Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention.

Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II-IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14-3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48-1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II-IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.

Tacrolimus plus sirolimus with or without ATG as GVHD prophylaxis in HLA-mismatched unrelated donor allogeneic stem cell transplantation.

HLA-matched related or unrelated donors are not universally available. Consequently, patients can be offered hematopoietic stem cell transplantation (HSCT) from alternative donors, including mismatched unrelated donors (MMURD), known to cause a higher incidence of acute GVHD (aGVHD) and chronic GVHD. In vivo T-cell-depletion strategies, such as antithymocyte globulin (ATG) therapy, significantly decrease the risk of GVHD. We performed a multicenter, retrospective study comparing tacrolimus (TAC) and sirolimus (SIR) with or without ATG in 104 patients (TAC-SIR=45, TAC-SIR-ATG=59) who underwent MMURD HSCT. Use of ATG was associated with a lower incidence, albeit not statistically significant, of grades 2-4 aGVHD (46% vs 64%, P=0.09), no difference in grades 3-4 aGVHD (10% vs 15%, P=0.43), a trend for a lower incidence of moderate/severe chronic GVHD (16% vs 37%, P=0.09) and more frequent Epstein-Barr virus reactivation (54% vs 18%, P=0.0002). There were no statistically significant differences in 3-year overall survival (OS) (TAC-SIR-ATG=40% (95% confidence interval (CI)=24-56%) vs TAC-SIR=54% (95% CI=37-70%), P=0.43) or 3-year cumulative incidence of relapse/progression (TAC-SIR-ATG=40% (95% CI=28-58%) vs TAC-SIR=22% (95% CI=13-39%), P=0.92). An intermediate Center for International Blood & Marrow Transplant Research disease risk resulted in a significantly lower non-relapse mortality and better OS at 3 years. Our study suggests that addition of ATG to TAC-SIR in MMURD HSCT does not affect OS when compared with TAC-SIR alone.

Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission.

Allogeneic hematopoietic cell transplantation offers improved survival in patients with ALL, but with regimens containing TBI, the nonrelapse mortality is 20-40%. Efforts to lessen transplant toxicities by reducing conditioning regimen intensity have led to increased relapse risk. Therefore, there is a need for less toxic regimens that maintain an anti-leukemia effect. We report here a retrospective review of 65 patients with ALL in first remission receiving grafts from allogeneic donors after fludarabine 40 mg/m(2)/day for 4 days and i.v. BU targeted to a median daily area under the concentration-time curve below 6000 µmoles min/L. At 2 years after transplantation, OS was 65% (95% confidence interval (CI): 52-77%), relapse-free survival was 61% (95% CI: 48-73%), cumulative incidence of relapse was 26% (95% CI: 17-39%) and cumulative incidence of nonrelapse mortality was 14% (95% CI: 8-26%). Age over 35 years, Ph chromosome positivity and minimal residual disease at transplant did not adversely affect outcomes. Pharmacokinetically targeted BU and fludarabine can provide intensive pre-transplant conditioning for adults with ALL in first remission, with promising relapse-free and OS rates.

Allogeneic hematopoietic cell transplantation for consolidation of VGPR or CR for newly diagnosed multiple myeloma.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m(2) i.v. if with bortezomib and 40 mg/m(2) i.v. when without bortezomib, × 4 days) plus melphalan (70 mg/m(2) intravenously × 2 days) with (n=13) or without (n=9) bortezomib (1.3 mg/m(2)). The cumulative incidence of grades II - IV acute GVHD at day 100 was 45% (95% CI: 24-65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19-69%). With a median follow-up of 18 (range, 2-61) months, the 2-year PFS estimate is 74.8% (95% CI: 45-90%), which compares favorably with the 52% (95% CI: 35-66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9-55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy.

Practice variation in physician referral for allogeneic hematopoietic cell transplantation.

Hematological malignancy patients not referred by their primary hematologist/medical oncologist suffer disparate access to allogeneic hematopoietic cell transplantation (HCT). However, investigation into physician, system and patient factors relevant to this decision making is lacking. We surveyed a national randomized sample of practicing hematologists/medical oncologists identified through the AMA (American Medical Association) masterfile. A modified Dillman approach was utilized to encourage survey response. From 1200 surveyed, a total of 113 physicians responded. In all, 68% were male, 62% identified as White/non-Hispanic, 79% practiced in non-academic settings and 80% reported spending 75-100% of their professional effort in clinical care. Using clinical vignettes, we detected significantly increased odds for HCT non-referral according to age (age 60 vs 30, odds ratio (OR) 8.3, 95% confidence interval (CI): 5.9-11.7, P<0.0001), insurance coverage (no coverage vs coverage, OR 6.9, 95% CI: 5.2-9.1, P<0.0001) and race (African-American vs Caucasian, OR 2.4, 95% CI: 1.9-2.9, P<0.0001). Physician (perception of HCT risks), system (insurance coverage) and patient (age, social support and co-morbid illness) factors were strongly endorsed by respondents as important determinants of their HCT referral practices. These data speak to important factors relevant to HCT referral practices, and highlight several opportunities for education and intervention to reduce current disparities.

Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization.

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n=531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P<0.0001) were more likely to find a donor. Younger age (P=0.01), Caucasian race (P=0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P=0.005), and 8/8 HLA matching (P=0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63-1.2), P=0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90-100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38-0.90, P=0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

Apheresis and transplant of hematopoietic progenitor cells (HPC) from allogeneic donors of age above 60 years.

Over the immediate past 4 years, our program has collected hematopoietic progenitor cells by apheresis from 48 individuals aged 61 and over (range 61-71 years of age). We have retrospectively analyzed the collection and transplant results associated with employing these donors, and have compared them with 175 donors aged 60 or less who were collected during the same time period. We have found no significant difference in venous access (P = 0.208), rate of post-transplant engraftment of neutrophils (P = 0.117) and platelets (P = 0.692), or in rate and grade of acute GVHD (P = 0.806). However, we have found that these older donors have a significantly lower mobilization of CD34 + cells as reflected in lower absolute counts of circulating CD34 + cells pre-apheresis (P = 0.016). This, in turn, results in lower CD34 + cell yields in apheresis products (P < 0.001), trending towards requiring more apheresis procedures (22.9 vs 13.7%, P = 0.095) to collect sufficient CD34 + cells for transplantation. We conclude that it is practical when necessary to employ donors aged 60 and above, as well as safe for both donor and intended recipient. However, concern over reduced CD34 + cell mobilization may be sufficient grounds to seek younger donors when possible.

Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review.

Graft-versus-host-disease (GVHD) is a major complication associated with allogeneic hematopoietic cell transplantation (allo-HCT). Antithymocyte globulin (ATG) is recommended for GVHD prophylaxis following allo-HCT, however, evidence on efficacy of ATG is conflicting. Accordingly, we undertook a systematic review. All phase III randomized controlled trials (RCTs) comparing ATG versus control for prevention of GVHD in patients undergoing allo-HCT were eligible. Medline and Cochrane databases were searched. Data on methodological quality, benefits and harms were extracted for each trial and pooled under a random effects model. Seven RCTs enrolling 733 patients met inclusion criteria. Pooled results showed no difference for overall survival with use of ATG (hazard ratio was 0.91; 95% confidence intervals (CI), 0.75-1.10; P = 0.32). There was a significant benefit for prevention of grade III/IV acute GVHD (risk ratio (RR) = 0.51; 95% CI, 0.27-0.94; P = 0.03). There was no benefit associated with ATG use for prevention of either grade II (RR = 0.79; 95% CI, 0.48-1.30; P = 0.35) or grade I acute GVHD (RR = 1.42; 95% CI, 0.75-2.69; P = 0.28). Use of ATG was not associated with significant reduction in non-relapse mortality (RR = 0.74; 95% CI, 0.53-1.03; P = 0.08). Future trials with adequate sample size are required to provide more definitive answers.

Targeted i.v. BU and fludarabine (t-i.v. BU/Flu) provides effective control of AML in adults with reduced toxicity.

Myeloablative doses of BU and fludarabine followed by allogeneic hematopoietic cell transplantation offer effective therapy for AML. We anticipated that pharmacokinetic targeting of i.v. BU to 5300 µM/L min/day × 4 (targeted i.v. BU and fludarabine (t-i.v. BU/Flu)) would limit nonrelapse mortality (NRM) in adults up to 70 years of age. We assessed the safety and efficacy of t-i.v. BU/Flu in a series of 100 adults (median age 48, range 22-69 years) with AML in the first CR (CR1) with high risk of treatment failure (n=49), second CR (CR2, n=25), relapsed disease (REL, n=9), primary induction failure (PIF, n=16) and untreated (n=1). NRM was 3% at 100 days and 15% at 1 year. The cumulative incidence of relapse was 30.6% for CR1, 41.7% for CR2, 55.6% for REL and 58.6% for PIF. OS for primary AML in CR1 was 66% (95% confidence interval (CI): 46-80%) at 1 year, and 62% (95% CI: 42-77%) at 2 years. On multivariable modeling, remission status, moderate/severe chronic GVHD and day-90 BM chimerism ≥90% predicted improved OS. Importantly, there was no effect of age. t-i.v. BU/Flu provides effective disease control with encouraging NRM in patients up to age of 70 years.

Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia.

We retrospectively compared clinical outcomes in 1593 T-replete unrelated donor (URD) marrow transplant recipients with AML, MDS and CML who received myeloablative conditioning regimens of either BU and CY (BuCy), standard-dose Cy/TBI (1000-1260 cGy) or high-dose Cy/TBI (1320-1500 cGy). Subjects were drawn from patients transplanted between 1991 and 1999 facilitated by the National Marrow Donor Program. Patients who received high-dose Cy/TBI regimens were slightly younger, more likely to receive a mismatched transplant and to have intermediate or advanced disease compared with patients in the BuCy or standard-dose TBI group. Neutrophil recovery was significantly higher in the standard-dose CY/TBI group compared with the high-dose Cy/TBI or BuCy group. Patients who received the high-dose Cy/TBI regimen had an increased risk of developing grades III-IV aGVHD when compared with the control group who received BuCy (P = 0.011). OS, disease-free survival (DFS), TRM and relapse were not significantly different between any of the regimens. We conclude that BuCy, standard-dose and high-dose Cy/TBI regimens have equivalent efficacy profiles for OS, DFS, TRM and relapse risk in patients undergoing T-replete URD marrow transplantation for AML, CML and MDS.

Pharmacokinetic targeting of i.v. BU with fludarabine as conditioning before hematopoietic cell transplant: the effect of first-dose area under the concentration time curve on transplant-related outcomes.

We used pharmacokinetic (PK) targeting of BU in 145 consecutive patients treated with fludarabine and i.v. BU. BU was given once daily at 130 mg/m(2) per day on days 1 and 2; doses for days 3 and 4 were adjusted in 92 patients (63%) to an average daily area under the concentration-time curve (AUC) of 5300 µM/min. In the remaining 53 patients, the first-dose AUC was within the target range and no dosing adjustments were required. First-dose AUC, maximum concentration and clearance were not correlated with age, race, ethnicity, performance status, or hematopoietic cell transplant comorbidity index. Women had higher clearance than men (median 2.9 vs 2.5 mL/min/kg; P=0.001). BU toxicities were not associated with first-dose AUC or any other PK parameter measured. First-dose BU AUC was not associated with non-relapse mortality (NRM) or survival, but higher AUC was predictive of relapse. We did not find an increased risk of toxicity or NRM in patients with high first-dose AUC presumably because of the dose adjustment. We conclude that PK targeting of BU as described here provides a simple, safe and effective method of delivering high BU doses before transplantation in a wide variety of patients.

Mycophenolate mofetil for the management of steroid-refractory acute graft vs host disease.

Acute graft vs host disease (aGVHD) is a significant obstacle to successful allogeneic hematopoietic cell transplantation, as only 30-40% of those with aGVHD show complete response to front-line glucocorticoids. The role of mycophenolate mofetil (MMF) as salvage therapy in steroid-refractory aGVHD remains incompletely defined. Here, we examine outcomes of 27 patients with refractory aGVHD treated with MMF as second-line therapy. Seven (26%) patients achieved complete remission (CR) of steroid-refractory aGVHD with only the addition of MMF as salvage therapy. CR of aGVHD differed by overall grade at salvage (grade I, 1/3; grade II, 5/12; grade III 0/5; grade IV, 1/7) with odds ratio for CR in grade I/II vs III/IV of 7.3 (95% CI: 0.7-72.6, P=0.09). Overall survival (OS) at 3 years was 40%. Overall aGVHD grade at salvage (hazard ratio (HR) grade I/II vs III/IV 0.18 (95% CI: 0.06-0.57), P=0.003) and achievement of CR (HR 0.12 (95% CI: 0.04-0.39), P=0.0004) were significant predictors of OS. MMF was overall well tolerated, with only two patients requiring discontinuation for myelosuppression. MMF shows activity in the salvage of steroid-refractory, grades I-II aGVHD.

5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation.

Relapse remains a leading cause for treatment failure after hematopoietic cell transplantation (HCT) in patients with intermediate- or high-risk myelodysplastic syndrome (MDS). To discern the impact of 5-azacitine treatment pretransplant on the risk for relapse after HCT, we analyzed the post transplant outcomes of all 54 consecutive patients with MDS or chronic myelomonocytic leukemia who received HCT from HLA-compatible donors according to pretransplant 5-azacitidine exposure. Thirty patients received a median of four (1-7) cycles of 5-azacitidine, and 24 patients did not receive 5-azacitidine before HCT. The 1-year estimates of overall survival, relapse-free survival and cumulative incidence of relapse were 47, 41 and 20%, for 5-azacitidine patients and 60, 51 and 32%, respectively, for non-5-azacytidine patients. These observations suggest that outcomes are similar in both groups with a trend toward decreased early relapse in patients receiving 5-azacitidine. 5-Azacitidine may be of value in stabilizing the disease, thereby allowing time for patients to reach transplant and does not appear to affect transplant outcomes.