60), and platelets (r = -0.66). The CFU-GM content of purged autologous bone marrow grafts may reflect the hematopoietic stem cell content of the grafts and thus predict the rate of hematologic recovery in patients undergoing autologous BMT.     

Allogeneic bone marrow transplantation in children failing prior autologous bone marrow transplantation

Twenty-three children with de novo acute myelogenous leukemia (AML) (n = 20), secondary AML (n = 1), or non-Hodgkin's lymphoma (NHL) (n = 2) underwent allogeneic bone marrow transplantation (alloBMT) for graft failure (n = 1) or recurrent malignancy (n = 22) between February 1992 and August 1999 following autologous BMT (ABMT). Induction chemotherapy was given to 14 patients and nine patients went directly to alloBMT. Five received marrow from matched siblings, 14 from matched unrelated donors and four from mismatched family members. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Nine patients are alive disease-free between 627 and 2433 days (1.7-6.7 years) post BMT resulting in a 4-year DFS of 39%. Eight patients relapsed at a median of 206 days (range, 35-669 days) post alloBMT and all eventually died. Eight patients (two of whom also relapsed) died of RRT. Although RRT and relapse remain significant problems, a significant percentage of pediatric patients failing ABMT may be cured with alloBMT.     

Airway inflammation predicts diffuse alveolar hemorrhage during bone marrow transplantation in patients with Hodgkin disease.

We determined risk factors present in patients with Hodgkin disease that predicted the development of diffuse alveolar hemorrhage syndrome (DAH) during autologous bone marrow transplantation (BMT). One hundred twenty-three patients with Hodgkin disease prospectively underwent bronchoscopy with bronchoalveolar lavage (BAL) before receiving BMT. The bronchitis index (BI) of the airways and bronchial and alveolar cell counts and differentials were determined in all patients and compared with 20 normal nonsmoking volunteers. Logistic regression analysis was used to determine factors that predicted for the development of DAH. Visual evidence of bronchial injury was observed regardless of smoking history (BI = 7.8 +/- 0.5 for BMT versus 2.3 +/- 0.5 for volunteers, p = 0.001). BMT patients who developed DAH (n = 14) had significantly greater numbers of bronchial neutrophils and eosinophils compared with DAH-negative (n = 109) patients (bronchial polymorphonuclear leukocytes (PMN), 33 +/- 7% versus 14 +/- 2%, p = 0.006; bronchial eosinophils, 0.9 +/- 0.3% versus 0.4% +/- 0.07%, p = 0.02). Logistic regression analysis revealed that the presence of bronchial PMN > 20% or bronchial eosinophils > zero% were predictive of DAH (p = 0.005 and 0.05, respectively). When both predictors were positive, the rate of DAH was 10 times greater than when both predictors were negative (43% versus 4% DAH occurrence). Survival was also significantly reduced when these predictors were positive. This study demonstrates that bronchial inflammation is present with or without intraluminal inflammatory cells in the majority of patients with Hodgkin disease before BMT. The subgroup of these patients with increased bronchial inflammatory cells are at greatly increased risk for development of DAH and death.     

Cytomegalovirus infection in leucocytes after bone marrow transplantation demonstrated by mRNA in situ hybridization

Summary. Cytomegalovirus (CMV) infection in leucocytes after bone marrow transplantation (BMT) was identified using a ³⁵S-labelled antisense RNA probe specific for CMV immediate early (IE) gene mRNA. 54 patients were examined regularly up to 14 weeks after BMT, 36 after allogeneic BMT and 18 after autologous BMT. Only mononuclear cells with monocyte morphology were CMV IE mRNA positive. The number of CMV positive leucocytes was higher after allogeneic BMT than after autologous BMT ( P =0.006), and in patients with acute graft-versus-host disease (GvHD) II-IV than with GvHD 0-I ( P =0.06). In patients who later developed chronic GvHD, the mean value of CMV infected leucocytes during the first week after BMT was higher than in patients without chronic GvHD ( P =0.034). Patients with symptomatic CMV infection had greater numbers of CMV infected leucocytes during the fourth and fifth week after BMT than patients without CMV disease, but the difference did not reach statistical significance.
CMV infection of monocytes may be an important factor in the early onset of CMV infection and of GvHD.     

Clinical and laboratory experience in marrow harvesting in children for autologous bone marrow transplantation

The laboratory and clinical experience of a single institution of 75 consecutive children undergoing bone marrow harvesting, 65 for subsequent autologous reinfusion and 10 for allogeneic infusion, was analysed and compared in detail with the adult literature. The median age was 9.3 years (range 6 months-20 years) with equal distribution between all childhood age groups. The median volume of marrow harvested was 15.94 ml/kg (range 4.94-27.7 ml/kg) and there was no significant difference within each age group. Fifty percent of autologous marrows (32/65) required Ficoll-Hypaque density separation and the other 50% (33/65) were separated by using the Cobe 2991 cell separator. Allogeneic harvests yielded 5.1 x 10(8) cells/kg vs 2.4 x 10(8) cells/kg for autologous harvests. Only 48% of children required red cell transfusions following this procedure (average volume 9.36 ml/kg). There were no episodes of postoperative fever or infection. There was only one episode of life-threatening morbidity (1.3%), a pulmonary embolus related to venous stasis from tumor obstruction. Lastly, the average time to engraftment following autologous reinfusion (n = 10) (neutrophils greater than or equal to greater than or equal to 500 x 10(6)/l for 2 days) was 19.8 +/- 5.3 (SD) days and time to platelet recovery (greater than or equal to 20 x 10(8)/l without transfusions) was 25.6 +/- 5.8 days. This study suggests that bone marrow harvesting in a large cohort of children with an active pediatric malignancy for a future autologous bone marrow transplantation is a safe and reliable procedure with a low incidence of serious morbidity.     

Assessment of graft status following allogeneic bone marrow transplantation for haematological disorders in children using locus-specific minisatellite probes

We have examined peripheral blood or bone marrow DNA following allogeneic bone marrow transplantation (BMT) in children suffering from a variety of haematological disorders. Using either locus-specific minisatellite probes separately or in combination with a Y specific probe for sex-mismatched transplants, complete haematological chimaerism, autologous reconstitution, or mixed chimaeric states have been defined immediately post-BMT. We have also been able to identify emerging autologous cells or relapse prior to morphological diagnosis.
Forty-two children, mean age 6.4 years (range 9 months to 15 years), received an allogeneic BMT for: acute lymphoblastic leukaemia (ALL), n = 17; acute myeloid leukaemia (AML), n = 5; biphenotypic leukaemia, n = 1; myelodysplastic syndrome (MDS), n = 5; chronic granulocytic leukaemia (CGL), n = 1; severe aplastic anaemia (SAA), n = 7; familial erythrophagocytic lymphohistiocytosis (FEL), n = 2; beta thalassaemia major (beta thal), n = 1; and juvenile chronic myeloid leukaemia (JCML), n = 3. Immediately post-transplant, 78% had achieved complete haematological chimaerism, 12% had failed to engraft (DNA analysis confirmed autologous reconstitution) and 10% had mixed chimaerism. SAA was the underlying disease in two of the chimaeric cases, the third case having had a matched unrelated donor (MUD) BMT for MDS. In 3/4 cases which subsequently relapsed, DNA analysis showed re-emergence of autologous cells (indicative of relapse), prior to their morphological identification. We conclude that DNA analysis using minisatellite probes to assess graft status provides a useful contribution to patient management following allogeneic BMT.     

A controlled trial of recombinant human erythropoietin after bone marrow transplantation

Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels > or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.     

Proliferation and cytolytic function of anti-CD3 + interleukin-2 stimulated peripheral blood mononuclear cells following bone marrow transplantation.

We evaluated the proliferation, cytolytic function, and phenotypic characteristics of anti-CD3 plus interleukin-2 (IL-2) stimulated peripheral blood mononuclear cells (PBMCs) from 44 patients with leukemia or non-Hodgkin's lymphoma (NHL) treated with multiagent chemotherapy or following bone marrow transplantation (BMT). BMT patients had decreased cell growth with only a 1.35 +/- 0.25 (autologous BMT for acute lymphoblastic leukemia [ALL]), 1.24 +/- 0.25 (autologous BMT for NHL), and 0.8 +/- 0.1 (allogeneic BMT for leukemia) mean fold increase by day 5 of culture compared with controls (4.0 +/- 0.4), P less than .001. Anti-CD3 + IL-2 activated cells from patients with ALL and NHL who had received autologous BMT and cells from patients with leukemia who underwent allogeneic BMT were more effective in lysing the natural killer (NK) sensitive target, K562, and the NK-resistant target, Daudi, compared with controls. In contrast, cytolysis of K562 and Daudi by cultured PBMCs from patients with ALL and NHL receiving multi-agent chemotherapy was similar to that of controls. Cultures from BMT recipients had a significant increase in CD16+ (autologous ALL 5.7 +/- 1.5%, P less than .01; autologous NHL 12.4 +/- 3.5%, P less than .001; allogeneic 14.3 +/- 2.9%, P less than .001) and CD56+ cells (autologous ALL 27.6 +/- 12.0%, P less than .01; autologous NHL 39.3 +/- 9.5%, P less than .001; allogeneic 42.7 +/- 7.4%, P less than .001) compared with controls (CD16+ 2.5 +/- 0.4%; CD56+ 6.9 +/- 0.9%). Stimulation of PBMCs with anti-CD3 + IL-2 is effective in generating cells with high cytolytic function post-BMT.     

Serum erythropoietin levels in patients undergoing autologous bone marrow transplantation

Serum erythropoietin (sEpo) levels were serially measured with a radioimmunoassay in 14 patients undergoing autologous bone marrow transplantation (BMT), starting before the institution of the conditioning regimen up to day +45. An increase in sEpo levels was observed soon after starting the chemotherapy regimen, and before an evident fall in hemoglobin (Hb) levels took place. The peak in sEPo levels (221 +/- 181 mU/ml) was reached at day 0 in 9/14 patients, and was delayed up to day + 10 in the remaining five. There was a negative correlation between loge sEpo and Hb values (r = -0.730; p less than 0.01); the regression line of this correlation was comparable to the one obtained in a group of 15 iron-deficiency anemic subjects. Therefore, patients undergoing autologous BMT appear to be able to develop adequately increased sEpo levels in response to the severity of anemia. No correlation was found between sEpo and white blood cell or platelet count. On the other hand, sEpo value at day 0 was significantly related to the day of neutrophil recovery (r = -0.806; p less than 0.001): patients with the highest sEpo levels at day 0 showed significantly faster (p less than 0.001) neutrophil recovery.     

Malignant neoplasms following bone marrow transplantation

We undertook an analysis of 2,150 recipients of bone marrow transplant (BMT) at the University of Minnesota to determine the incidence of post- BMT malignant neoplasms (MNs). Fifty-one patients developed 53 MNs, compared with 4.3 expected from general population rates (standardized incidence ratio [SIR], 11.6, 95% confidence interval [CI], 8.2-14.5). These included 22 occurrences of B-cell lymphoproliferative disorder (BLPD), 17 solid nonhematopoietic tumors, 10 myelodysplastic syndromes (MDS), 1 acute myelogenous leukemia (AML), 2 non-Hodgkin's lymphoma (NHL), and 1 Hodgkin's disease (HD). The estimated actuarial incidence of any post-BMT malignancy was 9.9% +/- 2.3% at 13 years posttransplant. The cumulative probability of BLPD plateaued at 1.6% +/- 0.3% by 4 years from transplant and factors independently associated with increased risk included in vitro T-cell depletion of marrow (relative risk (RR) = 11.9, P < .001), HLA mismatch (RR = 8.9, P < .001), use of antithymocyte globulin (ATG) for graft versus host disease (GVHD) prophylaxis (RR = 5.9, P < .001) or in the preparative regimen (RR = 3.1, P = .03) and primary immunodeficiency (RR = 2.5, P = .06). The cumulative probability of developing solid malignancy was 5.6% +/- 2.2% at 13 years from BMT. Malignant melanomas were the most common (SIR, 10.3, 95% CI 1.9 to 25.4). The actuarial incidence of MDS/AML plateaued at 2.1% +/- 0.8% at 9 years and was seen most often in older patients receiving autologous peripheral blood stem cells for HD or NHL. These data document that BMT recipients are at an increased risk of later malignancy, which may add significant morbidity and mortality to the transplant process. Methods for screening and identification of individuals at increased risk need to be addressed in future studies.     

Concentration of bone marrow progenitor cells by separation on a Percoll gradient using the Haemonetics model 30

To perform an optimal ex vivo bone marrow purge, it is necessary to concentrate the bone marrow progenitor cells and to eliminate both the red blood cells and the polymorphonuclear leucocytes. To achieve this goal which cannot be accomplished by using the Haemonetics model 30 alone, we used the Haemonetics model 30 and a density gradient together in a two-step procedure. In the first step we obtained the buffy coat from original bone marrow grafts and in the second we reintroduced these buffy coats into the Haemonetics bowl followed by Percoll, adjusted to 1.079 g/ml, at 5 ml/min in order to recover the light density mononuclear cells. After this second step, the mean volume of the marrow and the RBC and nucleated cell contaminations were reduced to 9%, 0.96% and 16% of their original values the unseparated bone marrow, respectively. This was far better than the values obtained after the first step (volume: 19%; RBC: 10%; nucleated cells: 54%). The CFU-GM recoveries after the first and second steps were 71% and 70% of the original samples, respectively. The entire procedure lasted between 75 and 150 min. At this time, 17 of the 24 patients whose bone marrow was separated using Percoll gradient in the Haemonetics bowl have been grafted. Thirteen of these 17 patients had an evaluable haematological recovery which was complete and rapid for all but one patient with acute myeloid leukaemia. These results demonstrate that the introduction of a density gradient into the Haemonetics model 30 bowl is possible and effective. The reduction in total volume and cell number permits ex vivo purging, without decreasing the grafting capability.     

Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group

A prospective, randomized trial was initiated in adult acute lymphoblastic leukemia (ALL) to compare (1) disease-free survival (DFS) after allogeneic or autologous bone marrow transplantation (BMT) and (2) the relapse rate of patients treated with or without interleukin-2 (IL-2) after autologous BMT. A total of 135 previously untreated patients, aged under 55 years, received the Berlin-Frankfurt-Muster (BFM) induction regimen: 126 patients (93%), of which 120 were HLA- typed, achieved complete remission (CR). According to this genetic randomization, patients with (n = 43) or without an HLA-identical sibling (n = 77) were to receive allogeneic or autologous BMT, respectively. The 3-year post-CR probability of DFS was significantly higher in the HLA-identical sibling group than in the non-HLA-identical sibling group (68% v 26%; P < .001). Eligible patients were randomized to receive (n = 30) or not to receive (n = 30) IL-2 after autologous BMT: the 3-year post-BMT probability of continuous CR was similar in both groups (29% v 27%, respectively). We conclude that, in ALL, early allogeneic BMT after the BFM induction regimen is an effective consolidation treatment and that IL-2 does not decrease the high relapse rate observed after autologous BMT.     

Neutrophils are responsible for the reappearance of chemiluminescence after allogeneic bone marrow transplantation

The nature of the cells generating the early chemiluminescence (CL) response after allogeneic bone marrow transplantation (BMT) was studied in six patients; five transplanted for acute leukaemia and one for multiple myeloma. Peripheral blood was fractionated into 14 fractions with Percoll narrow range density gradient centrifugation on days +14, +17, +20, and +27 after BMT. The leucocytes were recovered in fractions 7-14 which were analysed for cell morphology and CL response. On days +14 to +20 after BMT the CL response was detected in the fractions containing morphologically mature neutrophils. In one of these fractions the CL response per phagocyte was significantly higher than in the neighbouring fractions although morphologically the cells were similar. The results suggest that the cells responsible for the early CL after BMT are neutrophils and possibly an active subpopulation of neutrophils produced by the marrow graft.     

Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation

Cytomegalovirus (CMV) infection was detected in 65 of 143 (45%) autologous bone marrow transplant (BMT) patients. CMV pneumonitis occurred in only 2% of the patients and CMV retinitis occurred in none. Infection occurred in half of the 40 initially seronegative patients and 47% of the 94 initially seropositive patients. Among initially seropositive patients, platelet recovery was slower in infected patients than in those not infected (97 v 35 days median, P = .003), and neutrophil recovery was slightly delayed in infected patients (31 days v 24 days, P = .02). Although the incidence of CMV infection was comparable in autologous and allogeneic BMT patients, CMV pneumonitis was less frequent in autologous BMT patients (2% v 12%, P less than .001). The risk for CMV pneumonitis in autologous BMT patients was comparable with that in allogeneic BMT patients without graft-v-host disease (GVHD) (2% v 6%), but significantly lower than the risk in allogeneic BMT patients with GVHD (2% v 23%, P less than .001).     

Granulocyte-colony-stimulating factor induces increased serum levels of soluble interleukin 2 receptors preceding engraftment in autologous bone marrow transplantation

Summary The serum levels of soluble interleukin 2 receptors (sIL-2R) were determined in 19 patients who received highdose chemotherapy and an autologous or syngeneic bone marrow transplant (BMT) for treatment of Hodgkin's disease ( n = 18) or non-Hodgkin's lymphoma ( n = 1). Twelve patients received granulocyte colony-stimulating factor (G-CSF) from day 0 or day +1 after autologous BMT until the white blood cell count had been stable for 9 d above 1 × 10⁹/1, the remaining seven patients did not receive growth factors, In all G-CSF-treated patients the sIL-2R levels increased steadily in the early post-transplant course, even in the absence of infection. This increase was statistically significant 2-4 d prior to the appearance of leucocytes in the peripheral blood (median 340 pm versus median 256 pm immediately after BMT, P <0.025) and peaked with the appearance of first peripheral blood leucocytes (median 536 pm, P <0.001). Cessation of G-CSF administration resulted in a decline of sIL-2R levels. In contrast, five of seven patients without G-CSF treatment did not exhibit an sIL-2R increase before or at the time of engraftment. Infection was associated with a rise of sIL-2R levels. A correlation between sIL-2R levels and total leucocyte count, lymphocyte count, or CD25 + lymphocyte count was not evident.
These data suggest that after autologous BMT G-CSF induces increased sIL-2R levels, which occur independent of lymphocyte activation. This may be compatible with involvement of immature bone marrow cells in G-CSF-induced sIL-2R release.     

Autologous blood cell vs marrow transplantation for acute myeloid leukemia in complete remission: an EBMT retrospective analysis

In order to compare autologous bone marrow (BMT) and blood cell transplantation (BCT) in patients with acute myeloid leukemia (AML) in first remission (CR1), we retrospectively reviewed the data of 1393 patients registered to EBMT and undergoing either BCT (n = 100), purged (n = 252) or unpurged (n = 1041) BMT. Hematopoietic recovery was significantly quicker after BCT than after either purged or unpurged BMT. The 2-year leukemia-free survival (LFS), relapse incidence (RI) and overall survival for the entire population of patients were 52 +/- 1%, 43 +/- 1% and 58 +/- 1% and were significantly influenced by FAB subtype (M3 vs other) and the intervals between diagnosis and CR1 or CR1 and transplant. After BCT, LFS and RI were 44 +/- 6% and 50 +/- 6% and did not differ significantly from that found for unpurged BMT (49 +/- 2% and 45 +/- 2%; P = NS). However, LFS (57 +/- 3%) and RI (37 +/- 3%) of patients undergoing purged BMT were significantly different from that found for BCT patients (P = 0.01 and P = 0.006). As some characteristics of patients undergoing BCT or purged BMT differed significantly (age, intervals between diagnosis and CR1 or CR1 and transplant), the better outcome observed for purged BMT over BCT patients needs to be prospectively investigated.     

High frequency of antithrombin 3 and protein C deficiency following autologous bone marrow transplantation for lymphoma.

To investigate the possibility that a hypercoagulable state develops during autologous bone marrow transplantation (BMT), we measured levels of circulating natural anticoagulants and fibrinolytic proteins before and weekly during the hospital course of 18 patients undergoing autologous BMT for Hodgkin's and non-Hodgkin's lymphoma. Patients received either weekly (standard dose group) or daily (high dose group) vitamin K supplements with their total parenteral nutrition. By day 14 there had been a significant drop in protein C activity (mean of 95% of normal to 52%), protein C antigen (mean of 105% of normal to 70%), and antithrombin 3 activity (111% of normal to 83%), and an increase in fibrinogen (471-621 mg/dl) and tissue plasminogen activator (6.9-13.8 ng/ml). No changes were seen in free or total protein S, plasminogen activator inhibitor, prothrombin time or partial thromboplastin time. The decreases in protein C and antithrombin 3 persisted through day 28 after transplantation. The drop in protein C correlated strongly with decrease in serum albumin, suggesting impaired synthesis of these proteins by the liver. No differences were seen in any of these parameters between the standard and high dose groups. Deficiencies in anticoagulant proteins antithrombin 3 and protein C and a rise in fibrinogen without a concomitant improvement in fibrinolytic variables create a potentially hypercoagulable state which may contribute to the thrombotic complications of autologous BMT.