Elizabeth Kuczkowski

A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation

Summary:Cyclosporine (CSP) and short course methotrexate (MTX) have been the gold standard for GVHD prophylaxis for decades. Problems associated with MTX include increased time to hematopoietic engraftment, mucositis, and other organ toxicities. The combination of CSP with mycophenolate mofetil (MMF) has been used successfully for the prevention of graft rejection and GVHD in nonmyeloablative transplantation. We performed a prospective randomized trial comparing CSP and MTX with CSP and MMF in myeloablative (busulfan based) allogeneic 6/6 matched sibling bone marrow transplantation (BMT). The group receiving MMF (n=21) had significantly less severe mucositis than did the group receiving MTX (n=19) (21 vs 65%, P=0.008). Median time to neutrophil engraftment was more rapid in the MMF group (11 vs 18 days, P<0.001). The incidence of acute GVHD, as well as 100 day survival, was similar for both groups. The reduced toxicity of the CSP and MMF arm resulted in premature study closure. We conclude that a GVHD prophylaxis regimen of CSP and MMF after a myeloablative allogeneic preparative regimen is associated with faster hematopoietic engraftment, decreased incidence of mucositis, similar incidence of aGVHD, and comparable survival as compared to CSP and MTX.

Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course.

Summary:Vancomycin-resistant enterococcal (VRE) infection is a growing threat. We studied the incidence, risk factors, and clinical course of early-onset VRE bacteremia in allogeneic hematopoietic stem cell transplant recipients. We carried out a chart review of 281 allogeneic hematopoietic stem cell transplant recipients from 1997–2003, including preparative regimen, diagnosis, status of disease, graft-versus-host disease prophylaxis, antimicrobial therapy, and survival. VRE bacteremia developed in 12/281 (4.3%) recipients; 10 (3.6%) were within 21 days of transplant. Diagnoses were acute leukemia (7), NHL (2), and MDS (1). In all, 70% had refractory/relapsed disease; 30% were in remission. In total, 50% had circulating blasts. Nine of 10 had matched unrelated donors (7/9 with CD8+ T-cell depletion). The average time to positive VRE cultures was 15 days; average WBC was 0.05, and 80% had concomitant infections. Despite treatment, all patients died within 73 days of VRE bacteremia. Intra-abdominal complications were common. Causes of death included bacterial or fungal infection, multiorgan failure, VOD, ARDS, and relapse. A total of 60% of patients engrafted neutrophils, but none engrafted platelets. Early VRE bacteremia after allogeneic bone marrow transplant is associated with a rapidly deteriorating clinical course, although not always directly due to VRE. Early VRE may be a marker for the critical condition of these high-risk patients at the time of transplant.

Risk Factors Before Autologous Stem-Cell Transplantation for Lymphoma Predict for Secondary Myelodysplasia and Acute Myelogenous Leukemia

PURPOSE The risk factors for treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (AML) after autologous stem-cell transplantation (ASCT) are similar to those that increase the risk of difficult stem-cell harvests. We reviewed our experience in 526 patients with lymphoma treated by ASCT to determine whether difficult stem-cell harvests predict for an increased risk of t-MDS/AML. PATIENTS AND METHODS Autologous peripheral stem cells were initially mobilized with granulocyte colony-stimulating factor (G-CSF; or granulocyte-macrophage colony-stimulating factor) alone (n = 334), etoposide and G-CSF (n = 166), or cyclophosphamide and G-CSF with or without etoposide (n = 26). Difficult harvests were those that required more than 5 days to collect enough stem cells and those that required additional attempts with etoposide and/or cyclophosphamide plus G-CSF (n = 52). All patients were then treated with high-dose chemotherapy alone and observed for outcome. RESULTS With a median follow-up time for surviving patients of 69 months, 20 patients developed t-MDS/AML, for an actuarial incidence of 6.8% at 10 years. Pretransplantation characteristics, including age, diagnosis of non-Hodgkins lymphoma or Hodgkins disease, bone marrow involvement, prior radiation therapy, prior exposure to chemotherapy, lactate dehydrogenase at the time of ASCT, disease status, and method of stem-cell mobilization, were then analyzed with respect to the subsequent development of t-MDS/AML. By multivariable analysis, prior exposure to radiation therapy, four or more chemotherapy regimens, and more than 5 days of apheresis needed to harvest enough stem cells were identified as independent risk factors for t-MDS/AML. Bootstrap analysis confirmed these results. CONCLUSION These results suggest that identifiable pretransplantation factors predict for t-MDS/AML after ASCT.

A multivariable analysis of factors influencing mucositis after autologous progenitor cell transplantation.

Mucositis is a common and vexing complication of autologous progenitor cell transplantation (ABMT). A modified oral mucositis assessment scale (OMAS) has been found to be a reproducible and effective tool for monitoring mucositis after radiation therapy or chemotherapy. We utilized the modified OMAS scale to study clinical parameters associated with the development of mucositis in 79 patients undergoing ABMT. Median patient age was 52; 61% had non-Hodgkins lymphoma (NHL), 23% multiple myeloma and 14% Hodgkins disease. Patients were mobilized with G-CSF alone or the combination of etoposide plus G-CSF. Univariable correlates of worse mucositis were prior radiation therapy (P = 0.004), a diagnosis of NHL (P = 0.014), progenitor cell mobilizing regimen containing etoposide (P = 0.001), and ABMT preparative regimen containing etoposide (P = 0.006). Multivariable regression analysis revealed that NHL diagnosis (P = 0.007), prior radiation therapy (P = 0.001), and etoposide in the mobilizing regimen (P = 0.034) were associated with worse post-transplant mucositis. Worsening mucositis correlated with a longer inpatient length of stay. We conclude that several variables contribute to worsening mucositis during autologous transplantation, including etoposide in the progenitor cell mobilizing regimen.

Severe mucositis is associated with reduced survival after autologous stem cell transplantation for lymphoid malignancies

Mucositis is a known complication of autologous stem cell transplantation (ASCT). This study retrospectively reviewed 191 patients with lymphoid malignancies undergoing ASCT following a uniform mobilising regimen of etoposide (VP‐16)/granulocyte colony‐stimulating factor and a uniform high‐dose preparative regimen of busulfan/cyclophosphamide/VP‐16. Eighty‐seven patients experienced severe mucositis (modified Oral Mucositis Assessment Scale ≥1). Patient characteristics compared between mucositis groups were balanced according to disease status, prior exposure to radiation therapy, time from radiation therapy and actual body weight. Log‐rank analysis revealed that severe mucositis was associated with inferior overall survival (P = 0·002). A 12‐month landmark analysis showed this difference in survival occurred within 1 year post‐transplant. Multivariate analysis of all‐cause mortality showed lower pretransplant albumin and severe mucositis to be significant risk factors. Multivariate analysis for relapse mortality revealed severe mucositis to be a risk factor (P = 0·047), while lower pretransplant albumin was significant for non‐relapse mortality (NRM; P = 0·009). Kaplan–Meier estimates of survival based on relapse and NRM were significantly worse for patients with severe mucositis. Reduced pretransplant forced expiratory volume in 1 s (FEV1) and carbon monoxide (CO) diffusing capacity (DLCO) were also associated with severe mucositis. Our data suggest that studies of new treatment strategies for mucositis should include relapse and survival endpoints and that pretransplant factors, such as FEV1 and DLCO may be useful to risk‐stratify patients entered onto such trials.

Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation

Nonmyeloablative peripheral blood stem cell transplantation (PBSCT) is a novel therapeutic strategy for patients with malignant and non-malignant hematologic diseases. Infectious complications of this procedure have not been previously well described. Data on 12 patients transplanted at a tertiary care center were collected prospectively and verified retrospectively. Neutropenia developed in a third of patients, lasting for a median of 5 days. All patients developed some degree of graft-versus-host disease, as intended. Most patients achieved full chimerism by week 5. Bacterial infections occurred in two patients (17%). Cytomegalovirus (CMV) viremia occurred in five patients (42%) at a median of 80 days; none had received CMV prophylaxis. Viremia was associated with fever and fatigue in three patients, possible gastrointestinal involvement in one patient and was asymptomatic in one patient. All viremic patients responded to intravenous ganciclovir therapy. No fungal infections were documented. No patients died as a result of infection. The incidence of CMV viremia in our patients was high, but the incidence of invasive disease due to CMV was low. The best strategy to prevent CMV in patients undergoing nonmyeloablative PBSCT remains to be determined, but strategies employed in traditional allogeneic bone marrow transplantation should be considered in these patients. Bone Marrow Transplantation (2001) 28, 491–495.

Dendritic cells in autologous hematopoietic stem cell transplantation for diffuse large B-cell lymphoma: graft content and post transplant recovery predict survival

Summary:Allograft dendritic cell (DC) content has been identified as a predictor of relapse and event-free survival after allogeneic bone marrow transplantation. However, the prognostic importance of DCs has not been evaluated in the setting of autologous hematopoietic stem cell transplantation (HSCT). We prospectively determined pre-transplant and post transplant DC levels, including DC1 and DC2 subset levels, in 53 patients with diffuse large B-cell non-Hodgkins lymphoma (DLBC NHL) undergoing autologous HSCT. Pre-transplant DCs were measured in the collected stem cell products and were therefore indicative of cell numbers infused directly into patients; post transplant analysis of DCs was performed on the peripheral blood of patients 6 weeks after the infusion of autologous stem cells. Higher pre-transplant levels of DC1 cells and total DCs were significantly associated with improved survival. Similarly, greater post transplant levels of total DCs and both subsets were significantly associated with survival. These findings suggest a relationship between DC reconstitution and survival following autologous HSCT for DLBC NHL. Strategies to increase autograft DC content or accelerate DC recovery after autologous HSCT might improve outcomes in this setting.

High-dose busulfan and the risk of pulmonary mortality after autologous stem cell transplant

Abstract:  The non‐relapse mortality of autologous stem cell transplant is low enough that the procedure has been extended to older patients with non‐Hodgkins lymphoma. We treated 537 non‐Hodgkins lymphoma patients with high‐dose chemotherapy consisting of busulfan, cyclophosphamide, and etoposide followed by autologous stem cell transplant. Sixteen patients were identified who died of pulmonary complications at a five‐year incidence of 3.6%. Risk factors for pulmonary mortality included older age and lower baseline DCO and FEV1. We conclude that high‐dose busulfan is associated with pulmonary mortality after autologous transplant, particularly in older patients.

The efficacy of prophylactic outpatient antibiotics for the prevention of neutropenic fever associated with high-dose etoposide (VP-16) for stem cell mobilization.

High-dose etoposide (2 g/m2) plus G-CSF is a very effective regimen for peripheral blood progenitor cell (PBPC) mobilization. Unfortunately, neutropenia is common. The infectious complications associated with high-dose etoposide have not been previously described. After noting a high incidence of hospitalizations for neutropenic fever, we began a vigorous prophylactic antibiotic regimen for patients receiving high-dose etoposide plus G-CSF, attempting to reduce infectious complications. Ninety-eight patients underwent etoposide mobilization between December 1997 and June 2000. Three chronological patient groups received: (1) no specific antibiotic prophylaxis (n = 44); (2) vancomycin i.v., cefepime i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27); and (3) vancomycin i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27). The patients not receiving antibiotic prophylaxis had a 68% incidence of hospitalization for neutropenic fever. In the patients receiving prophylaxis, the incidence was reduced to 26% and 15% respectively, for an overall incidence of 20% (P < 0.001 for comparison between prophylaxed and unprophylaxed groups). We conclude that etoposide mobilization is associated with a significant incidence of neutropenic fever, which can be substantially reduced by a vigorous antimicrobial prophylactic program.

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens.

Summary:The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III–IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+ TCD for AML is a potentially curative treatment option.