Background: Immunosuppressive medications such as tacrolimus, sirolimus, and corticosteroids are known to cause insulin resistance in solid organ transplant patients (pts). Pts receiving alloHSCT are often on immunosuppressants and develop some degree of hyperglycemia. Diabetes and hyperglycemia are associated with complications such as renal disease, cardiovascular disease, an increase in inflammatory processes, and increased risk of infections. We reported the prevalence of hyperglycemia in the first 100 days following alloHSCT as well as average blood sugar values and the association between blood sugars, length of stay, renal, pulmonary, and infectious complications. Methods: Beginning Feb, 2007, blood sugars on all alloHSCT pts were monitored for 100 days. Inpts were treated with IV or subcutaneous insulin as appropriate for a goal blood sugar < 140 ng/dl. ADA guidelines for diagnosing diabetes (two fasting blood sugars of ≥126 on separate occasions, or one random blood sugar of ≥200) were used to diagnose hyperglycemia in the outpatients. Outpts were referred to Endocrine (in a timely manner) within 2 days and the diabetic educators who counseled the pts and family on diet, insulin therapy, and blood sugar monitoring. Results: 32 pts received alloHSCT during the study period. Seventeen pts (53%) required treatment for hyperglycemia. The median (range) glucose level was 150 (109–189) in pts who received treatment while those who did not receive hyperglycemia treatment was 108 (92–132; (p< 0.001) In pts who received treatment, 24% had a prior history of diabetes mellitus,82% were on systemic steroids vs 40% of the non-treatment group (p = 0.01), and 41% were on total parenteral nutrition vs none in the non-treatment group (p = 0.005). The treatment group had a higher rate of acute GVHD, 65% vs 27% in the non-treatment group (p = 0.03), while 82% developed some type of infection versus 20% in the non-treatment group (p = <0.001). 18% of the treatment group died within 100 days, while no deaths occurred in the non-treatment group. Conclusions: AlloHSCT pts that develop hyperglycemia have higher rates of infection and GVHD. Pts who developed hyperglycemia also had higher rates of steroid and TPN usage, indicating these are potential risk factors for the development of hyperglycemia and merit aggressive monitoring of blood glucose. Further studies should evaluate if early hyperglycemia recognition and treatment decrease the incidence of complications.

9026 Background: HSCT carries an increased risk of mortality. Thus, patients are encouraged to have ACP. However, discussions about ACP is not a casual process since it may elicit undue anxiety to the patients and their families. Anecdotally, pts fear that discussion of the possibility of death is inconsistent with hoping for the best outcome. We therefore compared the outcomes of pts with or without ACP who received HSCT for cancer. Methods: ACP was defined as having living will, power of attorney for health care, or life-support instructions conducted prior to transplant. ACP were reviewed in pts who were at least 19 yo and received first allogeneic or autologous HSCT for cancer between 2001 and 2003. Pts were classified into: 1) No ACP, 2) ACP prior to cancer dx, 3) ACP after cancer dx but prior to HSCT. Multivariate analysis (MVA) was done to evaluate the relative risk of mortality at 1 year according to ACP while adjusting for other prognostic factors. Results: 343 pts were included in the study: 172 (50%) did not have ACP, while 171 (50%) pts had ACP. Of those with ACP, 127 pts (74%) were available for review. Characteristics were similar between pts with and without reviewable ACP. 28 pts had ACP prior to cancer dx, 87 had ACP prior to HSCT, while 12 had ACP after HSCT. 64% of pts with ACP had both power of attorney and a living will, 16% had a living will alone and 19% had power of attorney alone. Older pts (p <0.001) and Caucasians (p = 0.04) were more likely to have ACP. MVA were confined to the 172 pts with no ACP and 115 who had ACP before HSCT and showed that pts with ACP prior to HSCT had a significantly lower risk of mortality (see table ). Conclusions: Despite a diagnosis of cancer and hospitalization for HSCT, only 50% of patients had engaged in ACP. ACP at any time before HSCT was associated with higher one-year survival. Engagement in ACP is not necessarily inconsistent with hoping for the best outcome in HSCT. Further study is warranted to explore the reasons for engaging or not in ACP. No significant financial relationships to disclose. [Table: see text]

Febrile neutropenia is an expected complication during treatment of aggressive hematological malignancies and hematopoietic cell transplantation. We conducted a prospective cohort trial to determine the effects and safety of prophylactic fluoroquinolone administration, and rotation of empiric antibiotics for neutropenic fever in this patient population. From March 2002 through 2004, patients were treated with prophylactic levofloxacin during prolonged neutropenia, and a cycling schedule of empiric antibiotic therapy for neutropenic fever was initiated. The rates of bacteremia, resistance and complications were compared to a retrospective cohort of previously treated patients. The rate of gram-negative bacteremia decreased after the initiation of prophylactic levofloxacin (4.7 vs 1.8 episodes/1000 patient days, P<0.05). Gram-positive bacteremia rates remained unchanged, but more isolates of Enterococcus faecium were resistant to vancomycin after the intervention began. Resistance to the antibiotic agents used in the rotation did not emerge. There was no change in mortality during the intervention period. A prophylactic and cycling antibiotic schedule was successfully implemented on a hematological malignancy and hematopoietic cell transplant unit. gram-negative bacteremia was significantly decreased, without emergence of resistance. Concerns with Gram-positive resistance will require further observation.

Background/Patients and Methods: NST is increasingly being used as a means of establishing a graft-versus-malignancy (GVM) effect with less regimen related toxicity. Between 9/01 and 7/04, 39 patients (pts) with high risk/relapsed/refractory HM who were not candidates for full intensity allogeneic stem cell transplantation underwent NST using Pentostatin/TBI. The median age of pts was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous stem cell transplantation in 22 pts. Diseases transplanted included chronic lymphocytic leukemia/indolent non-Hodgkin’s lymphoma (NHL, n=6), aggressive NHL (n=8), mantle cell lymphoma (n=3), Hodgkin’s disease (n=6), myeloproliferative disorders (n=4), myelodysplastic syndromes (n=4), and acute myelogenous leukemia (AML, n=8). Conditioning consisted of Pentostatin 4 mg/m2 daily on day −21, −20, and −19, followed by 200 cGy TBI on day −1. Post-grafting immunosuppression consisted of cyclosporine/mycophenolate mofetil. Results: Stem cell transplantation was from matched related (n=14) or unrelated (n=25) donors. Death prior to 100 days post transplant occurred in 7 patients. Grade III/IV toxicities included hematologic (n=10 pts), infectious (n=5) and other non-infectious (n=4). The median nadir values (day −21 to day 0) for hemoglobin, neutrophil count and platelet count were 10.7 g/dl (range 7.8–12), 1056/mm3 (range 0–5336), and 174/mm3 (range 24–523) respectively. Three pts failed to engraft; two patients with myelofibrosis (both of whom had autologous reconstitution) and one patient with high risk AML (who died of complications of fungal sepsis without hematologic recovery). The median chimerism values for CD3+ cells and WBC at day 28 are 80% and 95% donor cells respectively. The median chimerism values for CD3+ and WBC at day 70 are 95% and 95% respectively. There have been no late graft failures. The cumulative incidence of all grades of acute graft-versus-host disease at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%, P=0.012). Chronic graft-versus-host disease has developed in 69% of patients. The cumulative incidence of relapse for all patients is 30%, and is lower for unrelated donor transplants than matched related donor transplants (46% vs. 20%, P=0.02). The probability of event-free and overall survival at two years is 52% and 56% respectively. Conclusions: This regimen is associated with acceptable toxicity. Engraftment has not been an issue with the exception of two pts with myelofibrosis. Pts receiving unrelated donor grafts have a higher incidence of graft-versus-host disease and a lower relapse rate. This represents indirect support for the presence of a GVM effect. A prospective study using a modified Pentostatin schedule (starting at day − 10) is ongoing based on the nadir of host T-cells identified in this study.

B chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the elderly with heterogeneous clinical outcome. Rai stage, immunoglobulin heavy chain mutation status, Zap-70 expression, CD38 expression and chromosome abnormalities are used as prognostic markers. Among these, CD38, a differentiation marker of T lymphocytes, has been reported to have a role in B-CLL pathogenesis. High CD38 expression is associated with an unfavorable clinical course with advanced disease stage, poor responsiveness to therapy, short time to first treatment, and shorter survival, whereas B-CLL patients with low CD38 expression required minimal or no treatment, remained treatment free for longer time and had better survival. However, the molecular basis for the association of CD38 expression and clinical course of B-CLL patients is not known. Therefore, in this study we classified 35 B-CLL patients into CD38 high (>30%) and CD38 low (<30%) expressions, and the clinical course was correlated with gene expression profile using oligonucleotide DNA microarrays consisting 10,000 genes. There was a significant difference in CD38 expression levels in patients with good clinical outcome (mean CD38 ~ 20%) compared to poor clinical outcome (mean CD38 ~ 46%). Median time to treatment with high CD38 expression was 30 months compared to 69 months for low CD38 expressing patients. Significance analysis of microarray (SAM) identified 52 differentially expressed genes. From these genes, Hem1 and CTLA-4 were further studied because the Hem1 expression is limited to hematopoietic cells and CTLA-4 is involved in modulation of immune response. Also, CTLA-4 is a member of the immunoglobulin superfamily involved in the cell cycle regulation and prolongs the progression through the G1 phase of the cell cycle. The differential expression of Hem1 and CTLA-4 was also confirmed by semi-quantitative RT-PCR. Hem1 was found to be over expressed in B-CLL patients with higher CD38 expression compared to lower CD38 expression, whereas CTLA-4, was over expressed in B-CLL patients with lower CD38 expression compared to patients with high CD38 expression thus confirming the microarray results. Furthermore, to determine whether the expression levels of these two genes are associated with disease progression in B-CLL, log rank test was applied across the expression of Hem1 and CTLA-4 and disease progression. The higher expression of Hem1 was associated with shorter time to treatment (Figure 1), whereas lower expression of CTLA-4 was associated with shorter time to treatment (Figure 2). Thus, these results while confirming the prognostic value of CD38 expression, demonstrate the possible molecular basis of CD38 mediated clinical course in B-CLL patients involving key genes such as Hem1 and CTLA-4.

PURPOSE:Engagement in advance care planning (ACP) is viewed as a way to prepare for possible death. In patients undergoing hematopoietic stem-cell transplantation (HSCT), an aggressive but possibly curative procedure for cancer, encouraging engagement in ACP is difficult. We conducted this analysis to determine if engagement in ACP among patients who undergo HSCT is associated with adverse outcomes.PATIENTS AND METHODS:Adult patients who were undergoing their first HSCT for hematologic malignancies between 2001 and 2003 were included. ACP was defined as having a living will, a power of attorney for health care, or life-support instructions. Outcomes assessed included the length of hospital stay, in-hospital mortality, and overall survival.RESULTS:Of the 343 patients, 172 did not have ACP, whereas 171 did have ACP, and 127 of those were reviewable. Of those with reviewable ACP, 28 patients (22%) completed ACP before cancer diagnosis, 87 (68%) completed ACP after the cancer diagnosis but before HSCT, and 12 (10%) engaged in ACP after HSCT. Patients without ACP before HSCT had a significantly greater risk of death compared with patients with ACP (hazard ratio, 2.11; 95% CI, 1.34 to 3.33; P = .001) while adjusting for statistically significant factors.CONCLUSION:Our study demonstrated that lack of engagement in ACP is associated with adverse outcomes after HSCT. Thus, the patients least likely to have planned for poor outcomes are the ones most likely to face them. Additional studies should evaluate the nature of this association and should seek modifiable explanatory factors that could be the target of interventions.

The use of peripheral blood stem cells (PBSCs) for allogeneic transplantation continues to increase. The relationship between ease of mobilization of PBSC and engraftment after transplantation has not been extensively studied. We retrospectively analyzed the relationship between days of collection by apheresis (categorized as 1, 2, and> 2) and engraftment in 109 matched sibling donor/recipient pairs who underwent collection between March 1995 and November 2003. All donors recieved G-CSF at 10 μg/kg for 4 days, with collection started on the fifth day. Daily G-CSF administration and collection were continued until a minimum of 3× 106 CD34+ cells/kg per recipient had been collected. Cells were frozen and stored in DMSO until infusion. All grafts were unmanipulated, and all recipients received G-CSF posttransplantation. Fifty-one donors (47%) required 1 day to collect an adequate graft, 52 donors (48%) required 2 days, and 6 donors (6%) required> 2 days. Females were more likely to require> 1 day of collection (P= .01). Donors who required> 2 days for collection were older than donors who required only 1 or 2 days (P= .015). There was no association between days required for collection anddonor body size measurements (height, weight, body surface area), or between days required for collection and recipient body size measurements. There was a statistically significant association between product characteristics (CD34+ cell dose, CFU-GM, MNC cell dose) and number of collection days (P< .01 for CD34+, P< .001 for CFU-GM, and P< .0001 for MNC). For CD34+ cell dose (× 106/kg) the median number of cells collected was 6.56 (range, 3.1–21.1) for 1 day collection, 7.3 (range, 3.0–24.9) for 2 days collection, and 3.2 (range, 1.8–5.9) for> 2 days collection. The number of collections was not significantly related to engraftment in univariate analysis. However, after adjustment for CD34+ dose infused (using Cox regression), the number of collection days was significantly related to platelet engraftment (P= .05), but not to neutrophil engraftment (P= .17) or red cell engraftment (P= .94). We conclude that all donors were able to mobilize sufficient cells for engraftment, but that grafts requiring> 2 collections are associated with a delay in platement engraftment after correction for CD34+ cell dose.

Background: The administration of alemtuzumab (Campath 1H) as part of the conditioning regimen prior to allogeneic stem cell transplantation has been associated with a low incidence of acute and chronic GVHD. Initial studies employing doses of 100 mg have reported a high incidence of viral infections. Lower alemtuzumab doses combined with standard GVHD prophylaxis regimens (calcineurin inhibitor + MTX) have also resulted in a low incidence of acute GVHD in patients with CD52-positive malignancies. We investigated the effect of low-dose (40 mg) alemtuzumab on engraftment (VNTR chimerism studies), the incidence of acute and chronic GVHD, CMV reactivation, survival, and immune reconstitution (examined by TREC content at various time points after transplant). Patient and Transplant characteristics: Twenty-seven patients underwent a matched (n=24) or 1-antigen mismatched (n=3) related (n=13) or unrelated (n=14) allogeneic stem cell transplantation for various hematologic malignancies. Median age was 41 years (19–59). Disease stage at transplant was early for 48%, intermediate for 11% and late for 41%. Three patients received bone marrow and 24 received PBSC grafts. Conditioning regimen consisted of TBI 10 Gy with partial lung shielding, Thiotepa 500 mg/m 2 , and Alemtuzumab 20 mg IV on day -4 and day -1. GVHD prophylaxis was with cyclosporine (n=13) or tacrolimus (n=14) and full-dose MTX. High-dose viral prophylaxis with valacyclovir 2000 mg QID was given to all recipients from a CMV seropositive recipient/donor pair starting at patient #9, due to a high incidence of CMV reactivation amongst the first 8 patients. Three patients received DLI for disease relapse. Median follow-up for survivors is 13 months (6–26). Results: Of eighteen evaluable patients (3 relapsed, 5 expired, 1 not done) at day 100, 15 had ≥ 95% donor chimerism, and 3 had 90–94% donor chimerism. The cumulative incidence of acute GVHD grade II-IV at day 100 was 4% (95% CI 1–16%), and the cumulative incidence of chronic GVHD at 1 year was 31% (12–52%). Cumulative incidence of non-relapse mortality at day 100 was 18% (7–35%), and at 1 year 31% (14–49%). Cumulative incidence of relapse at 1 year was 28%, resulting in a projected 1-year disease-free survival of 41% (22–60%), and overall survival of 54% (33–71%). Amongst the first eight patients, all (5/5) at-risk recipients developed CMV reactivation. After initiation of prophylaxis with high-dose valacyclovir, 4/11 at-risk recipients developed CMV reactivation. No patient died from CMV disease. TREC analysis in a limited number of patients showed rapid increase in TREC between day 0 and day 180, but no further increment between day 180 and day 365. Conclusions: The use of low-dose alemtuzumab results in low incidences of acute and chronic GVHD. CMV reactivation is common, and can be partially prevented by use of high-dose valacyclovir. Immune reconstitution data on a small subset of patients show limited output of thymic emigrant T cells after 6 months.

Background: Patients with HD and NHL have been treated with autologous stem cell transplantation (SCT) since the 1980s at the University of Nebraska Medical Center. A wide variety of conditioning regimens have been used. TBI was a standard component until the mid-1990s. AML and MDS are known risks following chemotherapy, radiotherapy and transplant. Cases of sAML/MDS following autologous SCT have ranged from 4–15%. Various patient- and treatment-specific factors have been shown to increase that risk, such as specific chemotherapy drugs, number of pre-auto SCT regimens, TBI vs non-TBI containing conditioning regimens, and prior cytogenetic abnormalities. The development of sAML/MDS leads to poor prognosis. M&M: All patients who received their first autologous SCT between 1985–2003 for HD or NHL who survived and/or had follow-up data for at least 17 months post-transplant at UNMC were reviewed. Patients who developed sAML/MDS following SCT were assessed and its incidence computed. Risk factors at the time of auto-SCT were evaluated for their association with the development of sAML/MDS and include: age, sex, race, HD vs NHL, interval time from diagnosis to transplant, disease stage, number of prior chemotherapy regimens, chemosensitivity, bone marrow involvement, extranodal involvement, LDH levels, graft type, year of transplant, and conditioning regimen- TBI vs non-TBI.

Graft-versus-host disease occurs when transplanted donor-derived T lymphocytes recognize major or minor histocompatibility complex proteins and their associated peptides expressed by recipient antigen-presenting cells. A widely accepted paradigm for the pathophysiology of acute GVHD is based on the existence of 3 sequential steps: (1) injury to the host environment (as would occur during conditioning regimens); (2) donor T-cell activation, proliferation, and differentiation; and (3) damage to the target tissue caused by either cytotoxicity or indirectly by inflammatory cytokines. In order to reduce the incidence of GVHD, recent studies have focused on methods of prophylaxis as well as novel treatments for established GVHD. We review each phase in the development of acute GVHD and discuss recently developed interventions aimed to prevent or treat GVHD by interfering with these pathways.

Tacrolimus (FK506) is commonly used in allogeneic stem cell transplantation (SCT) to prevent rejection and graft-versus-host disease. Dosing recommendations are mostly based on studies performed in solid-organ transplant recipients. The package insert recommends a conversion rate of 1:4 when changing from the intravenous to the oral formulation. We retrospectively reviewed tacrolimus levels and toxicity in 32 patients who underwent allogeneic SCT between July 2001 and June 2003 using the package insert recommended conversion rate. All patients started tacrolimus on day -1 at a dose of 0.03 mg/kg actual body weight by continuous IV infusion. Levels were drawn peripherally on day +1, +3, +5 and then biweekly. Target range for tacrolimus levels was 8–12 ng/mL. Conversion from IV to PO at a conversion rate of 1:4 occurred when patients could tolerate P.O. medication. Thirty-two patients underwent alloSCT for a variety of hematologic malignancies. Median age at the time of transplant was 43 year (range 19–58), 78% underwent a MRD donor SCT, 3% a 5/6 MRD SCT, and 19% a MUD SCT, conditioning was Cy/TBI (89%) or Bu/Cy2 (11%). Ninety-three percent of patients with available data required at least one IV dose reduction, the median day of IV to PO conversion was +11 (range +7–+25). The median initial PO dose was 0.08 mg/kg (range 0.04–0.18) and the median conversion ratio was 0.26 (range 0.12–0.4). Median initial tacrolimus level after conversion was 16.9 ng/mL (range 5.3–52.4). Twenty-seven patients (93%) required a reduction in their PO dosing, only two patients immediately achieved a stable PO dose (defined as two consecutive tacrolimus levels within the therapeutic range). Nine patients (31%) developed a creatinine level greater than twice their baseline level, eleven patients (38%) required intervention to lower potassium, and three patients (10%) developed tremors. No irreversible complications were encountered. We conclude that the presently recommended conversion rate frequently results in toxic serum levels associated with mild renal insufficiency and other adverse effects. We have changed our conversion rate from 1:4 to 1:2.

Relapse of hematologic malignancies after allogeneic stem cell transplantation remains a common problem, in particular for patients who have advanced disease at the time of transplantation. Thiotepa has excellent antileukemic and immunosuppressive activity, and could therefore be a useful drug in the conditioning regimen for patients with advanced hematologic neoplasms. We retrospectively analyzed toxicity, engraftment and survival data of 41 patients who received a conditioning regimen of thiotepa (600 mg/m2) and hyperfractionated TBI (10 Gy) prior to matched related (n=25) or matched unrelated (n=16) allogeneic stem cell transplantation. The mean age at transplantation was 37.8 years (range 20–59), all but five patients had advanced hematologic malignancies at the time of transplantation. GVHD prophylaxis was with standard cyclosporine and methotrexate. Engraftment was excellent, but the regimen was associated with a high incidence of grade III renal (41%) and hepatic (15%) toxicity, and high transplant-related mortality (44% at day +90). The 3-year event-free survival was 13% and overall survival 14%. We conclude that this regimen requires modification to reduce toxicity.

Hematopoietic stem cell transplantation has become increasingly important in the treatment of hematologic malignancies over the past 20 years. While it is associated with significant morbidity, it offers the only chance of cure in many circumstances. Autologous and allogeneic transplantation have been used successfully to treat a variety of hematologic malignancies. These 2 approaches offer different risks and benefits which are discussed in this review. Timing of transplantation and selection of patients are also discussed. New innovations in stem cell transplantation including umbilical cord blood and non-myeloablative transplantation are reviewed.

We evaluated the results of high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with relapsed or primary refractory Hodgkin’s disease (HD), using a previously reported prognostic model based on the presence of three poor prognostic factors at the start of salvage therapy/preparative regimen: B symptoms, extranodal disease and the duration of last complete response of less than 1 year. Based on this model, the patients were divided into low-risk and high-risk groups. Between 1993 and 2001, 24 patients with HD were treated with HDT and ASCT. Eighteen of the 24 patients had 0–1 risk factors (low-risk group) and 6 patients had 2–3 risk factors (high-risk group). Using Kaplan-Meier analysis, after a median follow-up of 40.5 months, the progression-free survival (PFS) was 48%, and the overall survival (OS) was 55%. PFS in the low-risk group was 56%, and in the high-risk group 17% (p < 0.001). OS in the low-risk group was 68% and in the high-risk group it was 18% (p < 0.001). The 100-day transplant-related mortality for the entire group was 16%. Our results are comparable to those reported in previous clinical trials for patients with refractory and relapsed HD treated with HDT and ASCT. The use of a prognostic model appears useful for predicting the outcome of HDT and ASCT for HD patients, and may play an important role in choosing the appropriate therapy for these patients.

Allogeneic stem cell transplantation (SCT) is the treatment of choice for selected patients with chronic myeloid leukemia (CML). However, it is associated with a high risk of treatment-related mortality (TRM) and morbidity. To assist in decision making about transplantation, a simple scoring system to assess the risk is needed. We analyzed the utility of a scoring system, first reported by the European Group for Blood and Marrow Transplantation (EBMT). We analyzed the data from 31 patients who underwent allogeneic transplantation at our institution, using the EBMT scoring system. It was based on five pretransplant risk factors: donor type, stage of disease at time of transplantation, age of recipient, sex of donor and recipient, and interval between diagnosis and transplant. Seventeen patients had a risk score of 0–2, and 14 patients had a score of 3–7. Using Kaplan-Meier analysis, the estimated 4-year leukemia-free (LFS) and overall survival (OS) for patients with a score of 0–2 were 47 and 53%, respectively. In contrast, the estimated 4-year LFS and OS for patients with a score of 3–7 were 10.5 and 10.5%, respectively. Four-year TRM was 47% for the low-risk group (0–2), and 85% for the high-risk group (3– 7). This simple scoring system may play an important role in predicting the outcome of allogeneic SCT, and in choosing the appropriate therapy for patients with CML.