Diana Quinlan

High Busulfan Exposure Is Associated with Worse Outcomes in a Daily i.v. Busulfan and Fludarabine Allogeneic Transplant Regimen

Low plasma busulfan (Bu) area under the concentration-time curve (AUC) is associated with graft failure and relapsed leukemias, and high AUC with toxicities when Bu is used orally or i.v. 4 times daily combined with cyclophosphamide in myeloablative hematopoietic stem cell transplantation (SCT) conditioning regimens. We report Bu AUC and its association with clinical outcomes in 130 patients with hematologic malignancies given a once-daily i.v. Bu (3.2 mg/kg days -5 to -2) and fludarabine (Flu, 50 mg/m(2) days -6 to -2) regimen. Total-body irradiation (TBI) 200 cGy x 2 was added for 51 patients with acute leukemias. Plasma AUC varied 3.6-fold (2184-7794 microM.min, median 4699 microM.min). Patients with an AUC >6000 microM.min had lower overall survival (OS) than those with AUC < or =6000 microM.min at 12 months (38% versus 74%) and 36 months (23% versus 68%, P < .001). This effect was apparent in patients with standard-risk and high-risk disease, and persisted when potential confounders were considered (hazard ratio 3.2, 95% confidence interval 1.7-6.3). Nonrelapse mortality (NRM) at 100 days (6% versus 19%) and progression free survival (PFS; 58% versus 16%) at 3 years were better with AUC < or =6000 microM.min. These data support a role for therapeutic dose monitoring and dose adjustment with daily i.v. busulfan.

Outcomes following HSCT Using Fludarabine, Busulfan, and Thymoglobulin: A Matched Comparison to Allogeneic Transplants Conditioned with Busulfan and Cyclophosphamide

We have reported a lower incidence of acute graft-versus-host disease (aGVHD) with a novel conditioning regimen using low-dose rabbit antithymocyte globulin (ATG; Thymoglobulin [TG]) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single-center experience, we performed a retrospective matched-pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). One hundred twenty cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (TRM; 12% versus 34%, P < .001) and grades II-IV aGVHD (15% versus 34%, P < .001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% versus 20%, P < .001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and TRM after HLA-identical sibling HSCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials.

Transplantation from Matched Siblings Using Once-Daily Intravenous Busulfan/Fludarabine with Thymoglobulin: A Myeloablative Regimen with Low Nonrelapse Mortality in All But Older Patients with High-Risk Disease

Two hundred patients received hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) after myeloablative conditioning including fludarabine (Flu) and once-daily intravenous busulfan (Bu). Thymoglobulin (TG) was added to methotexate (MTX) and cyclosporine (CsA) as graft-versus-host disease (GVHD) prophylaxis. For low-risk (acute leukemia CR1/CR2, CML CP1) patients projected 5-year nonrelapse mortality (NRM) and overall survival (OS) were 4% and 76% for those <or=45 years old (n = 54) and 6% and 83% for those >45 (n = 31). For high-risk (HR) patients NRM was 6% versus 27% (18% at 1 year) (P = .04) and OS 64% versus 37% (P = .47) in younger (n = 40) and older (n = 75) patients, respectively. To correct for imbalance in HR diagnoses each of 17 younger HR patients were matched with 2 older HR (OHR) patients by diagnosis and details of stage, and thereafter for other risk factors. For the younger HR and OHR patients, respectively, OS was 70% versus 37% (P = .02) and NRM 0 versus 34% (P = .02). When outcomes of OHR patients were compared with the other 3 groups combined NRM was 27% versus 5%, respectively (P = .002). Incidence of acute graft-versus-host disease (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) was 23% versus 10% (P = .02), 4% versus 2% (P = ns), and 66% versus 41% (P = .001), respectively. Nine of 14 nonrelapse deaths in the OHR group were related to GVHD or its treatment compared with 3 of 6 in all others (P value for GVHD related death = .01). Multivariate analysis of OS and DFS correcting for potentially confounding pretransplant factors identified only the OHR patients as having significantly increased risk (relative risk [RR] 3.32, confidence interval [CI] 1.71-6.47, P < .0001, and RR 3.32, CI 1.71-6.43, P < .0001, respectively). The effect of age on NRM is only apparent in HR patients, and is not explained by heterogeneity in diagnoses. Older HR patients experience more GVHD and more GVHD-related death than others, but NRM is no higher than reported with many nonmyeloablative regimens.

The Addition of 400 cGY Total Body Irradiation to a Regimen Incorporating Once-Daily Intravenous Busulfan, Fludarabine, and Antithymocyte Globulin Reduces Relapse Without Affecting Nonrelapse Mortality in Acute Myelogenous Leukemia

A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). The addition of rabbit antithymocyte globulin (ATG) may reduce morbidity and mortality from graft-versus-host disease (GVHD), but lead to increased relapse. To compensate for this effect, we added 400 cGy of total body irradiation (TBI) to the Flu/Bu regimen in 89 patients, and compared outcomes with those achieved in 90 patients who received the drug combination alone. Although nonrelapse mortality (NRM) at 3 years did not differ between the groups, the inclusion of TBI significantly reduced relapse (hazard ratio [HR] = 0.29; 95% confidence interval [CI] = 0.15-0.54; P = .0001). Consequently, both overall survival (OS; HR = 0.50; 95% CI = 0.3-0.84; P = .009) and disease-free survival (DFS; HR = 0.43; 95% CI = 0.26-0.72; P = .001) were improved with the inclusion of TBI. This study confirms the importance of regimen intensity in allogeneic HSCT for AML. The combination of daily i.v. Bu, Flu, 400 cGy TBI, and ATG provides a well-tolerated regimen with antileukemic activity in AML comparable to that of other, conventional myeloablative (MA) regimens.

Donor Serostatus Has an Impact on Cytomegalovirus-Specific Immunity, Cytomegaloviral Disease Incidence, and Survival in Seropositive Hematopoietic Cell Transplant Recipients

More cytomegalovirus (CMV)-specific T cells are transferred with grafts from CMV seropositive than seronegative donors. We hypothesized that seropositive recipients of grafts from seropositive donors (D+R+) have higher counts of CMV-specific T cells than seropositive recipients of grafts from seronegative donors (D-R+), and that this is clinically relevant in the setting of in vivo T cell depletion using rabbit-antihuman thymocyte globulin (ATG). We reviewed charts of 298 ATG-conditioned, seropositive recipients for CMV reactivation (pp65 antigenemia or CMV DNAemia above institutional threshold for preemptive therapy), recurrent CMV reactivation, CMV disease, and death. In 77 of these patients, we enumerated CMV-specific T cells. Median follow-up was 564 days. CMV-specific CD4+ and, to a lesser degree, CD8+ T cell counts were higher in D+R+ than D-R+ patients. D+R+ patients had lower cumulative incidence of CMV reactivation (21% versus 48%, P < .001), recurrent reactivation (4% versus 15%, P = .003), CMV disease (3% versus 13%, P = .005) and mortality (42% versus 56%, P = .006). We conclude that in the setting of in vivo T cell depletion using ATG, seropositive donors should be used for seropositive recipients. For scenarios where only seronegative donors are available, strategies to improve CMV-specific immunity (e.g., donor vaccination) should be explored.

Mobilized blood cells vs bone marrow harvest: experience compared in 171 donors with particular reference to pain and fatigue

Summary:This prospective study compared the donor experience of blood cell (BC) mobilization and leukapheresis (n=116) with that of bone marrow (BM) harvest (n=55). Internal jugular catheters were inserted electively in 89% of BC donors. Most (80%) BM donors had a harvest with general anesthesia; 20% had epidural or spinal anesthesia. Pain and fatigue were frequent with both procedures and were compared in responses to questionnaires. A total of 85% of BM donors reported moderate or severe pain compared with 68% of BC donors (P=0.02). The median duration of pain was 14 days for BM donors compared with 3 days after BC mobilization (P<0.0001). More BM donors had pain for more than 7 days (75% vs 0%, P<0.0001). Severe fatigue was experienced by more BM donors (49 vs 16%, P<0.0001). Fatigue lasted significantly longer in BM donors (median 11 vs 4 days, P<0.0001) and more BM donors were fatigued for more than 1 week (69 vs 0%, P<0.0001). A total of 11 donors had both BM and BC collection; seven preferred the latter. Simply considered with respect to pain and fatigue, BC donation appears better tolerated by donors. However, there are other sequelae of both influencing the acceptability for individual donors.

Influence of comorbidities on transplant outcomes in patients aged 50 years or more after myeloablative conditioning incorporating fludarabine, BU and ATG.

Non-myeloablative (MA) and reduced intensity allo-SCT regimens are offered to older patients and/or those with comorbidities because the morbidity and mortality attributable to fully MA conditioning is thought to be unacceptably high. A total of 207 patients aged 50–66 years were treated between 1999 and 2008 with SCT after MA conditioning with fludarabine 50 mg/m2 daily × 5 and i.v. BU 3.2 mg/kg daily × 4.90 (43%) had additional TBI 200 cGy × 2. GVHD prophylaxis was CsA, MTX and thymoglobulin (4.5 mg/kg total dose). As defined by the hematopoietic cell transplantation co-morbidity index (HCT-CI) scoring system 117 (57%) pts scored 0 and 90 (43%) ⩾1. At 5 years OS was 39 vs 54% (P=0.008), disease-free survival 38 vs 49% (P=0.03), TRM 39 vs 19% (P=0.003) and relapse 36 vs 39% (P=ns) in those with scores of 0 and ⩾1, respectively. Multivariate analysis confirmed the influence of HCT-CI scores on TRM (subhazard ratios=2.29; 95% confidence interval=1.29–4.08; P=0.005). We conclude that comorbidities as assessed by the HCT-CI do influence TRM with this regimen but that age alone should not be an indication to prefer a less intense protocol.