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Due to the curative potential and improvement in progression-free survival (PFS), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered the standard of care for several hematologic malignancies, such as multiple myeloma, and lymphomas. ASCT typically involves support with blood product transfusion. Thus, difficulties arise when Jehovah’s Witness patients refuse blood transfusions. In order to demonstrate the safety of performing “bloodless” ASCT (BL-ASCT), we performed a retrospective analysis of 66 Jehovah's Witnesses patients who underwent BL-ASCT and 1114 non-Jehovah’s Witness patients who underwent transfusion-supported ASCT (TF-ASCT) at Cedars-Sinai Medical Center between January 2000 and September 2018. Survival was compared between the two groups. Transplant-related complications, mortality, engraftment time, length of hospital stay, and number of ICU transfers were characterized for the BL-ASCT group. One year survival was found to be 87.9% for both groups (P = 0.92). In the BL-ASCT group, there was one death prior to the 30 days post transplant due to CNS hemorrhage, and one death prior to 100 days due to sepsis. Based on our data, BL-ASCT can be safely performed with appropriate supportive measures, and we encourage community oncologists to promptly refer JW patients for transplant evaluation when ASCT is indicated.

The rapid evolution of blood and marrow transplantation (BMT), coupled with diverse outcomes associated with heterogeneous groups of patients, led to the formation of 2 important organizations early in the development of the field: the Center for International Blood and Marrow Transplant Research (CIBMTR) and the Foundation for the Accreditation of Cellular Therapy (FACT). These organizations have addressed 2 of the 9 elements identified by the National Quality Strategy (NQS) for achieving better health care, more affordable care, and healthy people and communities: a registry that promotes improvement of care and accreditation based on quality standards. More recently, a federally mandated database in the United States addresses the third element of the NQS: public reporting of treatment results. Here we describe the current process by which FACT incorporates patient outcomes reported by the CIBMTR into standards for accreditation, the requirements for accredited programs with performance below expected outcomes to maintain accreditation, and preliminary findings of an assessment of corrective action plans intended to improve outcomes.

Patient-centered medical home models are fundamental to the advanced alternative payment models defined in the Medicare Access and Children's Health Insurance Plan Reauthorization Act (MACRA). The patient-centered medical home is a model of healthcare delivery supported by alternative payment mechanisms and designed to promote coordinated medical care that is simultaneously patient-centric and population-oriented. This transformative care model requires shifting reimbursement to include a per-patient payment intended to cover services not previously reimbursed such as disease management over time. Payment is linked to quality measures, including proportion of care delivered according to predefined pathways and demonstrated impact on outcomes. Some medical homes also include opportunities for shared savings by reducing overall costs of care. Recent proposals have suggested expanding the medical home model to specialized populations with complex needs because primary care teams may not have the facilities or the requisite expertise for their unique needs. An example of a successful care model that may provide valuable lessons for those creating specialty medical home models already exists in many hematopoietic cell transplantation (HCT) centers that deliver multidisciplinary, coordinated, and highly specialized care. The integration of care delivery in HCT centers has been driven by the specialty care their patients require and by the payment methodology preferred by the commercial payers, which has included bundling of both inpatient and outpatient care in the peritransplant interval. Commercial payers identify qualified HCT centers based on accreditation status and comparative performance, enabled in part by center-level comparative performance data available within a national outcomes database mandated by the Stem Cell Therapeutic and Research Act of 2005. Standardization across centers has been facilitated via voluntary accreditation implemented by Foundation for the Accreditation of Cell Therapy. Payers have built on these community-established programs and use public outcomes and program accreditation as standards necessary for inclusion in specialty care networks and contracts. Although HCT centers have not been described as medical homes, most HCT providers have already developed the structures that address critical requirements of MACRA for medical homes.

Introduction: Inflammatory breast cancer (IBC) is a rare aggressive form of breast cancer. It is well known that the long-term survival and progression-free survival of IBC are worse than that of non-IBC. We report the long term outcomes of patients with IBC and non-IBC who had undergone high-dose chemotherapy (HDC) with autologous hematopoietic cell transplantation (AHCT). Methods: All 3387 patients with IBC or non-IBC who underwent HDC with AHCT between1990-2002 and registered with CIBMTR were included in this analysis. Transplant-related mortality (TRM), disease relapse/progression, progression-free survival (PFS) and overall survival (OS) were compared between the two cohorts. Multivariate Cox regression model was used to determine the independent impact of stage on outcomes. Results: 527 patients with IBC and 2,860 patients with non-IBC were included; the median age at transplantation (47 vs 46 years old) and median follow-up period in the 2 groups (167 vs 168 months) were similar. The most common conditioning regimen was cyclophosphamide and carboplatin based in both groups (54% in IBC and 50% in non-IBC). AHCT was well tolerated in both groups. TRM was similar in both groups (one year TRM was 2% for IBC and 3% for non-IBC, p=0.16). The most common cause of death was disease progression or relapse (81% in IBC and 75% in non-IBC). The median survival for both IBC and non-IBC was the same at 40 months. The PFS at 10 years was 27% (95% CI: 23-31%) for IBC and 24% (95% CI: 22-26%) for non-IBC (p=0.21), and the OS at 10 years was 31% (95% CI: 27-35%) for IBC and 28% (95% CI: 26-30%) for non-IBC (p=0.16). In univariate analysis, patients with stage III IBC and no active diseases at transplantation had lower PFS and OS than that in non-IBC. In multivariate analysis, controlling for age, disease status at AHCT, hormonal receptor status, time from diagnosis to AHCT, and performance status at AHCT, patients with stage III IBC had higher mortality (HR 1.16, 95% CI: 1-1.34, p= 0.0459), worse PFS (HR: 1.17, 95% CI: 1.01-1.36, p= 0.0339) and higher risk of disease relapse/progression (HR: 1.24, 95% CI: 1.06-1.45, p= 0.0082) as compared to stage III non-IBC. Amongst all patients a higher stage disease was associated with worse PFS, OS and disease relapse/progression. Conclusions: Long-term outcomes of stage III IBC patients who underwent AHCT were poorer than that in non-IBC patients confirming that the poor prognosis of IBC even in the setting of HDC with AHCT.

Aim: Patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) may experience oral complications associated with chronic graft-versus-host disease (cGVHD). These complications may significantly affect quality of life, even many years post-HSCT. Current treatment options for oral cGVHD are limited and often include steroid or other immunomodulatory medications, which may not adequately control the oral condition. A non-immunosuppressive intervention for symptomatic relief in oral cGVHD would thus be a welcome addition to the treatment paradigm. Materials and methods: We report seven cases of oral cGVHD that were treated with photobiomodulation therapy (PBM), previously known as low-level laser therapy (LLLT). Patients underwent at least two PBM treatments per week in addition to local treatment with steroids, and if on systemic therapies, these were either unchanged or dosage was reduced during the period of PBM therapy. Follow-up data is presented for 4 weeks of treatment. Results: Oral pain, sensitivity, and dry mouth improved in most patients. These findings suggest PBM therapy may represent an additional approach for management of oral cGVHD, and suggest that controlled studies should be conducted to confirm the efficacy and safety of PBM therapy in oral cGVHD and to determine optimal PBM therapy protocols.

Oral mucormycosis is a rare and high risk of infection in patients following hematopoietic cell transplantation few cases in the literature. We review the literature and present an additional case to emphasize the subtle changes that resulted in positive outcome when diagnosed and managed in a comprehensive transplant team.A patient was diagnosed with gingival mucormycosis on day +25 following a hematopoietic stem cell transplant for lymphoblastic transformation of chronic myeloid leukemia. The patient was diagnosed with minor and nonspecific symptoms and was successfully treated with local dental extraction, a short course of liposomal amphotericin B and 4 months of oral posaconazole.The good outcome of this case highlights the subtle clinical changes that present early in mucormycosis and the importance of early detection and treatment of post-transplant oral infections by an experienced multidisciplinary team.

Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee–assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.

Topic Significance & Study Purpose/Background/Rationale Patients being considered for allogeneic Blood and Marrow Transplant (Allo-BMT) undergo rigorous evaluations of which can influence Allo-BMT plan and outcomes. The goal of this project was to improve the patient selection process prior to admission for Allo-BMT. The process was modeled after the Universal Protocol (UP) used prior to surgery. UP is a National Patient Safety Goal, supported by Joint Commission, Institute of Medicine, and World Health Organization. Our center aimed to standardize the approach to determine patient suitability and treatment plan with the goal of improving 1-year survival. A UP approach was employed prior to BMT to secure consensus on patient suitability and treatment plan. Methods, Intervention, & Analysis A 1-page comprehensive BMT-Time Out (BMT-TO) checklist was created with critical domains selected to provide programmatic workflow (Figure 1). All Allo-BMT recipients underwent systematic BMT-TO reviews through progressive handoffs beginning July 2016. Checklists were audited monthly for completeness and adherence to standard operating procedures. Blood Marrow Transplant Information Patient System ("bmTIPS™") generated Allogeneic Transplant Intake Dashboard (ATID) reports, providing real-time numerical data on intake distribution patterns (Figure 2). The 2017 Allo-BMT 1-year survival data reported by Center for Blood and Marrow Transplant Research(CIBMTR) were used to set confidence levels and forecast CY18,19 projected 1-year survivals. Findings & Interpretation ATID for calendar years (CY)13,14, and 15, showed acceptance rates at presentation of 92%(n=98), 94%(n=105), and 77%(n=89), respectively. ATID for CY16, 17, 18 after implementation of BMT-TO showed lower acceptance rates: 83%(n=89), 86%(n=92), 85%(n=72), respectively. CIBMTR results showed improvement in our center's Allo-BMT 1-year survival rates with use of BMT-TO checklist (Figure 3): CY14(64%/reported); CY15=64%(n=45/reported); CY16=78%(n=28/reported); CY17=89%(n=37/predicted). Discussion & Implications Implementation of systematic review of patient selection-suitability data and BMT treatment plans using structured BMT-TO checklist before Allo-BMT, correlated with improved allogeneic 1-year survivals. Further evaluation and validation of the BMT-TO form is warranted.

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.

Relapse acute lymphoblastic leukemia (ALL) is the leading cause of childhood cancer deaths. Although relapse usually occurs in the bone marrow (medullary), extramedullary relapse occasionally occurs. Currently, the clonal origin and evolution of extramedullary relapse remain elusive. We selected two pediatric B-ALL patients who experienced testicular ALL relapse and interrogated their leukemic cells (diagnosis, remission, bone marrow relapse and testicular relapse) with whole exome sequencing. Case D483 (5.6 years old at diagnosis of ALL) developed bone marrow and testicular relapse 5 years after diagnosis of B-ALL. At diagnosis he was treated as an intermediate risk with hyperdiploid-ALL with the absence of any well-known ALL fusion-oncogene. Mutations of KRAS (G12D) and CREBBP (S1436C) were found in the founding leukemic clone at diagnosis and persisted in the bone marrow and testis at relapse). Mutation of CREBBP has been frequently found in ALL (particularly in hyperdiploid subtype) and is correlated with increased incidence of relapsed ALL. A MEF2B mutation (R17Q) was found in the bone marrow and testicular relapse sample. Missense mutation of this gene is frequently found in diffuse large B cell lymphoma (DLBCL); this protein regulates the expression of the proto-oncogene BCL6 and contributes to malignant transformation. Second child, case D727 (1.3 years old at diagnosis) harbored a MLL-AF9 fusion and was assigned as a high risk-ALL at diagnosis. Two NT5C2 mutations occurred at relapse, being present at different VAF in bone marrow and testicle: missense mutation R367Q was present with a VAF of 33.5% in bone marrow and 4.5% in testicle; while D407V was present with a VAF of 6.5% in bone marrow and 35.5% in the testicular relapse. NT5C2 encodes a 5'-nucleotidase involved in purine metabolism. The missense mutations (R367Q and D407V) identified here, have been reported as recurrent mutational hotspots of NT5C2 in relapse ALL and have been functionally validated. These mutations increase the 5'-IMP nucleotidase activity of NT5C2 protein leading to resistance to 6-mercaptopurine, a drug that was a component of the treatment regime of this patient. To understand the evolutionary trajectories of these two ALL cases, we analyzed clonal evolution based on their sequencing data. In patient D483, the relapse leukemia was directly evolved from the diagnosis leukemia clone: all of the mutations at diagnosis were persisted at relapse, and four mutated genes (MEF2B, KCNG1, AIM1, OTUD5) were acquired at both bone marrow and testicular relapse with different variant allele frequency (VAF). In patient D727, however, a faction of mutations present at diagnosis were subsequently lost at relapse, suggesting that relapsed leukemia arose from an ancestral subclone that developed before the overt leukemia at diagnosis. The mutational pattern and VAF cluster analysis results suggest that relapse in the patients' testicle represents an independently subclones from the relapse in their bone marrows. Taken together, our sequencing results suggest that relapse of patient D483 was directly evolved from the diagnosis leukemic clone; while the relapse leukemia cells (both bone marrow and testicle) of patient D727 was likely derived from a common ancestral clone, and the testicular relapse arose independently from the bone marrow relapse leukemia. Disclosures Lill: Sanofi: Speakers Bureau; California Cord Blood Services: Consultancy; Kite: Research Funding.

Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing4 × 10(6) CD34(+)/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34(+) dose6 × 10(6) CD34(+)/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses4 × 10(6) CD34(+)/kg and6 × 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.

Objectives We sought to investigate the magnitude and clinical importance of thrombocytopenia post transcatheter aortic valve replacement (TAVR). Background Thrombocytopenia has been observed after TAVR but has not been well studied. Methods Major thrombocytopenia (platelet count

Introduction: Adult T-cell Leukemia-Lymphoma (ATL) is a rare malignancy of T-cells infected with HTLV-1 and has the worst prognosis of the T-cell lymphomas. CC chemokine receptor 4 (CCR4) is overexpressed on ATL cells (>90% of ATL patients [pts]). Mogamulizumab (Moga) is a monoclonal antibody directed against CCR4 that has been approved in Japan for the treatment of CCR4+ ATL. There is no standard or effective treatment for relapsed/refractory (R/R) ATL pts outside of Japan. Methods: Pts from the USA, EU, and Latin America with R/R ATL (acute, lymphoma, and chronic subtypes) were randomized 2:1 to treatment with Moga, 1.0 mg/kg, given weekly for the first 4-week cycle and then biweekly, or to 1 of 3 investigator choice (IC) regimens (gemcitabine/oxaliplatin, DHAP, or pralatrexate). Pts randomized to the IC arm were permitted to cross over to Moga upon progression. The primary endpoint was confirmed objective response rate (ORR), defined as a response that is maintained for approximately 8 weeks, in those randomized to the Moga arm (based on modified Tsukasaki criteria). ORR was assessed by the treating investigator (IA) and in blinded fashion by independent review (IR). Key secondary endpoints were ORR for IC and after cross over to Moga, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: 71 pts were randomized (47 to Moga, 24 to IC). Tissue /blood from 65/71 pts (91.5%) expressed CCR4. Although randomized, there were baseline imbalances in known ATL prognostic factors. Pts with adverse prognostic features were more often randomized to Moga: these features included older age, poor ECOG performance status of 2, bone marrow involvement, and refractory to (vs having relapsed from) their most recent ATL therapy. Based on data through 31 March 2016, ORR (all responses, confirmed and unconfirmed) by IA was 34.0% (16/47) in the Moga group and 0% (0/24) in the IC group; these rates were largely concordant with ORR findings by IR of 27.7% (13/47) for the Moga group and 8.3% (2/24) for the IC group. Confirmed ORR for Moga was 14.9%; there were no confirmed responses in the IC group. 18 IC pts crossed over to Moga and 3 responded, including one confirmed response. The median (m) DoR for Moga was 5.65 months [mo] (95% CI 3.63, not reached). Two pts had responses lasting >9 mo. The 16 responders in the Moga arm (as assessed by IA) were evenly distributed over ATL subtypes: chronic 5/16 (31%), acute 5/16 (31%), and lymphoma 6/16 (38%). Of the 65 pts with any exposure to Moga (randomized plus crossover), response according to subtype was: chronic 5/10 (50%), acute 7/31 (23%), and lymphoma 7/24 (29%). While the study was not powered to demonstrate a difference between the treatment arms, the Kaplan-Meier plots of PFS and OS for the ITT population are presented below. The PFS curves deviate modestly in favor of the Moga group. The mPFS for Moga was 0.93 mo (min-max: 0.03-26.20 mo) with 21.5% of subjects progression free at 3 mo, while the mPFS for IC was 0.88 mo (0-4.23 mo) with 12.5 % of subjects progression free at 3 mo. The OS curves overlap. The mOS for the Moga arm was 4.90 mo (0.27-37.33 mo) with 38.9% alive at 12 mo, and the mOS for the IC arm was 6.87 mo ( 0.57-33.87 mo) with 37.5% alive at 12 mo. The OS curves may have been affected by the imbalance in prognostic factors and are confounded by the crossover of 75% of IC pts to Moga. Treatment emergent adverse events (TEAEs) occurring more often in the Moga group than the IC group were infections (51.1% vs 20.8%); respiratory disorders (48.9% vs 29.2%); infusion related reactions (46.8% vs 0%); and skin disorders (42.6% vs 8.3%). TEAEs ≥Grade 3 were 29/47 (61.7%) for Moga and 13/24 (54.2%) for IC. With the exception of known Moga-related events (infusion related reactions and drug eruptions), TEAE rates are similar when adjusted for exposure time to Moga or IC; for example, the AE rate per pt-mo of exposure for infections is 0.296 for the Moga group vs. 0.234 for the IC group. Conclusions: In the largest randomized clinical trial of pts with R/R ATL thus far conducted, commonly used cytotoxic regimens provided limited to no therapeutic benefit whereas treatment with Moga resulted in objective responses, a trend for favorable PFS, no clear survival advantage or disadvantage, and adverse events that are predictable, thereby supporting Moga's therapeutic potential in this setting. Figure Figure. Disclosures Phillips: Takeda: Speakers Bureau; Kyowa Kirin: Research Funding; Celgene: Speakers Bureau. Hermine:AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Research Funding; Alexion: Research Funding. Lill:Kite: Research Funding; California Cord Blood Services: Consultancy; Sanofi: Speakers Bureau. Feldman:Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Abbvie/Pharmacyclics/Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Sawas:Gilead Sciences: Speakers Bureau; Seattle Genetics: Honoraria. Cook:Kyowa Kirin Pharmaceutical Development, Inc.: Consultancy. Kurman:Kyowa Kirin Pharmaceutical Development, Inc: Consultancy. George:Kyowa Kirin Pharmaceutical Development: Employment. Dwyer:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Leoni:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Gonsky:Bioclinica: Other: Compensation for independent review of trial data. Horwitz:Infinity Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Kyowa Kirin Pharmaceutical: Research Funding; Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Huya Bioscience International: Consultancy, Honoraria; Forty Seven, Inc.: Consultancy, Honoraria; ADC Therapeutics: Other: Travel.

Background Final Transplant Center-Specific Survival Reports are published annually by CIBMTR to display center's 1-year expected and actual survival. CIBMTR Data Audits are conducted every 4-years to determine a center's error rate by evaluating accuracy and completeness of data reported. Insurance contracts and accreditations are directly affect by these reports. Our center aimed to create a process improvement (PI) procedure to ensure highly accurate data was submitted to CIBMTR by incorporating BMT physician reviews with DCCs using a checklist. Method Firstly, 100% of data submitted to CIBMTR within the past 5 years (CY 12-17), were internally audited. Internal audit revealed common errors in comorbidity index, Karnofsky Performance Status, and disease stage. Secondly, our center voluntarily requested a CIBMTR SIA to provide objective validation of forms accuracy. Results CIBMTR SIA demonstrated an overall passing score, showcasing a marked improvement in comparison to previous audit (Figure 1). The common errors influencing survival outcomes were used to design Pre-Transplant Essential Data (TED) and Post-TED checklists (Figure 2). Physician 1:1 data reviews were conducted bi-monthly to corroborate data and/or to resolve discrepancies with DCCs. Following implementation of pre-TED/post-TED checklist and physician 1:1 reviews our center met CIBMTR's expected 1-year outcomes survival, fulfilling insurance contract(s), and accreditation(s) requirements (Figure 3). Conclusion Internal and external data audits led to the creation of the Pre-TED/Post-TED checklists. Implementation of physician 1:1 reviews positively impacted the data accuracy of CIBMTR data submitted. In conclusion, data accuracy improvements can potentially impact reported survival outcomes.

The National Marrow Donor Program, in partnership with the American Society for Blood and Marrow Transplantation, sponsored and organized a series of symposia to identify complex issues affecting the delivery of hematopoietic cell transplantation (HCT) and to collaboratively develop options for solutions. "Hematopoietic Cell Transplantation in 2020: A System Capacity Initiative" used a deliberative process model to engage professional organizations, experts, transplant centers, and stakeholders in a national collaborative effort. Year 2 efforts emphasized data analysis and identification of innovative ideas to increase HCT system efficiency, address future capacity requirements, and ensure adequate reimbursement for HCT programs to meet the projected need for HCT. This report highlights the deliberations and recommendations of Year 2 and the associated symposium held in September 2011.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

With increasing use of high dose chemotherapy with autologous and allogeneic transplants the need for the transplant physician workforce requires reassessment. The types of transplants and patients are also shifting toward transplants being done in patients with more comorbidities and more commonly these types of patients require more work effort per patient from the transplant physician. Additionally, HSCT survivors often require ongoing care at the transplant center due to the inability of the primary care workforce or the hematology/oncology workforce to absorb caring for post complex post transplant patients. The adult transplant workforce has had very few physicians join under age 40. Nearly 50% of adult transplant physicians are over age 50 whereas only 28% of pediatric transplant physicians are over age 50. By 2020, it is projected that we will need 1,264 new adult transplant physicians and 94 pediatric transplant physicians. Training time for a physician is approximately 15 years. The capping of both medical school slots and residency slots since the early ’80s is now having a very big impact on supply, but other factors are also affecting supplies such as generational differences, lifestyle expectations, and the change of the medical workforce from being mostly men. Workforce shortages are being reported for many specialities. Workforce problems are also present for nurses, pharmacists and medical technologists. So increasing use of general internists and mid-level providers may not exist as a solution. Transplant physicians must be actively engaged in the medical education process to show young medical students and residents who are not committed to another sub specialty career the excitement and challenges of a career in bone marrow transplantation, so that our field will have providers for the future.

Although a significant minority of patients with cyanotic congenital heart disease (CCHD) are thrombocytopenic, the pathogenesis and prevalence have not been established. This study was designed to address these 2 issues. We included 105 patients with CCHD (60 men and 45 women; aged 21 to 54 years). Systemic arterial oxygen saturations were 69% to 78%. Hematocrits were 62% to 74% with normal iron indexes. In 26 of 105 patients (25%), platelet counts were

Background: While first line therapy for FL with chemotherapy or chemoimmunotherapy produces durable responses, most patients (pts) with FL eventually relapse. Those who become resistant to chemoimmunotherapy have limited treatment options. Ibrutinib, an inhibitor of BTK (Bruton's tyrosine kinase) and ITK (interleukin-2-inducible T-cell kinase), has demonstrated robust clinical activity in various B-cell non-Hodgkin lymphomas. Previous Phase 1 and 2 studies have shown promising results with single-agent ibrutinib in pts with relapsed or refractory FL (Bartlett NL. Blood. 2014; 800 & Fowler N. Blood. 2015; 2706). The aim of the DAWN study was to provide additional efficacy and safety data with single-agent ibrutinib in a chemoimmunotherapy-refractory FL pt population. Methods: The DAWN study (FLR2002) was an open-label, multicenter, single-arm, Phase 2 study of ibrutinib in pts with chemoimmunotherapy-refractory FL (NCT01779791). Eligible pts had ≥ 2 prior lines of therapy with documented progressive disease (PD) within 12 months after last dose of chemotherapy in a chemoimmunotherapy regimen comprising an anti-CD20 monoclonal antibody. All pts received 560 mg oral ibrutinib once daily until disease progression or unacceptable toxicity. A protocol amendment allowed clinically stable patients with radiographic PD to remain on ibrutinib to allow for the possibility of tumor flare and delayed responses. The primary objective was Independent Review Committee (IRC)-assessed objective response rate (ORR; complete response [CR] + partial response [PR]). Secondary/ exploratory objectives included duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), resolution of lymphoma-related symptoms, and safety. Results: The final analysis included 110 pts enrolled at 45 centers in 10 countries. The median age was 61.5 years, median number of prior therapies was 3; 40.9% of pts had refractory disease (defined as failure to achieve at least PR to the last prior regimen). Median follow-up is 27.7 months and median (range) ibrutinib exposure was 7.0 (1-37) months. The mean (SD) ibrutinib exposure was 11.2 (9.9) months. The ORR by IRC was 20.9% (23/110) and CR rate was 10.9% (12/110) with a median duration of response of 19.4 months; of the 23 pts who responded, 5 had refractory disease. ORR was 24.7% in pts with non-bulky disease (longest diameter ≤6 cm). The disease control rate (CR + PR + stable disease [SD for ≥ 6 months]) was 56.3% (62/110). 30 pts were allowed to remain on ibrutinib after initial radiographic PD (termed pseudo-progression); 7 pts had IRC-confirmed response when allowed to remain on therapy. Median TTNT on ibrutinib was 16 months compared with 10 months on the last line of treatment prior to enrollment. Median PFS was 4.6 months. The median OS has not been reached; the 24-month OS was 63% (95% CI, 0.53-0.72). Of 39 pts who had lymphoma-related symptoms at baseline, resolution of symptoms was seen in 26 pts (66.7%), including 10 whose best response was SD and 8 pts who had PD. The median duration of symptom resolution was 10.4 months. The most common adverse events (AEs) were diarrhea (50.9%; 51/56 pts had grade 1/2), fatigue (40.0%; 38/44 pts had grade 1/2), and cough (35.5%; all were grade 1/2). Serious AEs were reported in 48.2% of pts. Major hemorrhage and atrial fibrillation were consistent with previous reports at 3.6% and 9.1%, respectively. Seven pts (6.4%) discontinued ibrutinib because of an AE (none due to AF); 1 pt required a dose reduction due to AE. Biomarker analyses identifying classifiers for response or progression are ongoing. Conclusion: Treatment with single-agent ibrutinib in pts with chemoimmunotherapy-refractory FL achieved durable responses of 20.9%. The clinical benefit for these pts is also supported by disease control rate, resolution of symptoms, TTNT and OS. Safety results in this study were consistent with the current known profile of ibrutinib; the majority of events reported were grade 1/2. In pts with chemoimmunotherapy-refractory FL who have limited treatment options, treatment with ibrutinib resulted in a clinical benefit with acceptable safety and good tolerability. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Gopal: Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Schuster:Celgene: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Research & Development: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Honoraria; Hoffman-LaRoche: Research Funding; Merck: Research Funding. Fowler:Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy; Infinity: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding. Hess:Roche: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Martin:Novartis: Consultancy; Teva: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Acerta: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses. Vitolo:Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Morphosys: Consultancy; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Sandoz - Novartis, Morphosys, Roche: Speakers Bureau. Osmanov:Seattle Genetics Inc.: Research Funding. Gartenberg:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment. Balasubramanian:Janssen Research & Development: Employment. Wang:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment. Salles:Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Gilead: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding.

Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated robust clinical activity in various B-cell malignancies, whose mechanism of action, beside BTK signaling inhibition in B-cells may also depend partially on immune modulation as it also an inhibitor of ITK (interleukin-2-inducible T-cell kinase), a key regulator of T-cell activity. Immune-modulatory cancer therapy, such as check-point inhibitors, may result in different response patterns than traditional cytotoxic therapy, eg, resembling "tumor flare." In a recent study of single-agent ibrutinib for treatment of refractory follicular lymphoma (FL), 7 patients (pts) had documented tumor responses after initial radiological progressive disease (PD), a phenomenon termed "pseudo-progression." We describe these cases that led to a study protocol amendment. Methods: The FLR2002 (DAWN) study was an open-label, multicenter, single-arm, phase 2 study of ibrutinib in pts with chemoimmunotherapy-refractory (ie, ≥ 2 prior lines of therapy & PD within 12 months after last dose of chemotherapy in a chemoimmunotherapy regimen) FL (NCT01779791). All pts received ibrutinib (560 mg QD) until PD or unacceptable toxicity. A protocol amendment was made to address the novel situation of delayed responses that were observed after PD to allow for continuation of ibrutinib in pts with radiological evidence of PD (any new lesion or increase by ≥ 50% of previously involved sites from nadir), but who were clinically stable/improving/exhibiting signs of tumor flare without documented PD by other methods. The primary end point was Independent Review Committee (IRC)-assessed overall response rate (ORR; complete response [CR] + partial response [PR]). T-cell subsets in peripheral blood were monitored by flow cytometry at various timepoints. Results: The sentinel case was a pt diagnosed with grade 1 FL in 2008 and subsequently treated with 3 lines of therapy including autologous stem cell transplant. At time of enrollment, pt had stage III disease, an ECOG score: 0 and FLIPI (Follicular Lymphoma International Prognostic Index) score: 1. At Week 12, the pt was assessed as having PD. Ibrutinib was discontinued, and no other anti-cancer treatment was instituted. However, PET & CT scans performed 4 months later showed CR. Thereafter, 2 other investigators reported similar phenomena, prompting the aforementioned protocol amendment. Investigator assessment of the pt in the sentinel case was confirmed by IRC and ibrutinib treatment was resumed. The pt remains on treatment in CR for 30 months at the time of this report. On the basis of the protocol amendment, approximately 30 pts were approved to continue ibrutinib treatment after radiographic PD. Of these, an additional 6 pts were identified (7 in total) with IRC-confirmed "pseudo-progression" (confirmed by imaging) at a median of 22.0 (range: 11.6-59.6) weeks after starting Ibrutinib. Three of these pts (2 CR, 1 PR) maintained their response for > 1 year and 2 continue to respond. Two pts (1 CR, 1 PR) maintained responses for > 8 months, but eventually progressed. One pt maintained a PR > 1 year, but discontinued ibrutinib therapy due to an adverse event (grade 3 diarrhea). Sufficient sample was available in 2 of these 7 pts and examination of the T-cell profiles showed a strong downregulation of regulatory Tcells (Tregs) at early timepoints after initiation of therapy in both, an effect that was significant also in other responders (CR+ PR, mean decrease 17 to 12.9% CD4, p=0.02) but not in non-responders (SD+PD, 11.5 to 10.4% CD4, ns). Conclusion: Experience from the DAWN study suggests that pts with relapsed or refractory FL treated with ibrutinib may experience initial pseudo-progression followed by robust and durable responses when continued on ibrutinib. This effect may be related to the immune-modulatory effects of ibrutinib as seen by the decrease in Tregs after start of therapy. Biomarker studies are continuing to further understand this phenomenon. Nevertheless, these and other observations have prompted a revision in response criteria that recognize specific response patterns such as these in pts treated with immune modulating agents. Therefore current and future clinical trials should consider the observed phenomenon and physicians should be aware of this pattern of response when utilizing immune-related or targeted therapies to avoid premature discontinuation of therapy. Disclosures Salles: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding. Radford:GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Schaffer:Janssen Research & Development: Employment. Damle:Janssen Research & Development: Employment. Gartenberg:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment. Balasubramanian:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment.

This paper summarizes a pilot, sequential dose-escalation study of PEG-rHuMGDF in patients with advanced malignancies who had delayed platelet recovery after autologous stem cell transplantation (ASCT). Patients were randomized to receive either placebo (n = 11) or PEG-rHuMGDF at 5 (n = 9), 10 (n = 6), or 25 (n = 7) microg/kg/day by subcutaneous injection for 14 days and were monitored for 5 weeks. Across all treatment groups, eight patients had platelet recovery to > or = 20 x 10(9)/l by day 21. The proportion of patients achieving platelet recovery, the median number of days and units of platelet transfusions were similar for the placebo and the PEG-rHuMGDF groups. PEG-rHuMGDF was well tolerated at all dosages. The incidence rates of adverse events in all groups were similar. No deaths on study, no drug-related serious adverse events, and no development of neutralizing antibodies to MGDF occurred.

Graft-versus-host disease (GVHD) is a major complication after allogeneic stem cell transplantation, causing significant morbidity and mortality. A similar autoimmune syndrome has been described af...

In 1995, the National Heart Lung and Blood Institute (NHLBI) solicited requests for a proposal (RFP) entitled "Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells." Three banks, six transplant centers, and one medical coordinating center (MCC) (Table 1) were funded with the overall goal of banking cord blood units (CBU) using a single manual of operations. Furthermore, the clinical protocols to evaluate the transplant outcome for adult and pediatric recipients of these well-characterized CBU would be analyzed in a uniform fashion. Because of the intense interest of the transplantation community in the policies and procedures for cord blood collection and processing, the principal investigators of the cord blood banks (CBB) and NHLBI elected to submit for publication the rationale and an abridged, but detailed, version of the standard operating procedures (SOP) developed between October 1996 and July 1998 prior to the initiation of the clinical protocols to be performed with these CBU. As the SOP will be refined over time, the complete SOP and subsequent amendments will be published and continually updated on the websites from the MCC-The EMMES Corporation (www.EMMES.com). All forms referred to in this document may be obtained from the EMMES website. It is hoped that the publication of this document will lay down a framework that will not only facilitate the development of other CBB but also help us more rapidly define what constitutes an "acceptable" CBU product.

The safety and optimal dose and schedule of stem cell factor (SCF ) administered in combination with filgrastim for the mobilization of peripheral blood progenitor cells (PBPCs) was determined in 215 patients with high-risk breast cancer. Patients received either filgrastim alone (10 μg/kg/d for 7 days) or the combination of 10 μg/kg/d filgrastim and 5 to 30 μg/kg/d SCF for either 7, 10, or 13 days. SCF patients were premedicated with antiallergy prophylaxis. Leukapheresis was performed on the final 3 days of cytokine therapy and, after high-dose chemotherapy and infusion of PBPCs, patients received 10 μg/kg/d filgrastim until absolute neutrophil count recovery. The median number of CD34+ cells collected was greater for patients receiving the combination of filgrastim and SCF, at doses greater than 10 μg/kg/d, than for those receiving filgrastim alone (7.7 v 3.2 × 106/kg, P < .05). There were significantly (P < .05) more CD34+ cells harvested for the 20 μg/kg/d SCF (median, 7.9 × 106/kg) and 25 μg/kg/d SCF (median, 13.6 × 106/kg) 7-day combination groups than for the filgrastim alone patients (median, 3.2 × 106/kg). The duration of administration of SCF and filgrastim (7, 10, or 13 days) did not significantly affect CD34+ cell yield. Treatment groups mobilized with filgrastim alone or with the cytokine combination had similar hematopoietic engraftment and overall survival after PBPC infusion. In conclusion, the results of this study indicate that SCF therapy enhances CD34+ cell yield and is associated with manageable levels of toxicity when combined with filgrastim for PBPC mobilization. The combination of 20 μg/kg/d SCF and 10 μg/kg/d filgrastim with daily apheresis beginning on day 5 was selected as the optimal dose and schedule for the mobilization of PBPCs.

The purpose of the study was to evaluate the feasibility and efficacy of high-dose cytarabine-anthracycline consolidation chemotherapy followed by autologous transplantation of chemotherapy/rHuG-CSF-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Fifty-nine consecutive patients (median age 45, range 18-69) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine-mitoxantrone consolidation chemotherapy used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 7 x 10(8) peripheral blood mononuclear cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-six patients received myeloablative chemo-radiotherapy followed by the infusion of chemotherapy/rHu-G-CSF-mobilized autologous peripheral blood progenitor cells. The median time to both neutrophil and platelet recovery from transplant was 15 days (range, 11-36 and 5-253+ days, respectively). After a median follow-up of 27 months, 31 patients remain alive with 27 in complete remission. Median remission duration for all eligible patients is 12 months, and actuarial leukemia-free survival at 3 years is 42 +/- 14%. The actuarial risk of relapse is 54 +/- 15%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in two patients and grade III/IV organ toxicity in six. Advanced age was a negative prognostic factor for leukemia-free survival. Our results demonstrate that autologous transplantation of chemotherapy-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission producing improved leukemia-free survival with minimal toxicity.

International audience; We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Herpes simplex virus (HSV) infection commonly occurs during the immunosuppression associated with hematopoietic stem cell transplantation (HSCT). Prophylaxis of recurrent infection and management of clinical infection have relied upon acyclovir and congeners. More recently, resistant HSV infection is seen in HSCT and presents new challenges in management. We present a case of HSV following HSCT that provided effective symptomatic management. Oral symptoms and lesions were repeatedly reduced when topical cidofovir was used, strongly supporting the effect of cidofovir used in a host who could not tolerate systemic antiviral medications. Topical cidofovir can provide effective management of symptomatic oropharyngeal HSV while reducing risk of systemic toxicity and drug interaction and represents an additional approach to management for management in medically compromised patients.

Transplantation of both skeletal myoblasts and stem cells into the region of infarcted myocardium results in improved myocardial function in both the murine and porcine infarct models. Intravenous injection of stem cells and bone marrow stimulating cytokines also improves cardiac function [(1–4)][

Summary. Bone marrow transplantation from a histocompatible donor may produce complete remission in patients with induction failure or relapsed acute leukaemia. Through the National Marrow Donor Program, histocompatible bone marrow from unrelated donors has become available for high-risk patients. In this study we analyse the results of matched unrelated bone marrow transplant in 55 patients with highly advanced acute myelogenous and acute lymphoblastic leukaemia. 28 patients with advanced acute lymphoblastic leukaemia and 27 patients with advanced acute myelogenous leukaemia, age 2–51, were treated withy high-dose chemoradiotherapy and transplantation of of 6/6 HLA matched (n= 46) or one antigen mismatched (n= 9) unrelated donor bone marrow. After a median follow-up of 36 months, 13 patients remain alive 17–24 months after transplant for a 2-year actuarial disease-free and overall survival of 23 ± 12% (median disease-free survival 3.5 months). The actuarial risk of relapse is 24 ± 16% at 1 year. Moderate to severe graft-versus-host disease occurred in 27/47 evaluable patients (57%). Significant prognostic factors for poor leukaemia-free survival include age >21, abnormal karyotype, and active leukaemia at the time of transplant. Other pretreatment characteristics such as gender or type of leukaemia were not significant prognostic factors. Our results show that matched unrelated bone marrow transplant for patients with advanced acute bone marrow transplant for patients with advanced acute leukaemia may provide long-term leukaemia-free survival, but transplant-related complications produce a sigbificant impact on survival with older age and adverse disease characteristics predicting for poor prognosis

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is a rare and aggressive malignancy that usually presents with diffuse cutaneous lesions. While a favorable response to therapy occurs in a majority of cases, a sustained long-term response is uncommon. Most patients subsequently relapse within a year. In the following report, we present the case of a 41-year-old woman who has not displayed many of the clinical features traditionally associated with BPDCN. The patient received sporadic chemotherapy treatment over the course of 2 years, before undergoing an allogeneic stem cell transplant. Although she ultimately relapsed following her transplant, her disease has repeatedly returned into remission after donor lymphocyte infusion (DLI). Currently, the patient is in remission following her fourth DLI. We believe that allogeneic transplantation should be considered as front-line therapy for the treatment of this rare malignancy.

We present the 16th reported case of Acute Lymphoblastic Leukemia (ALL) with involvement in the bladder. Our patient was a 22 yearold man with T-cell ALL with a mediastinal mass. He received hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (HyperCVAD) with mediastinal radiation. Prior to starting maintenance, he relapsed in the bladder and marrow. He received a nelarabine- based induction regimen and achieved remission. This was followed by an unrelated 11/12 HLA-matched myeloablative allogeneic stem cell transplant. He is in complete remission for the past 409 days.

Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001).

Although reduced intensity (RIC) and nonmyeloablative (NMA) conditioning regimens have been used for over a decade, their relative efficacy versus myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. Five year univariate probabilities and multivariate relative risk (RR) outcomes of relapse, transplant related mortality (TRM), disease free survival (DFS) and overall survival (OS) are reported. Adjusted OS at 5 years was 34%, 33%, and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs. leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.

Tandem autotransplants are used to treat advanced testis cancer patients but their value compared to a single autotransplant is unknown. To evaluate the results of autotransplant in relapsed testicular/germ cell cancer, data from 300 patients undergoing autotransplants 1989-2002 were reported to the Center for International Blood and Marrow Transplant Research. We compared results for those patients intended to undergo tandem autotransplant procedures (N = 102) versus patients in whom a second autotransplant was not planned (N = 198). Five-year survival probability was 35% (95% confidence interval = 25%-46%) in the planned tandem transplant cohort compared to 42% (35%-49%) in the group not planned to have a second transplant (P = .29). Probability of progression-free survival at 5 years for these cohorts was 34% (25%-44%) and 38% (31%-45%), respectively (P = .50). The planned tandem autotransplant cohort had significantly more advanced disease at diagnosis and greater likelihood of cisplatin resistance. Patients intended to receive tandem transplants had a lower treatment-related mortality at 1 year (3% versus 10%, P = .02). Using propensity score analysis the planned tandem autotransplant cohort had significantly lower treatment-related mortality (P = .044) but no different risk of relapse (P = .541) compared to the planned single transplant cohort. Tandem autotransplants for testicular cancer are associated with less treatment-related mortality than a planned single transplant, with no differences in disease-related outcomes or overall survival at 3 years. Patient selection bias for either transplant approach, however, may affect the results of this observational study; a randomized trial is needed to determine which approach, if either, is better.

Background: We investigated the efficacy of directly injected allogenic bone marrow-derived mesenchymal stem cells in improving left ventricular function in a porcine model of myocardial infarction. Methods: Left ventricular infarction was created in 16 adult Yorkshire pigs by coil embolization and thrombotic occlusion distal to the second diagonal artery. One month after myocardial infarction was induced, the animals were randomized to either direct injection of allogenic mesenchymal stem cells or sham treatment (culture medium). Allogenic bromodeoxyuridine-labeled mesenchymal stem cells (2 ± 0.1 × 108) were directly injected into the infarct and peri-infarct areas during an open chest procedure. No immunosuppressive therapy was used. The left ventricular function was measured using serial biplane left ventricular angiography at baseline, 30, 60, and 90 days before sacrifice. Mesenchymal stem cells were localized using bromodeoxyuridine, and differentiation of mesenchymal stem cells was assessed by confocal microscopic colocalization of bromodeoxyuridine with immunofluorescent antibodies specific for cardiomyocytes (troponin I and MF-20) and endothelial cells (von Willebrand factor). Results: Mesenchymal stem cells labeled with bromodeoxyuridine engrafted the peri-infarct zone and colocalized with both cardiomyocyte-specific and endothelial cell-specific immunofluorescence. No intramyocardial bromodeoxyuridine was observed in sham-treated animals. At the time of the mesenchymal stem cell injection 30 days after myocardial infarction, the left ventricular ejection fraction (LVEF) was 58% ± 3% in mesenchymal stem cell-treated pigs and 56% ± 2% in sham-treated pigs ( P = NS). LVEF deteriorated progressively thereafter in untreated pigs (8.5% and 10.5% decline at 60 days and 90 days after myocardial infarction, respectively), but was preserved in mesenchymal stem cell-treated pigs (2.1% increase and -2.0% decline at 60 and 90 days post-MI respectively) ( P < .05). Conclusions: Direct intramyocardial injection of mesenchymal stem cells results in successful intramyocardial engraftment and differentiation into cardiomyocytes and endothelial cells and preserves left ventricular function after myocardial infarction in pigs.

Background Stem cell therapy has been shown to attenuate the reduction of left ventricular function following myocardial infarction. Most studies have utilized either a direct injection or intra-coronary infusion of cells, but cytokine mobilization of stem cells in the murine model of acute myocardial infarction has been reported to induce similar improvement in cardiac function. Methods An antero-apical infarction was induced in swine by balloon occlusion, followed by the daily administration of granulocyte colony stimulating factor (G-CSF) or placebo for 5 days. We used left ventricular angiograms and 2D echocardiograms to assess global function, and 3D echocardiograms to assess regional function prior to infarction, immediately following infarction, and at 8 weeks. Histologic evaluation was performed after sacrifice at 8 weeks. Results There was no significant difference in early or late post-infarction left ventricular ejection fraction or in myocardial histology between the two groups. Following G-CSF therapy, however, 3D echocardiography demonstrated that the regional ejection fractions of the infarcted segments showed a 50.3% improvement in the G-CSF pigs compared to a 7.4% deterioration in the untreated pigs ( p =0.005). Conclusions Global left ventricular ejection fraction remained unchanged, and there is no histologic evidence for infarct attenuation following G-CSF infusion in the porcine infarct–reperfusion model. There was recovery of regional function in the infarcted segment in the G-CSF pigs. These data suggest that bone marrow mobilization in larger species has limited potential as a therapy designed to replace infarcted myocardium or to improve overall cardiac function, although further studies are needed to examine regional effect in the infarct area.

Direct intramyocardial injection of mesenchymal stem cells (MSCs) improves left ventricular ejection fraction (LVEF) and may increase ventricular arrhythmia in hearts with myocardial infarction (MI). We hypothesized that intravenous MSCs given early after acute MI would engraft in injured myocardium, improve LV function, and result in pro-arrhythmic electrical remodeling. We created an apical infarction in swine by balloon occlusion/reperfusion, administered diI-labeled allogeneic bone marrow derived MSCs intravenously 30 min post-reperfusion and measured LVEF and wall thickness at baseline, 1 month, and 3 months. Epicardial effective refractory periods (ERPs) were determined before sacrifice. At 3 months, treated pigs [ n =7] had significantly higher LVEF than controls [ n =8] (49±2% vs. 44±3%, P =0.015)and significantly less wall thickening of non-infarcted myocardium. ERPs were significantly shorter than controls at all pacing cycle lengths ( P ≤0.002), suggesting a pro-arrhythmic potential. DiI was found in the lungs, in infarct, and peri-infarct myocardium. Conclusion: IV infusion of MSCs soon after acute MI in swine improves LVEF and limits wall thickening in the remote non-infarcted myocardium, consistent with a beneficial effect on post-MI ventricular remodeling. Since there is no need for immune suppression or clinical expertise, IV infusion of MSCs may expand the potential clinical application of stem cell therapy.

Treatment with the anti-CD20 antibody rituximab prior to stem cell collection may lead to tumor-free stem cell collections in patients with B-cell lymphoma undergoing autologous stem cell transplantation. To test the feasibility of obtaining polymerase chain reaction (PCR)-negative stem cell collection, 30 patients with a variety of B-cell lymphomas were enrolled in a protocol employing a common MINE (mitoxantrone/ifosfamide/etoposide) salvage regimen with rituximab (in vivo purging). Rituximab 400 mg/m2 was administered weekly for 3 weeks on days 1, 6, and 8 in relation to the last MINE cycle, which was followed by growth factor-stimulated peripheral stem cell collection. The median number of CD34(+) cells/kg was 2.5 million cells/kg collected over a median of 5 days. Polymerase chain reaction amplification for the t (14;18) or the heavy-chain gene rearrangement was performed prior to treatment and on the leukapheresis sample. Out of 15 patients who had a positive PCR signal prior to treatment, 10 had PCR-negative stem cell collections, whereas 5 had PCR-positive stem cell collections. After high-dose chemotherapy and stem cell transplant, all patients with a PCR-positive signal pretreatment became PCR negative. We conclude that rituximab may increase the yield of tumor-free stem cells. Higher rates of PCR negativity have been reported when more intense and protracted chemoimmunotherapy regimens have been employed. The magnitude of clinical benefit and the significance of the PCR analysis in stem cells after rituximab requires larger studies.

Matched Pair Comparison of Busulfan/ Cyclophosphamide/Etoposide (BuCyE) to Carmustine/ Etoposide/Cytarabine/Melphalan (BEAM) Conditioning Regimen Prior to Autologous Hematopoietic Cell Transplantation (autoHCT) for Lymphoma Marcelo C. Pasquini , Jennifer Le Rademacher , Christopher Flowers , Michael Lill , Luciano J. Costa , Tsiporah B. Shore , William Vaughan , Michael Craig , Cesar O. Freytes , Thomas C. Shea , Mitchell E. Horwitz , Joseph W. Fay , Shin Mineishi , Damiano Rondelli , James Mason , Vijay Reddy , Ira Braunschweig , Weiyun Ai , Elizabeth Armstrong , Angela Smith , Cathy Zhao , Agnes Elekes , Jeanette Carreras , Kazunobu Kato , Edmund K. Waller . 1 CIBMTR, CIBMTR/ Medical College of Wisconsin, Milwaukee, WI; 2 Biostatistics, Medical College of Wisconsin, Milwaukee, WI; 3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Division of BMT, Emory University, Atlanta, GA; 4 Cedars Sinai Medical Center, Los Angeles, CA; Medical University of South Carolina, Charleston, SC; 6 Cornell Medical Center Hematology/ Oncology, The New York Hospital, New York, NY; 7 Bone Marrow Transplantation and Cell Therapy Program, University of Alabama in Birmingham, Birmingham, AL; West Virginia University Health Science Center, Morgantown, WV; 9 South Texas Veterans Health Care System and University of Texas Health Science Center San Antonio, San Antonio, TX; 10 Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC; 11 Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC; 12 Baylor University Medical Center, Dallas, TX; 13 Bone Marrow Transplantation Program, University of Alabama at Birmingham, Birmingham, AL; 14 Department of Medicine, Section of Hematology-Oncology, University of Illinois Hospital & Health Sciences System, Chicago, IL; 15 Scripps Clinic, La Jolla, CA; 16 University of Florida, Gainesville, FL; 17 Oncology, Montefiore Medical Center, Bronx, NY; 18 University of California San Francisco, San Francisco, CA; 19 Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ; 20 CIBMTR, Medical College of Wisconsin, Milwaukee, WI; 21 Department of Hematology and Medical Oncology, Winship Cancer Institute, Division of BMT, Emory University, Atlanta, GA

Fifty-five patients with advanced multiple myeloma received purified CD34-selected peripheral blood progenitor cell transplants following myeloablative chemotherapy. A median of 4.1 x 10(6) CD34 cells/kg (range 1.2-30.7) were infused after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg); granulocyte-macrophage colony-stimulating factor was used until hematopoietic recovery. Median time to neutrophils0.5 x 10(9)/l and platelets20 x 10(9)/l were 12 days (range 10-16 and 8-184 days, respectively). Median follow-up of survivors from the time of transplantation is 33 months (range 7 to 44 months). Thirty-one patients are alive, 19 progression-free. Median progression-free survival is 14 months. Actuarial 3-year progression-free and overall survival are 29+/-14% and 47+/-17%. CD34-selection of peripheral blood progenitor cells provides effective hematopoietic support with significant progression-free and overall survival.