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Background Letermovir (LTV) has reduced non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (allo-HCT) recipients by reducing the rate of clinically significant cytomegalovirus infections (CS-CMVi). The impact of LTV prophylaxis (PP) on other infections is unclear. We investigated the effects of LTV on human herpes virus 6 (HHV6) DNAemia in HCT recipients with or without CS-CMVi and studied the interaction of HHV6 DNAemia with CS-CMVi and its impact on NRM. Methods We performed a single center, retrospective cohort study from March 2016 to December 2018 of consecutive allo-HCT recipients who are CMV recipient seropositive (R+) with or without LTV prophylaxis. Baseline characteristics and infectious complications data were collected. Outcomes of interest was NRM at 100 days, 24 weeks and 48 weeks post allo-HCT. Univariate analysis was performed to identify risk factors for HHV6 reactivation within the first year including CS-CMVi and risk factors for NRM at 48 weeks post transplant. A logistic regression was performed to identify independent risk factors for HHV6 DNAemia and NRM at 48 weeks. Patients with relapse were excluded from NRM analysis. Results A total of 539 allo-HCT recipients were included in our analysis; 124 (23%) with and 415 (77%) without LTV PP. HHV6 DNAemia was identified in 111 (21%) allo-HCT recipients within the first year of transplant, where CS-CMVi occurred in 241 (45%) (table 1). Risk factors for HHV6 DNAemia included African American race, underlying ALL, Haploidentical or cord HCT, marrow or cord source of stem cells, use of Post-cyclophosphamide, and CS-CMVi. On multivariate analysis, CS-CMVi was the only independent predictor of HHV6 reactivation (Adjusted OR: 1.69) (table 1). Independent predictors of NRM on logistic regression included CS-CMVi (OR: 1.67, CI 95% 1.03-2.62), and age > 40 years (OR: 2.21, CI 95% 1.24-3.95), and matched related donor allo-HCT (OR: 0.36, CI 95% 0.18-0.70) as a protective factor (table 2). Conclusion HHV6 DNAemia is strongly associated with CS-CMVi, which is probably a reflection of poor T cell recovery post HCT such as Haploidentical or Cord blood HCT. Furthermore, CS-CMVi was associated with NRM whereas HHV6 DNAemia was not. Larger studies are needed to better elucidate this interaction. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Background The Coronavirus Disease 2019 (COVID-19) has significantly impacted cancer patients with some reported mortality as high as 25%. The Immunodeficiency Scoring Index (ISI) was developed as a prognostic tool in allogeneic hematopoietic cell transplant (allo-HCT) recipients with respiratory syncytial virus but also for other respiratory viruses to predict severe infections and mortality. The purpose of our study was to correlate the ISI in HCT recipients with COVID-19 and associated complications such as hospitalization, supplemental oxygen use, and mortality. Methods We performed a cohort study of HCT recipients of all ages with COVID-19 between March 2020 and October 2021. We included only patients who were diagnosed by a PCR-based assay. We excluded patients for whom an ISI score, as previously described, could not be calculated. Outcomes of interest included 60-day mortality, hospital and ICU admission due to COVID-19, and supplemental oxygen requirements. A univariate analysis using Fischer exact testing for nominal variables was performed. Results Out of the 219 HCT with COVID-19, 101 were excluded due to alternative methods of diagnosis (13), lack of laboratory values needed to calculate an ISI at time of COVID-19 diagnosis (79), or COVID-19 diagnosed prior to transplant (9). Out of the remaining 118 patients, the median age was 60 years (range 6-85), most were male (56%), Caucasian (57%), and had no smoking history (64%). Most patients had an alloHCT (66%) with matched related donor [MRD] (25%), or matched unrelated donor [MUD] (21%) (Table 1). Median time from transplant to COVID-19 was 615 days (range 2-5692), median ISI was 3 (range 0-11), and 92% of patients were unvaccinated prior to COVID-19 (Table 1). On univariate analysis, an ISI of moderate to high (score ≥3) was associated with COVID-19 related hospitalization [p=0.0147] and an ISI ≥ 4 was associated with 60-day all-cause (p=0.045) and COVID-19-related (p-0.019) mortality (Table 2). Table 1: Patient Characteristics Abbreviations: Hematopoietic Cell Transplant (HCT); Chronic Obstructive Pulmonary Disease (COPD); Chronic Kidney Disease (CKD); End-Stage Renal Disease (ESRD); Acute Lymphocytic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Lymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML) Myeloproliferative Disorder (MDS); Matched Related Donor (MRD); Matched Unrelated Donor (MUD); Mismatched Unrelated Donor (MMUD); Graft versus Host Disease (GvHD); Lower Respiratory Tract Infection (LRI); White Blood Cell (WBC); Absolute Neutrophil Count (ANC); Absolute Lymphocyte Count (ALC). Table 2: Univariate Analysis of Outcomes due to COVID-19 in HCT Recipients Abbreviations: Immunodeficiency Scoring Index (ISI); Hematopoietic Cell Transplant (HCT); Allogenic (Allo); Autologous (Auto); Lower Respiratory Infection (LRI); High-Flow Nasal Cannula (HFNC) Figure 1: Survival Curve (Kaplan-Meier Curve) Comparing Time to Death in Patients with an ISI Score of 4 or Greater. (Log-rank 0.0295) Conclusion An ISI of 4 or greater was a prognostic marker for worse outcomes such as COVID-related and all-cause mortality in HCT recipients. Whether an aggressive and prompt management of high-risk patients with COVID-19 may impact these outcomes needs to be determined in future studies. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Purpose/Objective(s) Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplant (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. We retrospectively examined the possible effect of RT on PBPC collection. Materials/Methods We reviewed the charts of 732 MM patients (pts) seen from 1997–2016 at our institution and included pts who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM RT) were reviewed to estimate the percentage (%) bone marrow (BM) treated using published estimates of skeletal BM distribution. Statistics were performed using Pearson correlations and t-tests. Results Of 732 MM pts, ASCT was planned for 485 pts; of these, 223 pts received RT prior to PBPC collection and were included in the final cohort. 133 pts (60%) were male. Median age at PBPC collection was 59 years (range 33—80). For SIT, pts received combination regimens including the following agents: bortezomib (142 pts, 64%); lenalidomide (111 pts, 50%); alkylators (46 pts, 21%). Nine pts (4%) received dexamethasone alone. RT plans and/or a description of the fields, were available to estimate treated BM% for 221 pts. The median cumulative BM% treated per pt was 6.7 (range 0.0—47.4). The median RT dose was 24 Gy (range 10.0—75.6 Gy). Mobilization was performed using granulocyte-colony stimulating factor (G-CSF) alone (189 pts, 85%), G-CSF with plerixafor (15 pts, 7%), or chemotherapy (19 pts, 8%). PBPC collection data was available for 199 pts. A median of 7.8 × 106 CD34+/kg PBPCs (range 0.5—54.8) were collected in a median of 3 (1—9) apheresis procedures. 196 pts (99%) collected more than 2.0 × 106 CD34+/kg (minimum PBPC no. required for engraftment), and 167 pts (84%) collected more than 5.0 × 106 CD34+/kg (preferred no. of PBPCs collected). The number of PBPCs collected was not associated with BM% treated (P = 0.15) or RT dose (P = 0.56). The number of apheresis procedures performed was not associated with BM% treated (P = 0.54) or RT dose (P = 0.85). The number of PBPCs collected did not differ significantly for pts receiving RT to the pelvis (P = 0.96), lumbar spine (P = 0.35), or thoracic spine (P = 0.059). Time to platelet engraftment was longer for patients with higher %BM treated (P = 0.02). Eleven pts did not undergo a confirmed ASCT due to: pt preference (3 pts), trial therapy (1 pt), comorbidities (1 pt), election for hospice (1 pt), inadequate collection (4 pts) and inadequate follow up (1 pt). Conclusion Among pts with MM, RT prior to ASCT did not prevent adequate PBPC collection or impair successful ASCT. RT must be carefully planned and delivered to ensure safe incorporation into pre-ASCT treatment regimens.

BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with a curative potential for myelodysplastic syndrome (MDS) patients. Allo-HSCT has substantial risks, particularly in the elderly, and its role for older MDS patients has yet to be defined. METHODS We analyzed 88 MDS patients aged ≥ 60 years with allo-HSCT after reduced intensity conditioning regimens over the last decade. The study cohort had high risk features; 47 of 88 (53.4%) patients were > 65 years of age, 24 (27%) patients had cytogenetic abnormalities consistent with monosomal karyotype (MKpos), 33 (38%) patients had histological subtype of RAEB-1 and RAEB-2 at diagnosis, and 45 (51%) patients had a hematopoietic cell transplantation–comorbidity index (HCT-CI) of ≥ 3. RESULTS The 3-year incidence of progression, transplant-related mortality (TRM), and overall survival (OS) were 26% (95% confidence interval [CI], 18%-37%), 35% (95% CI, 26%-47%), and 41% (95% CI, 30%-52%), respectively. MKpos was the only prognostic factor that increased the risk of disease progression compared with good-risk cytogenetics (hazard ratio [HR] = 9.5, P = .003) as well as MKneg (HR = 3.3, P = .01). For TRM, HCT-CI ≥ 3, but not age >65 years, was associated with worse outcomes (HR = 3.1, P = .007). Cytogenetics and HCT-CI enabled us to identify prognostic groups for OS. MKpos patients had the worst 3-year OS (17%), whereas patients with good-risk cytogenetics and HCT-CI

We hypothesized that IV Busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation (allo-HSCT). To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine (Flu) 40 mg/m2 once daily ×4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6,000 µM-min (N=111), stratified for remission-status, and allo-grafting from HLA-matched donors. Toxicity and graft vs. host disease (GvHD) rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease-control, leading to improved overall and progression-free survival, most prominently in MDS-patients and in AML-patients not in remission at allo-HSCT. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu-dosing. This could be considered an alternative to fixed dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Hematopoietic stem cell transplantation (SCT) can be curative for patients with severe aplastic anemia (SAA).1, 2 Concerns about graft failure and graft-versus-host disease (GVHD), more so for human leukocyte antigen (HLA) -mismatched donors, have impeded the utility of SCT for these patients. The introduction of post-SCT cyclophosphamide (PTCy) has been shown to decrease alloreactivity in the host-versus-graft and graft-versus-host directions and could be particularly well suited for SAA patients.3 Only a few patients in two recent reports have documented outcomes of patients with SAA treated with a haploidentical transplant and PTCy-based GVHD prophylaxis, both using non-myeloablative (NMA) conditioning with fludarabine, cyclophosphamide and 2 Gy total body irradiation (TBI).4, 5 Concern for higher rejection rate, both primary and secondary, has prompted us to use a more intense conditioning regimen, as previously described.6 Here, we report clinical outcomes in transfusion dependent (n=6, 5 were refractory to first line immunosuppressive therapy, one patient received hypomethylating agent for hypoplastic MDS subsequently diagnosed as AA) SAA patients who underwent HLA-mismatched bone marrow SCT from haploidentical (n=2) and 9/10 matched unrelated donors (n=4) at our center between January 2010 and May 2013. Conditioning regimen consisted of melphalan (140 mg/m2) on day-8, thiotepa (5 mg/kg) on day-7 and fludarabine (160 mg/m2) on days −6 to −3. GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4, tacrolimus for 180 days and mycophenolate mofetil for 100 days post transplant. Median age of patients at the time of SCT was 37 years (range 21–50), median Karnofsky performance score was 90 (range 80–100) and median time from diagnosis to transplant was 9 months (range 2–15 months). Of the six patients, two of them had a concomitant PNH clone>20% prior to SCT. All patients engrafted the donor cells with 100% chimerism noted for both myeloid and T-cell lineage at day +30 post SCT. Of the four-long-term survivors, 100% donor (lymphoid and myeloid) chimerism was noted starting from day 30 until 1 year post SCT in three patients and for up to 6 months for one patient (follow-up care was transferred to an outside institution and was found to be disease-free at 1 year post SCT). Median time to neutrophil and platelet engraftment was 16 and 13 days, respectively (Table 1). Acute GVHD was seen in three patients (grades-1, 2 and 4 each) and led to death in one patient who had a 9/10 MUD SCT (Table 1). No chronic GVHD (cGVHD) or disease relapse was noted. After a median follow-up of 949 days (range 735–1617), 4/6 (66.6%) patients (two haploidentical and two 9/10 MUD) were alive, fully engrafted without cGVHD.

Pretransplant chest computed tomography screening in asymptomatic patients with leukemia and myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with a curative potential for myelodysplastic syndrome (MDS) patients. Allo-HSCT has substantial risks, particularly in the elderly, and its role for older MDS patients has yet to be defined.We analyzed 88 MDS patients aged ≥ 60 years with allo-HSCT after reduced intensity conditioning regimens over the last decade. The study cohort had high risk features; 47 of 88 (53.4%) patients were 65 years of age, 24 (27%) patients had cytogenetic abnormalities consistent with monosomal karyotype (MKpos), 33 (38%) patients had histological subtype of RAEB-1 and RAEB-2 at diagnosis, and 45 (51%) patients had a hematopoietic cell transplantation-comorbidity index (HCT-CI) of ≥ 3.The 3-year incidence of progression, transplant-related mortality (TRM), and overall survival (OS) were 26% (95% confidence interval [CI], 18%-37%), 35% (95% CI, 26%-47%), and 41% (95% CI, 30%-52%), respectively. MKpos was the only prognostic factor that increased the risk of disease progression compared with good-risk cytogenetics (hazard ratio [HR] = 9.5, P = .003) as well as MKneg (HR = 3.3, P = .01). For TRM, HCT-CI ≥ 3, but not age65 years, was associated with worse outcomes (HR = 3.1, P = .007). Cytogenetics and HCT-CI enabled us to identify prognostic groups for OS. MKpos patients had the worst 3-year OS (17%), whereas patients with good-risk cytogenetics and HCT-CI 3 had the best OS (92%).Our results confirm that allo-HSCT can provide long-term survival in older MDS patients. Cytogenetics and HCT-CI identify prognostic risk groups and guide selection of older MDS patients who are candidates for allo-HSCT. Cancer 2017;123:2661-70. © 2017 American Cancer Society.

We found earlier that high-dose chemotherapy with Allo-SCT produced a tumor response in patients with chemorefractory metastatic breast cancer. In this study, we examined the efficacy and toxicity of nonmyeloablative allogeneic PBSC transplantation in patients with chemosensitive metastatic breast cancer. Twelve patients with metastatic breast carcinoma who had stable disease after standard-dose chemotherapy and six who had a partial response underwent allogeneic transplantation. The conditioning regimen consisted of reduced-intensity fludarabine and melphalan. All patients achieved engraftment and hematopoietic recovery. Nine patients developed grade II or higher acute GVHD; seven of these nine responded to immunosuppressive therapy. Fourteen patients developed chronic GVHD. The treatment-related mortality rate was 11%. With a median follow-up of 565 days, the median survival duration was 643 days and the median progression-free survival duration was 202 days. Two patients are alive with a complete response 1555 and 2526 days after SCT, and one patient is alive with progressive bone disease at day 1118. We conclude that among patients with chemotherapy-sensitive metastatic breast cancer, a fraction will achieve a durable complete response after SCT with a reduced-intensity conditioning regimen. The question remains how to improve the overall efficacy and reduce the mortality rate for this approach.

Our aim was to describe the incidence, clinical course, and risk factors for idiopathic pneumonia syndrome (IPS) after high-dose chemotherapy with cyclophosphamide, carmustine, and thiotepa followed by autologous stem cell transplantation for high-risk breast cancer. Charts for patients who underwent high-dose chemotherapy for high-risk breast cancer at a single center from 1992 to 2000 were retrospectively reviewed, and potential risk factors for development of IPS were sought with the log-rank test. Of 164 patients reviewed, 20 developed IPS at a median onset of 87 days after the transplant (range, 2-257 days). The actuarial incidence of IPS in the first 100 days after the transplant was 8%, and 95% of patients developed symptoms within the first 6 months after transplant. Patient age, smoking status, breast cancer stage at diagnosis, and pretransplant lung function did not predict development of IPS. Three patients died of progressive pulmonary failure and the IPS resolved in the other 17. We concluded that IPS is an important cause of morbidity and mortality in patients with high-risk breast cancer undergoing high-dose chemotherapy. Given the absence of predictive factors, any pulmonary symptoms appearing in the first year after the transplant should be evaluated carefully.

We retrospectively analyzed the effect of maintenance endocrine therapy (MET) after high-dose chemotherapy with hematopoietic progenitor cell transplant (HDCT) on the progression-free survival (PFS) of patients with hormone-dependent metastatic breast cancer (MBC). One hundred and nine consecutive patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive MBC, who were progression free for at least 4 months after HDCT with cyclophosphamide, carmustine and thiotepa (CBT), were analyzed. Of these, 55 were non-randomly submitted to MET. After a median follow-up of 34.4 months (17.1-91.0), univariate analysis showed that MET was significantly associated with improved median PFS (31.1 vs 19.2 months, P = 0.022). Complete response to HDCT, pattern of metastatic spread, extent of the disease, single vs multiple metastatic sites, prior endocrine therapy for metastatic disease and prior exposure to any hormonal therapy (adjuvant and/or for the advanced disease) were also associated with PFS at univariate analysis. A multivariate Cox proportional hazard model was fitted to the data in order to correct the effect of MET for the other significant covariates. After correcting for these covariates, MET was still significant, predicting improved PFS (hazard ratio (HR) 0.580, 95% CI; 0.362-0.931). Administration of MET after optimal cytoreduction might result in increased efficacy of HDCT in hormone-dependent metastatic breast cancer.

With improving expertise and supportive care, cord blood (CB) transplants are now associated with outcomes comparable to unrelated and sibling donor transplants.1 There is a need to increase the size and diversity of international CB inventories and to retain cryopreserved CB units for as long as safely possible. There are in vitro data supporting >90% recovery of hematopoietic progenitor cells from frozen CB cells stored for up to 12 years,2 and data showing that progenitor cell recoveries from short-term freeze samples ranging from 2 to 8 weeks are comparable to those cryopreserved for 10–15 years.3,4 Broxmeyer et al.5 reported adequate recovery (80–100%) of granulocyte–macrophage and multi-potential hematopoietic progenitors from functional CB units cryopreserved for up to 23.5 years as well as recovery of viable progenitor cells from CBs frozen for 15 years, which were able to generate CD45+ human cell engraftment when infused into sublethally irradiated NOD-SCID mice and were comparable to that reported with fresh CB.6 Despite this in vitro evidence, transplant physicians still remain concerned about the possible loss of integrity of frozen CB units associated with longer durations of storage.7 In one report, the incidence of bag breaks over a 6.5-year period was 3.5%, where 75% of the breaches occurred in units that had been cryopreserved for >2 years.7 Therefore, it is important to determine whether prolonged time of cryopreservation and storage may adversely affect clinical transplant outcomes, and with the new US Food and Drug Administration licensing regulations for CB units this question has become even more relevant: ‘is there an expiration date for CB unit in storage?’.

Abstract 4569 Background: Allogeneic hematopoietic cell transplantation (allo HCT) is a potentially curative therapy for multiple myeloma (MM), but has high treatment-mortality (TRM). In addition, disease relapse occurs in a significant number of patients. We sought to evaluate if the recent advances in the field of HCT and MM have impacted the results of allo HCT for MM. We present the results of allo HCT performed at a single center over last 25 years. Methods: 149 patients with MM who underwent allo HCT between 11/1985 and 6/2010 using myeloablative (MA) N= 52, or reduced intensity conditioning (RIC) N=97 at our institution were retrospectively analyzed. Results: Patient characteristics and pertinent outcomes are summarized in the Table. 62 (42%) were female. Median age was 50 (28-70) years. Median follow up is 2.4 years [11.3 years for the patients who received allo HCT prior to year 2000( Conclusion: Allo HCT for MM can offer long term disease control in a subset of MM patients. TRM has declined and outcomes have significantly improved over the last decade. Maintenance therapy may have a role post allo HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Qazilbash:Celgene: Speakers Bureau.

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P = 0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with

The role of high-dose chemotherapy (HDCT) in patients with refractory breast cancer is not well established. Forty-two female patients (median age of 46 years) with breast cancer refractory to neoadjuvant chemotherapy received HDCT (cyclophosphamide, carmustine and thiotepa) supported by an autologous peripheral blood stem cells transplant. Their disease had been refractory (defined as less than partial response) to one (18 patients) or two (24 patients) regimens of neoadjuvant chemotherapy. Twenty-nine patients had surgery before HDCT. The best response after surgery, HDCT, and radiation therapy was assessed 60 days after transplantation. Thirty patients had complete remission, eight had a PR, one had a minor response, and three had progressive disease. In seven of 13 patients whose disease was inoperable before HDCT, it became operable. After a median follow-up of 42 months, 21 patients were alive, and 15 remained disease free. Five-year overall survival (OS) was 57% (CI, 50-64%), and the estimated 5-year progression-free survival was 40% (CI, 32-48%). Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable. A randomized study is warranted in this patient population.

PURPOSE To evaluate the feasibility of allogeneic peripheral-blood progenitor-cell (PBPC) transplantation and to assess graft-versus-tumor effects in patients with metastatic breast cancer. PATIENTS AND METHODS Ten patients with metastatic breast cancer that involved the liver or bone marrow were treated with high-dose chemotherapy and allogeneic PBPC transplantation. The median age was 42 years (range, 29 to 55). The median number of metastatic sites was three (range, one to five). The conditioning regimen was cyclophosphamide (6,000 mg/m2), carmustine (BCNU; 450 mg/m2), and thiotepa (720 mg/m2) (CBT regimen). Patients received graft-versus-host disease (GVHD) prophylaxis using cyclosporine- or tacrolimus-based regimens. RESULTS All patients had engraftment and hematologic recovery. Three patients developed grade > or = 2 acute GVHD and four patients had chronic GVHD. After transplantation, one patient was in complete remission (CR), five achieved a partial remission (PR), and four had stable disease (SD). In two patients, metastatic liver lesions regressed in association with skin GVHD after withdrawal of immunosuppressive therapies. The median follow-up time was 408 days (range, 53 to 605). The median progression-free survival duration was 238 days (range, 53 to 510). CONCLUSION We conclude that allogeneic PBPC transplantation is a feasible procedure for patients with poor-risk metastatic breast cancer. The regression of tumor associated with GVHD provides suggestive clinical evidence that graft-versus-tumor effects may occur against breast cancer. Compared with autologous transplantation, allogeneic PBPC transplantation is associated with the additional risks of GVHD and related infections. Allogeneic transplantation should only be performed in the context of clinical trials and its ultimate role requires demonstration of improved progression-free survival.

PURPOSE To examine the feasibility of escalating carboplatin area under the concentration-time curve (AUC), using dose predictions based on individual estimates of drug clearance, in a phase I trial of multicycle carboplatin, paclitaxel, and cyclophosphamide chemotherapy with peripheral-blood stem-cell (PBSC) replacement. PATIENTS AND METHODS Forty-four patients (37 breast, seven ovarian) received 165 courses. Initial target carboplatin AUC was 10 mg/ml x min, with interpatient escalation in increments of 25%. Initial carboplatin dose estimates used creatinine clearance (CrCl) to estimate carboplatin clearance. Subsequent clearance and dose estimates were determined using a model incorporating Bayesian estimation and two measured carboplatin plasma ultrafiltrate concentrations. RESULTS Median clearance was 80.5 mL/min/m2 (range, 41.6 to 131.8). Carboplatin doses up to 2,440 mg/m2 per course were administered without major extramedullary toxicity. Doses varied 2.6-fold at each exposure level. Using the Bayesian model, AUC was predicted with a mean accuracy of 101.2% (83% using CrCl). Ninety-six of 117 courses were within 25% of the target AUC. This model was less biased (0.15 v -2.35 mg/mL x min) and more precise (2.76 v 3.52) in predicting AUC compared with one using CrCl. Hematologic recovery was not prolonged with increasing exposure. The carboplatin maximum-tolerated systemic exposure (MTSE) was 13.3 mg/mL x min (level five). The dose-limiting toxicity was cardiac toxicity, which occurred at dose levels six and seven. CONCLUSION Results demonstrate that (1) CrCl is a poor estimator of carboplatin clearance in this population, and (2) the use of a model incorporating limited sampling and Bayesian estimation improves the precision of carboplatin clearance estimation and is suitable for targeting carboplatin exposure in an ambulatory setting.

6608 Background: Outcomes of pts with APL have dramatically improved, especially with availability of all-trans retinoic acid (ATRA), arsenic trioxide, and better supportive care. However, a small but significant number of pts relapse despite optimal upfront therapy. Methods: We reviewed pts with APL treated at our institution (1980-2010). Outcome of pts who received autologous (auto) or allogeneic (allo) HCT for relapsed disease was compared with those who did not. Results: We identified 42 pts with relapsed/refractory APL. 25 (60%) pts received auto (8) or allo HCT (17: related 5, unrelated 12). Median (med) age of pts receiving HCT: 29 years (range 6-61). RT-PCR was negative for PML/RARα at time of HCT in 6 of 6 evaluable auto pts and in 6 of 8 evaluable allo pts. Of the 8 auto pts, 5 were in CR2 and 3 in ≥ CR3. Preparative (prep) regimen: Busulfan (Bu) + Cyclophosphamide (CY) in 7 pts and Bu + Fludarabine (Flu) in 1 pt. Of the 17 allo pts, 12 were in CR2 and 5 in ≥CR3. Prep regimens for allo HCT: Bu +...

Abstract 4576 Introduction: High dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) for multiple myeloma (MM) has shown improved survival compared to conventional chemotherapy. However, the larger clinical trials evaluating the role of auto HCT in MM have included patients who are generally younger than 65 years. Here we report the results of MM patients, age ≥70 years, who received auto HCT at our institution. Methods: We retrospectively analyzed 84 patients, who underwent auto HCT between January 1999 and June 2010 at MDACC. Conditioning regimen was Melphalan 140 mg/m2 (MEL 140) (N=9), 180 mg/m2 (MEL 180) (N=20), and 200 mg/m2 (MEL 200) (N=55). Disease response was assessed at day 100 post transplant. Results: Pertinent patient and disease characteristics are summarized in the Table. Median age at transplant was 72 (70-80) years. Median number of prior treatments was 1 (range: 1–8). Median time from diagnosis to transplant was 8.5 (2.4-151) months. No patient was in CR prior to auto HCT. Median CD34+ cell count and TNC was 4.56 (0.72-11.1) × 106/kg and 10.53 (2.25-57) ×108/kg, respectively. Median follow up is 2 (0.1-7.3) years. Grade III-IV organ toxicity was seen in 35 (51%) patients. Grade III-IV toxicity in patients who received MEL 140, MEL 180, and MEL 200 was 25%, 45%, and 44%, respectively (p value > 0.05). Non-relapse mortality (NRM) at 100 days was 2%. Two patients died in first 100 days. Disease response in evaluable patients (N=79) at day 100 was: CR=15 (19%); VGPR=7 (9%); PR=41 (52%); and SD=10 (13%). Median progression free survival (PFS) and overall survival (OS) from auto HCT was 2.1 years (95% CI 1.78–3.69) and 5.6 years (95% CI 5.51-NA), respectively. 2-year PFS and OS were 56% (95% CI 0.44–0.71) and 80% (95% CI 0.7–0.91), respectively. There was no difference in NRM, PFS, or OS in different MEL groups. Similarly there was no difference in TRM, PFS, and OS in patients ≥ 75 years compared to the patients < 75 years. Conclusion: Auto HCT in myeloma patients age ≥ 70 years is safe and feasible. Toxicity, NRM, response and survival were comparable to younger myeloma patients. The age alone should not be a contraindication for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

6532 Background: The benefit of allogeneic HCT in patients with AML in CR1 is frequently offset by excessive transplant related mortality (TRM), which can deny the benefit of the graft-versus-leukemia effect. Conversely, decreasing TRM while preserving antileukemic activity can have marked impact on outcomes. Methods: We transplanted 44 patients in CR1 using the conditioning regimen of IV busulfan (Bu)130 mg/m2 (day-6 to -3), fludarabine (Flu) 40 mg/m2 (day-6 to -3) and antithymocyte globulin (4.0 mg/kg). Graft-versus-host-disease (GVHD) prophylaxis consisted of mini-MTX and tacrolimus, with (n=14) or without pentostatin (n=30). High-resolution allele level HLA typing was performed for all donors/recipients (HLA-A, B, C, DRB1, DQB1 and DPB1). Eligibility: age

6539 Background: Disease relapse is a major cause of treatment failure after allogeneic HCT for AML and MDS. Therapeutic options after relapse are limited and the prognosis remains dismal. Methods: We analyzed 245 patients who received allogeneic HCT for MDS/AML using the conditioning regimen of fludarabine 40 mg/m2 and busulfan 130 mg/m2 for four days, between April 2001 and June 2008: 88 patients recurred. Results: Median age was 45 (range:18-66) years. Diagnosis was AML (n=72; 82%) or MDS (n=16; 18%). Donors were related (n=56) or unrelated (n=32). Relapse treatment: 21% (N=18) received supportive care only while 76% (N=67) received salvage (3 patients were lost to follow-up). Median complete remission (CR) duration after first HCT for the recurred group was 4 months; 67% of the patients relapsing 4 months (p=0.02). Salvage included: chemotherapy only (N=31), donor lymphocyte infusion (DLI) with or without chemotherapy (N=11), o...

The use of CB for stem cell transplantation is increasing. A major disadvantage of CB is delayed and failed engraftment when compared to marrow or blood transplantation. Double CBT and ex-vivo expansion are both strategies being investigated in order to improve hematopoietic reconstitution. We compared these approaches with the aim of improving the clinical outcomes of CBT patients. 48 patients were randomized to receive either two unmanipulated (UNM) CB units (N=24) or one UNM unit and one unit from which all the cells were EXP ex-vivo (N=24). Most CB units were HLA 4/6 matches. Diagnoses were AML (N=16), ALL(N=13), NHL(N= 5), HD(N=7), CML (N=5), and CLL(N=2). Patients (Table 1) were heavily pre-treated, with a median of 3 (1–8) prior regimens including autotransplants in 18%. Preparative regimens included ATG and either fludara plus dose-adjusted busulfan(N=13; myeloid diseases), or melphalan and thiotepa (N=21; lymphoid malignancies/HD); patients not eligible for high-dose therapy received non-myeloablative fludara plus cyclophosphamide and 200 GyTBI (=11) or melphalan(n=3). GVHD prophylaxis was tacrolimus plus either 3 doses of 5 mg/m2 methotrexate or MMF (table 1). Ex-vivo expansion: the smallest unit was CD133-selected using the CliniMACS device (day -14). The T cell-containing CD133-negative fraction was frozen. The CD133+ fraction was cultured for 14 days in media containing SCF, G-CSF and TPO. On day 0, the 2nd UNM unit was infused, followed by the CD133-negative and the EXP fractions. Results. Infused median total nucleated cells (TNC)×108/Kg was 0.36 and 0.36, and median CD34×106/Kg was 0.16 and 0.13, respectively for EXP and UNM pts. Median TNC fold-expansion was 26 (0.44–275) and for CD34+ cells, 2.2 (0–18). There was a nonsignificant trend to more rapid engraftment in patients receiving EXP cells. Patients with >50-fold versus 20K/ul at a median of 29 days(17–44) versus 42(29–56). 25 patients are alive [median follow up is 11.1 mo (2–33.6)]. 100-day and 1-year non-relapse mortality rates are 10% and 22%, respectively (table 2). Chimerism showed that 1 CB unit dominated in all patients. Among 19 evaluable EXP patients, in 63% the UNM unit provided 100% of the hematopoiesis from day +30; the EXP unit was predominant in 3 cases (for 12, 2 and 2 mo.) and present but not predominant in 4 (5–25%, for 12, 7, 3 and 3 mo). Conclusion: EXP CBT was safe. The range of fold-expansion was highly variable. Accrual continues focusing on strategies which improve CB expansion. Outcomes Expanded Unmanipulated P C.Incid.: cumulative incidence Time to ANC500 (median/95%CI) 20 days (15, 31) 23.5 (21, 34) 0.4 Proportion engrafting ANC500 82% (n=19) 79% (n=19) 1 Time to PLT20K (median/95%CI) 41 (32, NA) 54 (40, NA) 0.4 Proportion engrafting PLT 67% (n=16) 58% (n=14) 0.38 1-year survival 60% 40% 0.45 aGVHD gd II–IV/ III–IV 32% / 5% 41% / 9% NS C.Incid. cGVHD 47% (28–78) 31% (15–65) NS Expanded Unmanipulated P Complete remission at UCBT 42% 67% 0.15 Median weight 82 (20-113) 76 (51-144) 0.6 Median age 40.4 (4-66) 38.1 (9-65) 0.8 Ablative preparative regimen 67% 75% 0.8 GVHD prophylaxis with methotrexate 48% 48% NS

569 Background: The skeleton is the most common and sometimes the only site of metastatic disease in breast cancer. We tested the feasibility of using 166Ho-DOTMP, which localizes to bone surfaces to deliver targeted high-dose radiation to bone metastases and the adjacent marrow. Patients received autologous stem cell infusions to restore hematopoiesis. Methods: Six women < 65 years old with breast cancer and bone-only disease participated in the study. They had received a median of 2.5 prior chemotherapy or hormonal treatment regimens. Five patients had stable disease and one patient had progressive disease before the high-dose radiation. A 30-mCi test dose of 166Ho-DOTMP was given to assess skeletal uptake; if uptake was adequate, a therapeutic dose estimated to deliver 22 Gy (n=3) or 28 Gy (n=3) was prescribed. Treatment was followed by autologous stem cell transplantation when the ongoing radiation dose to the marrow was < 1 cGy/hour. Results: 870–2065 mCi 166Ho-DOTMP dose was administered.? All subje...

568 Background: The lack of accurate criteria for assessing the response of bone metastases from breast cancer has led to bone disease being considered unmeasurable. Criteria from the UICC and the WHO based on radiography (XR) and skeletal scintigraphy (SS) are not satisfactory for clinical use. Criteria for computed tomography (CT) and magnetic resonance imaging (MR) have yet to be validated. We recently proposed a set of CT- and MR-inclusive criteria (MDA) to assess bone response (JCO 22:2942, 2004). Here we retrospectively reviewed image sets to evaluate the accuracy of MDA criteria (vs UICC, WHO) and the accuracy of each imaging modality for assessing bone response. Methods: XR, SS, CT, and MR images from patients with breast cancer and bone-only metastases were reviewed by musculoskeletal radiologists at baseline and after treatment (early: 2–6 mo, late: 11–13 mo). Responses were characterized as complete or partial, or stable or progressive disease (CR, PR, SD or PD) according to the 3 sets of crite...

6664 Background: We found that patients with MBC who had a > 50% reduction in Swenerton score after induction standard-dose chemotherapy (SDC) had higher rates of complete response (CR) conversion and survival after HDC/AHST than those with ≤ 50% reduction (Biol Blood Marrow Transplant. 9:330, 2003), with disease progression the major cause of failure. We studied the effect of ex vivo IL-2 activation of peripheral blood progenitor cells (PBPCs) and IL-2 maintenance therapy after AHST for poor-risk MBC. Methods: Patients with MBC with < CR to SDC were assigned to 4 days' G-CSF for PBPC mobilization (Grp 1) or 8 days' IL-2 (1.8 mIU/day s.c.) plus 4 days' G-CSF (Grp 2). HDC was cyclophosphamide (2.0 g/m2), carmustine (150 mg/m2), and thiotepa (240 mg/m2) i.v. daily from day –7 to –5. PBPCs were treated ex vivo with IL-2 (6000 IU/ml) for 24 hours and reinfused on day 0. Patients were given low-dose IL-2 (0.3 mIU/m2/day s.c.) from day 1 x 21 days, followed by 4 days' rest, then intermediate-dose IL-2 (1 mIU/m2...

We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively (P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P

Risk stratification is important to identify patients with acute myelogenous leukemia (AML) who might benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission. We retrospectively studied 150 patients with AML and diagnostic cytogenetic abnormalities who underwent myeloablative allo-HSCT while in first complete remission to evaluate the prognostic impact of persistent cytogenetic abnormalities at allo-HSCT. Three risk groups were identified. Patients with favorable/intermediate cytogenetics at diagnosis (n = 49) and patients with unfavorable cytogenetics at diagnosis but without a persistent abnormal clone at allo-HSCT (n = 83) had a similar 3-year leukemia-free survival of 58%-60% despite the higher 3-year relapse incidence (RI) in the latter group (32.3%, versus 16.8% in the former group). A third group of patients with unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT (n = 15) had the worst prognosis, with a 3-year RI of 57.5% and 3-year leukemia-free survival of only 29.2%. These data suggest that patients with AML and unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT are at high risk for relapse after allo-HSCT. These patients should be considered for clinical trials designed to optimize conditioning regimens and/or to use preemptive strategies in the posttransplantion setting aimed at decreasing RI.