Autologous Hematopoietic Progenitor Cell Transplantation Research Articles

Ongoing production of tissue-resident macrophages from hematopoietic stem cells in healthy adult macaques

AbstractMacrophages orchestrate tissue immunity from the initiation and resolution of antimicrobial immune responses to the repair of damaged tissue. Murine studies demonstrate that tissue-resident macrophages are a heterogenous mixture of yolk sac–derived cells that populate the tissue before birth, and bone marrow–derived replacements recruited in adult tissues at steady-state and in increased numbers in response to tissue damage or infection. How this translates to species that are constantly under immunologic challenge, such as humans, is unknown. To understand the ontogeny and longevity of tissue-resident macrophages in nonhuman primates (NHPs), we use a model of autologous hematopoietic stem progenitor cell (HSPC) transplantation with HSPCs genetically modified to be marked with clonal barcodes, allowing for subsequent analysis of clonal ontogeny. We study the contribution of HSPCs to tissue macrophages, their clonotypic profiles relative to leukocyte subsets in the peripheral blood, and their transcriptomic and epigenetic landscapes. We find that HSPCs contribute to tissue-resident macrophage populations in all anatomic sites studied. Macrophage clonotypic profiles are dynamic and overlap significantly with the clonal hierarchy of contemporaneous peripheral blood monocytes. Epigenetic and transcriptomic landscapes of HSPC-derived macrophages are similar to tissue macrophages isolated from NHPs that did not undergo transplantation. We also use in vivo bromodeoxyuridine infusions to monitor tissue macrophage turnover in NHPs that did not undergo transplantation and find evidence for macrophage turnover at steady state. These data demonstrate that the life span of most tissue-resident macrophages is limited and can be replenished continuously from HSPCs.

CRISPR/Cas9-mediated Cxcr4 disease allele inactivation for gene therapy in a mouse model of WHIM syndrome

AbstractWHIM syndrome is an autosomal dominant immunodeficiency disorder caused by gain-of-function mutations in chemokine receptor CXCR4 that promote severe panleukopenia because of retention of mature leukocytes in the bone marrow (BM). We previously reported that Cxcr4-haploinsufficient (Cxcr4+/o) hematopoietic stem cells (HSCs) have a strong selective advantage for durable hematopoietic reconstitution over wild-type (Cxcr4+/+) and WHIM (Cxcr4+/w) HSCs and that a patient with WHIM was spontaneously cured by chromothriptic deletion of the disease allele in an HSC, suggesting that WHIM allele inactivation through gene editing may be a safe genetic cure strategy for the disease. We have developed a 2-step preclinical protocol of autologous hematopoietic stem and progenitor cell (HSPC) transplantation to achieve this goal. First, 1 copy of Cxcr4 in HSPCs was inactivated in vitro by CRISPR/Cas9 editing with a single guide RNA (sgRNA) that does not discriminate between Cxcr4+/w and Cxcr4+/+ alleles. Then, through in vivo natural selection, WHIM allele–inactivated cells were enriched over wild-type allele–inactivated cells. The WHIM allele–inactivated HSCs retained long-term pluripotency and selective hematopoietic reconstitution advantages. To our knowledge, this is the first example of gene therapy for an autosomal dominant gain-of-function disease using a disease allele inactivation strategy in place of the less efficient disease allele repair approach.

521 - KRD vs. VRD as Induction before Autologous Hematopoietic Progenitor Cell Transplantation for High-Risk Newly Diagnosed Multiple Myeloma

521 - KRD vs. VRD as Induction before Autologous Hematopoietic Progenitor Cell Transplantation for High-Risk Newly Diagnosed Multiple Myeloma

For Better or for Worse: COVID-19 Vaccination during or Early after (Immuno-) Chemotherapy or Hematopoietic Progenitor Cell Transplantation

Background: Patients with hematologic conditions have a high mortality rate when infected with SARS-CoV-2 (Williamson, Nature 2020). Protection of this group from severe COVID-19 is therefore important. However, according to available vaccination guidelines, one should consider to postpone vaccination of patients on or early after chemotherapy, hematopoietic progenitor cell transplantation (HCT) or with graft versus host disease, because of anticipated poor efficacy. Based on previous (non-COVID-19) vaccination studies among hematology patients, we hypothesized that a significant group of patients may acquire sufficient protection following COVID-19 vaccination, despite disease and therapy related immunodeficiencies.Methods: We conducted a prospective cohort study with 17 cohorts of hematology patients of particular risk for severe COVID-19 who are considered to have no or limited benefit from vaccination. We evaluated humoral immune responses following 2 doses (28 days apart) of the mRNA-1273 vaccine (Moderna/Spikevax) in 722 patients, at baseline and 28 days after each vaccination as SARS-COV-2 S1- (spike)-specific serum IgG antibody concentrations by bead-based multiplex immune assay. The threshold for adequate antibody response is set at ≥300 binding antibody units (BAU)/ml according to the international WHO standard, and is associated with virus plaque reducing neutralization test titers of ≥40 PRNT 50. This study is registered as EudraCT 2021-001072-41, NL76768.029.21.Results: Patient cohorts and corresponding vaccine responses are depicted in Table 1. Vaccine efficacy, as measured by antibody concentration, 4 weeks after the 2 nd mRNA-1273 vaccination was available for 691 out of 722 participants. The majority of patients (389/691; 56%) obtained an S1 antibody titer that is considered adequate (≥300 BAU/ml). Twenty-nine percent of patients (198/691) did not seroconvert (S1 antibody titer <10 BAU/ml), while the remaining 15% (104/691) did seroconvert but not to sufficient levels (10-300 BAU/ml). Adequate responses were observed in the majority of patients with sickle cell disease using hydroxyurea, chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor therapy, acute myeloid leukemia (AML) on or early after high dose chemotherapy, patients with myeloproliferative disorders on ruxolitinib, patients with multiple myeloma (MM), including those on daratumumab and those early after high-dose melphalan and autologous HCT, patients with untreated chronic lymphocytic leukemia (CLL), and patients with chronic GvHD. Insufficient or absent antibody responses were observed in the majority of AML patients receiving hypomethylating agents, CLL patients on ibrutinib, patients with B-cell non-Hodgkin's Lymphoma (NHL) during or shortly after rituximab-chemotherapy or following BEAM chemotherapy and autologous HCT, allogeneic HCT recipients <6 months after transplantation, and CAR-T cell therapy recipients. However, even in these low-responder groups considerable numbers of patients did mount sufficient antibody titers. In others, titers increased after each of both vaccinations, suggesting that booster vaccination may enhance antibody titers to sufficient levels (Figure 1).Conclusion: Vaccination with mRNA-1273 had significant efficacy in severely immunocompromised hematology patients. Adequate humoral immune responses after two dose vaccination were reached in the majority of patients receiving therapy for sickle cell disease, MPD, MM, CML and AML, in patients early after HCT and in patients with GvHD. We are currently evaluating clinical and immunologic parameters that correlate with sufficient antibody responses, pseudovirus neutralization and SARS-COV-2-specific B and T cell numbers, phenotype and function. Per study design, all participants with absent or insufficient antibody responses (<300 BAU/ml) will receive a booster vaccination 5 months after initial vaccination, and antibody responses to booster vaccinations will be presented as well. Unlike currently available guidelines, COVID-19 vaccination should not be postponed. Moreover, as antibody titers increased after each of both vaccinations, booster vaccination of patients with absent or insufficient antibody responses seems warranted. [Display omitted] DisclosuresMutsaers: AstraZeneca: Research Funding; BMS: Consultancy. Van Meerten: Janssen: Consultancy; Kite, a Gilead Company: Honoraria. Kater: BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nijhof: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Mieloma múltiple

Multiple myeloma is a clonal proliferation of plasma cells in the bone marrow. It is characterized by its synthesis of a paraprotein detectable in serum and/or urine, on most occasions, along with evident organ damage or biomarkers of malignancy. Typical symptoms include bone pain as the main symptom, along with weakness and symptoms arising from hypercalcemia, renal insufficiency, and anemia. It is necessary to differentiate quiescent multiple myeloma, which does not lead to organ damage or have biomarkers of malignancy. In order to diagnose it, laboratory tests, a bone marrow study, and a radiological evaluation of the bone by means of computerized tomography scan or whole-body magnetic resonance imaging are necessary. Survival is around 7-8 years and has increased in recent years thanks to the emergence of new immunomodulatory treatments. In younger patients without organ dysfunction, standard treatment is induction therapy with a proteasome inhibitor (bortezomib), an immunomodulator (thalidomide or lenalidomide), and dexamethasone followed by an autologous hematopoietic progenitor cell transplantation with high doses of chemotherapy. Among patients who are not candidates for transplantation, various treatment schedules with very encouraging survival data are available, which will be adapted according to the patient's comorbidities.

Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes.

Hematopoietic stem cell gene therapy has become a successful therapeutic strategy for some inherited genetic disorders. Pre-clinical toxicity studies performed to support the human clinical trials using viral-mediated gene transfer and autologous hematopoietic stem and progenitor cell (HSPC) transplantation are complex and the use of mouse models of human diseases makes interpretation of the results challenging. In addition, they rely on the use of conditioning agents that must induce enough myeloablation to allow engraftment of transduced and transplanted HSPC. Busulfan and total body irradiation (TBI) are the most commonly used conditioning regimens in the mouse. Lenticular degeneration and atrophy of reproductive organs are expected histopathological changes. Proliferative and nonproliferative lesions can be observed with different incidence and distribution across strains and mouse models of diseases. The occurrence of these lesions can interfere with the interpretation of pre-clinical toxicity and tumorigenicity studies performed to support the human clinical studies. As such, it is important to be aware of the background incidence of lesions induced by different conditioning regimens. We review the histopathology results from seven long-term studies, five using TBI and two using busulfan.

Mobilization of hematopoietic progenitor cells for autologous transportation: consensus recommendations

Selected patients with certain hematological malignancies and solid tumors have the potential to achieve long-term survival with autologous hematopoietic progenitor cell transplant. The collection of these cells in peripheral blood avoids multiple bone marrow aspirations, results in faster engraftment and allows treatment of patients with infection, fibrosis, or bone marrow hypocellularity. However, for the procedure to be successful, it is essential to mobilize a sufficient number of progenitor cells from the bone marrow into the blood circulation. Therefore, a group of Brazilian experts met in order to develop recommendations for mobilization strategies adapted to the reality of the Brazilian national health system, which could help minimize the risk of failure, reduce toxicity and improve the allocation of financial resources.

A novel hematopoietic progenitor cell mobilization regimen, utilizing bortezomib and filgrastim, for patients undergoing autologous transplant.

Adequate hematopoietic progenitor cell (HPC) collection is critical for patients undergoing autologous HPC transplant (AHPCT). Historically, 15 - 30% of patients failed HPC mobilization with granulocyte-colony stimulating factor (G-CSF) alone. Bortezomib, a proteasome inhibitor, has been shown to down regulate very late antigen-4 (VLA-4), an adhesion molecule expressed on HPCs. In this pilot study, bortezomib was administered on days -11 and -8 at a dose of 1.3 mg/m2 intravenously (IV) or subcutaneously (SQ), followed by G-CSF 10 mcg/kg SQ, on days -4 to -1 prior to HPC collection (Day 1). Nineteen patients, with multiple myeloma (n = 12) or non-Hodgkin lymphoma (n = 7) undergoing AHPCT for the first time, were enrolled. Patients were excluded if they had worse than grade II neuropathy or platelet count less than 100 x 109 /L. Bortezomib was well tolerated and all patients had adequate HPC collections with no mobilization failures. One patient (6%) had a CD34+ cell count of 3.9 cells/µL on Day 1 and received plerixafor per institutional algorithm. Eleven patients completed HPC collection in 1 day and eight in 2 days. All patients underwent AHPCT and had timely neutrophil and platelet engraftment. Comparison with a historical control group of 70 MM and lymphoma patients, who were mobilized with G-CSF, showed significantly higher CD 34+ cells/kg collected in the bortezomib mobilization study group. Bortezomib plus G-CSF is an effective HPC mobilizing regimen worth investigating further in subsequent studies. J. Clin. Apheresis 31:559-563, 2016. © 2015 Wiley Periodicals, Inc.

Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation

IntroductionThe objective of this study was to evaluate the outcome of patients affected with different subtypes of metastatic breast cancer (MBC) following treatment with high-dose chemotherapy (HDC) and autologous haematopoietic progenitor cell transplantation (AHSCT). MethodsAll consecutive female patients treated for MBC with HDC and AHSCT at the Institut Paoli-Calmettes between 2003 and 2012 were included. Patient, tumour and treatment characteristics were collected. Patients were categorised in three subtypes based on hormonal receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary tumour: luminal (L), (HR+/HER2–), HER2 (HER2+, any HR), and triple negative (TN) (HER2– and HR–). The main objective was the analysis of overall survival (OS) according to the immunohistochemical (IHC) subtypes. ResultsA total of 235 patients were included, median age was 46 (range 21–62). Median follow up was 53.28 months (95% confidence interval [CI] 45.12–57.6). The TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95% CI 11.76–44.4) compared to 44.64 months (95% CI 40.32–67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (p < 0.01). In the multivariate analysis, the TN subtype retained an independent poor prognosis value compared to the luminal subtype, with a hazard ratio of 2.03 (95% CI 1.26–3.29, p = 0.037). ConclusionHDC-AHSCT does not change the prognostic value of IHC subtypes in MBC patients. OS favourably compares with data available in the literature on similar groups of patients. These findings provide additional information and options for patients with MBC and who could potentially benefit of HDC-AHSCT.

Autologous Hematopoietic Progenitor Cell Infusion Adverse Event Associated with Apheresis Product Granulocyte Content

Introduction: Autologous hematopoietic progenitor cell (HPC) transplantation after high-dose chemotherapy has been used for several years in the treatment of various diseases. Over the past few years, peripheral blood have become the standard hematopoietic progenitor cell source. This process requires frozen HPC graft storage in mechanical freezers or liquid nitrogen for their subsequent infusion. Addition of a cryoprotectant solution such as dimethylsulfoxide (DMSO) is required in order to prevent ice crystals formation during HPC freezing process. Clinical toxicity has been classically attributed to thawed HPC DMSO content. However, adverse events still have been described after DMSO removal. The amount of granulocytes in the apheresis product has been correlated to adverse event occurrence and severity. In this study, we evaluated correlation between pre leukapheresis peripheral blood granulocytes count and adverse event occurrence during thawed HPC infusion.Patients and Methods: We retrospectively analyzed data from 361 patients submitted to autologous HPC transplantation from January 1999 to December 2013. HPC collection was performed with large volume leukapheresis, in a continuous-flow blood separator (Spectra, TerumoBCT, USA), with the mononuclear cell collection protocol, and ACD-A as anticoagulant solution. The apheresis product was diluted to maintain cell concentration less than 150x109 cells/L or 300x109 cells/L for storage in mechanical freezer or liquid nitrogen, respectively. A 5% DMSO solution was added to the HPC stored in mechanical freezer, whereas 10% DMSO was added for storage in liquid nitrogen. Complete blood count and CD34+ cell determination were performed in pre collection peripheral blood and the apheresis product. CD34+ cell determination was performed in the equipment Coulter Epics XL-MCL Flow Cytometer (Beckman Coulter, USA) according to the ISHAGE protocol. The HPC graft was thawed and infused without further manipulation. Infused volume limit was 10 ml/kg b.w or 40 mL of DMSO/day. Infusion was fractionated whenever required. Antihistamine drug and corticosteroid were given before all infusion. Adverse events included: nausea, vomiting, fever; hemodynamic, neurological, gastrointestinal, renal disorders; cardiac conduction disturbances, and hypersensitivity.Results: The patients´ median age was 50±17 yo (min: 1 max: 86), weight 74±19 kg (10-143). The underlying diseases were: Multiple Myeloma, 105 (29%), NonHodgkin lymphoma, 99 (27%), Acute Myeloid Leukemia, 37 (10%), solid tumor and multiple sclerosis 32 (9%) each and Hodgkin Lymphoma, 30 (8%) patients. CBC median values: hemoglobin, 10.9±1.6 g/dl (9.8-12.0), platelet 74,2±86 x109/L (44-138), white blood cell 20.8±18.3x109/L(9.6-34.4), granulocyte 16.5±15.8x109/L (6.6-28.9), and CD34+ cell, 23±79/mm3 (12-54). Apheresis product median values: total volume 235±47 mL (215-256), white blood cell 175±113x109/L (122-257), granulocyte 43.5±67.6x109/L (13.4-93.9), and CD34+ 0.8±2.4x109/L (0.4-2.0). Total nucleated cell collected was 5.7±4.5x108/kg b.w (3.9-8.5), total CD34+ 2.5±7.3x106/kg b.w (1.2-6.3). A total of 490 (74%) apheresis products were stored in mechanical freezer. A total of 289 thawed HPC infusions occurred in the study period. Adverse event occurred in 28 (10%) cases. The most common manifestations were hypertension and nausea/vomiting. Mild or moderate adverse event occurred in 26 infusions and severe adverse event in 02 cases. There was no difference in the infused HPC variables between patients with and without adverse event. However, significant difference was found in the apheresis product variables: median granulocyte count in the group with adverse reaction 74.7±52.5x109/L (39.2-103.6) vs. 43.1±61.6x109/L (12.6 to 89.2) in the group without adverse reaction, p=0.0158; total nucleated cells 8.1± 8.3x108/kg b.w (5.8-13) vs. 5.8±4.7x108/kg b.w (3.8-8.6), p=0.0033.Conclusion: The apheresis product granulocyte count and total nucleated cells were correlated with adverse event during infusion of HPC cryopreserved without further manipulation after thawing. DisclosuresNo relevant conflicts of interest to declare.

432. Aurora A Kinase Inhibition Enhances Oncolytic Herpes Simplex Virotherapy in Models of Neuroblastoma

Neuroblastoma, a heterogeneous tumor that arises from the neural crest, is the most common extracranial solid tumor in children. Fewer than half of patients with high-risk features survive long-term, despite multi-modal therapy with surgery, chemotherapy, antibody therapy, retinoic acid, high-dose chemotherapy, and autologous hematopoietic progenitor cell transplant. We previously reported neuroblastoma xenograft models were responsive to direct intratumoral injection of oncolytic Herpes Simplex Viruses (Parikh et al., Ped Blood Can 44:469, 2005; Mahller et al., Can Res 68:1170, 2008). We have confirmed these findings using an oncolytic HSV, Seprehvir (HSV1716), which is in clinical trials that include pediatric patients (NCT00931931, NCT02031965). The models showed wide variability, however, with CHP134 being highly responsive (4/8 complete responses (CR), 4/8 maintained complete responses (MCR)), CHLA-20 intermediately responsive (4/7 partial responses (PR), 3/7 MCR), SKNBE(2) somewhat responsive (6/7 PR, 1/7 MCR) and SK-N-AS minimally responsive (3/7 progressive disease (PD), 4/7 delayed progression (PD1), 0/7 PR). Because DNA viruses are highly dependent on normal nuclear machinery for DNA synthesis/replication and virus packaging/assembly, we postulated that increased transit time in mitosis may be beneficial to an oncolytic DNA virus. Aurora A Kinase is an enzyme critical for formation of centrioles and mitotic spindles during mitosis and is often dysregulated in cancer. The selective AAK inhibitor, Alisertib (MLN8237), arrests cells in G2/M and is highly effective in neuroblastoma models, making it an attractive candidate for combination studies with Seprehvir. We administered repeated 7-day cycles of combination therapy (10 mg/kg Alisertib once daily by gavage, days 1-5; 10e7 pfu Seprehvir day 5) to mice bearing SK-N-AS xenografts and found significant antitumor synergy (2/10 PD1, 4/10 SD, 2/10 PR, 2/10 CR). Our preliminary data assessing kinetics of virus infection suggest that Alisertib pretreatment enhances virus uptake and spread, accounting for the combinatorial effects. Overall, our findings support clinical testing of Alisertib combined with Seprehvir in patients with refractory neuroblastoma.

Early mortality in multiple myeloma

The life expectancy of patients diagnosed with multiple myeloma (MM) in the US has improved substantially over the last two decades, a phenomenon affecting predominantly, but not exclusively, younger patients.1 This improvement in survival has been attributed to the broader use of autologous hematopoietic progenitor cell transplantation (AHPCT)2 and increasing availability of novel drugs both in the newly diagnosed and relapsed setting,1 as well as improved supportive care. The impact of these interventions in early mortality (EM, henceforth defined as death in the first year after the diagnosis) is less well known.

Transfusion of ABO non-identical platelets does not influence the clinical outcome of patients undergoing autologous haematopoietic stem cell transplantation.

There are ABO antigens on the surface of platelets, but whether ABO compatible platelets are necessary for transfusions is a matter of ongoing debate. We retrospectively reviewed the ABO matching of platelet transfusions in a subset of patients undergoing autologous haematopoietic progenitor cell transplantation during a 14-year period. Our aim was to analyse the characteristics and outcomes of patients who received platelet transfusions that were or were not ABO identical. We analysed 529 consecutive patients with various haematological and non-haematological diseases who underwent 553 autologous progenitor stem cell transplants at the University Hospital la Fe between January 2000 and December 2013. We retrospectively analysed and compared transfusion and clinical outcomes of patients according to the ABO match of the platelet transfusions received. The period analysed was the time from transplantation until discharge. The patients received a total of 2,772 platelet concentrates, of which 2,053 (74.0%) were ABO identical and 719 (26.0%) ABO non-identical; of these latter 309 were compatible and 410 incompatible with the patients' plasma. Considering all transplants, 36 (6.5%) did not require any platelet transfusions, while in 246 (44.5%) cases, the patients were exclusively transfused with ABO identical platelets and in 47 (8.5%) cases they received only ABO non-identical platelet transfusions. The group of patients who received both ABO identical and ABO non-identical platelet transfusions had higher transfusion needs and worse clinical outcomes compared to patients who received only ABO identical or ABO non-identical platelets. In our hospital, patients undergoing autologous haematopoietic stem cell transplantation who received ABO identical or ABO non-identical platelet transfusions had similar transfusion and clinical outcomes. The isolated fact of receiving ABO non-identical platelets did not influence morbidity or survival.

Comparison of Engraftment Syndrome with G-CSF Versus GM-CSF after Autologous Hematopoietic Progenitor Cell Transplantation for Multiple Myeloma

IL-6 (pg/mL) < 2.15 18 11% (3-38%) 5 0% 2.15 42 57% (42-72%) <0.01 7.11 (1.67-30.27) <0.01 19 59% (38-80%) 0.04 IL-10 (pg/mL) < 1.65 44 30% (19-47%) 17 30% (14-58%) 1.65 16 75% (53-92%) <0.01 4.17 (1.88-9.29) <0.01 7 86% (54-99%) <0.01 sCD30(U/mL) < 8.65 39 32% (19-49%) 18 33% (17-60%) 8.65 21 63% (43-82%) <0.01 2.88 (1.31-6.32) <0.01 6 100% 0.01 sIL-2R (U/mL) < 1276 52 37% (26-52%) 19 37% (20-63%) 1276 8 75% (44-96%) <0.01 3.38 (1.34-8.54) 0.01 5 80% (42-99%) 0.03 CCL17 (pg/mL) < 343.6 26 16% (6-36%) 8 13% (2-61%) 343.6 34 63% (47-79%) <0.01 6.10 (2.08-17.93) <0.01 16 63% (47-79%) 0.04 Galectin-1 (ng/mL) < 9.8 13 8% (1-43%) 3 0% 9.8 47 52% (38-67%) <0.01 8.60 (1.16-63.54) 0.04 21 53% (34-75%) 0.14 CD68 (pg/mL) < 3.895 13 8% (1-43%) 5 0% 3.895 47 51% (38-67%) <0.01 8.53 (1.15-63.08) 0.04 19 59% (38-80%) 0.04 Abstracts / Biol Blood Marrow Transplant 21 (2015) S127eS146 S145

Disparities in Utilization of Autologous Hematopoietic Progenitor Cell Transplantation for Multiple Myeloma in the US

Introduction: Autologous hematopoietic progenitor cell transplantation (AHPCT) is an established modality in the treatment of patients with multiple myeloma (MM) with impact in depth and duration of remission and, in some studies, overall survival. Utilization of AHPCT for treatment of MM in US is increasing but still low. Race-ethnicity, sex and age-disparities may affect AHPCT utilization, although they do not impact benefit from AHPCT.Methods: MM incidence derived from Surveillance, Epidemiology and End Results (SEER-18) database and AHPCT for MM reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2005-2009 were analyzed. Cases were grouped in 4 racial-ethnic categories (REC): non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics (irrespective of race) and Asians. We assessed utilization as the ratio between first AHPCT for MM and number of newly diagnosed cases in the period of interest and calculated the relative utilization ratio (RUR), as [utilization for a given category] / [utilization for the entire population].Results: Data was obtained from 22,462 actual MM cases reported to SEER and 13,311 actual AHPCT reported to CIBMTR. NHW, NHB, Hispanics and Asians corresponded respectively to 72.0%, 18.7%, 6.7% and 2.6% of the new MM cases and 77.4%, 15.85, 5.2% and 1.6% of the AHPCT procedures. Median age at diagnosis of MM was higher in NHW (P=0.0002)and was higher in women than in men in all RECs. Age-adjusted RUR was 1.17 (95% C.I. 1.15-1.19) among NHW, higher than in NHB [0.69 (95% C.I. 0.67-0.72), P<0.0002], Hispanics [0.64 (95% C.I. 0.60-0.69), p<0.002] and Asians [0.65 (95% C.I. 0.58-0.73), P<0.0002]. There was higher utilization of AHPCT in men than in women detected among Hispanics (age adjusted RUR 0.72 vs 0.56, P=0.007), but not among NHW, NHB or Asians. Only 3.1% of the NHW patients younger than 65 were identified as uninsured vs. 8.1% of NHB, 11.9% of Hispanics and 3.2% of Asians (P<0.0001). Correction of sex disparity would lead to an overall increase of 1.3% in AHPCT for MM, higher among Hispanics (11.7%) but lower in the other categories (Figure, panel a). The hypothetical correction of racial-ethnic disparity would result in 15.9% increase in volume of AHPCT, with a pronounced increase among NHB, Hispanics and Asians (Figure, panel b). Increase in age at transplant will strongly affect AHPCT volumes with dissimilar impact in different RECs according to their age structure (Figure, panel c).Conclusions: Race-ethnicity disparity greatly affects AHPCT utilization for management of MM in US. Sex disparity plays a much lesser role, except among Hispanics. The profound age disparity is decreasing over time and will likely continue to drive major increase of AHPCT activity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autologous Hematopoietic Progenitor Cell Transplant in Patients with Multiple Myeloma in Hospital Central Sur De Alta Especialidad in Petróleos Mexicanos

INTRODUCTION Multiple Myeloma (MM) is a clonal B cells disorder producing an accumulation of plasmatic abnormal cells and abnormal light or heavy immunoglobulines. The onset of multiple myeloma is usually insidious, and the subclinical phase may vary in duration from 1 to 3 years. Bone pain is the most frequent initial feature and 60% of patients present with this symptom. Other clinical features may result from anaemia, uraemia, hypercalcaemia, infections, paraplegia, hyperviscosity syndrome and sensorimotor peripheral neuropathies. It accounts for approximately 1% of all neoplastic diseases and 10% of haematological malignancies. The sex incidence of myeloma is approximately equal until the age of 65 years, after which it is somewhat more common in men than in women. The incidence is approximately 3.8 per 100,000 population, it is lower in the white than the black population. In the last decades different treatments have been described with 60 to 80% of complete response, nevertheless disease free survival rate goes from 22 to 50% in the best treatment international centers. That is why autologous transplantation has been used in patients below 65 years old with very good response. OBJECTIVE Describe the experience of patients treated with autologous hematopoietic progenitor cell transplant with diagnosis of Multiple Myeloma in Hospital Central Sur de Alta Especialidad de Petróleos Mexicanos (PEMEX). MATERIAL AND METHODS We analyzed clinical data of patients with diagnosis of Multiple Myeloma that were transplanted from april 2008 to may 2014. RESULTS Ten patients were studied, three of them were over 65 years. Only 7 patients were considered for autologous hematopoietic progenitor cell transplantation, there ages were from 40 to 55 years with a median of 46 years. Transplants were performed from april 2008 to may 2014, 66% were men and 34% women. 66% were IgG and 18% IgA. Presence of Bence-Jones protein without monoclonal peak was found in 16% of the patients. In regard to prognosis index 66% were ISS-I and 34% were ISS-I. Cytogenetic studies were not performed because we did not have molecular cytogenetics so we could not perform the usual FISH translocations described in this disease. One hundred percent of the patients received the first line treatment with dexamethasone, cyclophosphamide, thalidomide and bortezomib. Only one patient received radiotherapy because he had a tumor in the leg, before the transplant was done 68% had complete response and 16 % partial response. Six autologous transplants were doned with conditioning by giving melphalan 200 mg/m2 orally because we did not have IV presentation. The 7 transplanted patients are alive and 71% had complete response and 29% had partial response. Patients that were transplanted responded 11 or 12 days after the transplant. CONCLUSIONS Patients with multiple myeloma that were transplanted were below 46 years, there were below the age reported in the literature, the predominant gender was masculine (2:1). The majority was IgG. The overall survival after the transplant was 40 months (72-6), the most common complication associated to transplant was fever and neutropenia and only in 16% of the patients we could isolate the germ. The patients are currently alive and in complete remission until june 2014. We think that this is the most adequate actual treatment for patients with Multiple Myeloma. We found in the literature that lenalidomide, carfilzomib and dexamethasone may achieve the same response that autologous hematopoietic cell transplant but the results are still in intense investigation. Disclosures No relevant conflicts of interest to declare.

Access to Advanced Care and Survival in Multiple Myeloma

Background: There has been major improvement in the survival of patients with multiple myeloma (MM), mostly due to the availability of more effective drugs and increased use of autologous hematopoietic progenitor cell transplantation (AHPCT). Access to AHPCT has been linked to demographic, geographic and socioeconomic parameters. We hypothesize that the distance between the patient county of residence and a transplant center is an adequate surrogate of access to advanced care (comprising not only AHPCT, but also experimental therapies) and may affect survival of MM patients.Methods: We conducted an analysis of patients diagnosed with MM between 2002 and 2011 reported to the Surveillance Epidemiology and End Results program (SEER-18). Cases reported from death certificate or autopsy only, and cases with missing race or county of residence were excluded (1% of total). Patients were classified according to the distance between county of residence and the nearest program accredited by the Foundation for the Accreditation of Cellular Therapy (FACT): Cohort A (<20 miles), B (20-70 miles), C (70-200 miles) and D (>200 miles).Results: We included 45,079 patients with median follow up of survivors of 30 months. There were substantial differences between the cohorts, particularly in race-ethnicity, income and education (Table 1). Median survival was 34, 37, 31 and 30 months for cohorts A, B, C and D respectively (Figure 1). Using Cox proportional hazards, we built two different survival models. Model 1 included demographic parameters and distance to transplant center. Compared to cohort A, risk of death was lower in cohort B and higher in cohorts C and D (Table 2). Model 2 included all parameters of model 1 plus median household income and proportion of adults in the county of residence with at least bachelor degree. Income and education were strongly associated with survival and displaced distance to transplant center from the model (Table 2). Other factors associated with worse survival were age, earlier year of diagnosis, male sex, presentation with plasma cell leukemia, and race-ethnicity.Conclusion: Distance to transplant center, a surrogate for access to advanced care, is associated with survival in patients with MM, likely reflecting underlying differences in demographics, income and education. Abstract 858. Table 1 –Characteristics of the patientsTotalABCDN=45,079N=19,476N=15,614N=8,262N=1,727PFemale20,419 (45.3%)8,967 (46.0%)7,036 (45.1%)3,654 (44.2%)762 (44.1%)0.02Age68.468.468.868.368.20.005Race-ethnicity<0.001AIAN211 (0.5%)39(0.2%)36 (0.2%)36 (0.4%)100 (5.8%)API2282 (5.1%)1381(7.1%)751 (4.8%)124 (1.5%)26 (1.5%)Hispanic4557 (10.1%)2504 (12.9%)1,129 (7.2%)470 (5.7%)454 (26.3%)NHB8615 (19.1%)4708 (24.2%)2,236 (14.3%)1,600 (19.4%)71 (4.1%)NHW29,414 (65.2%)10,844 (55.7%)11,462 (73.4%)6,032 (73.0%)1,076 (62.3%)Year of diagnosis0.022002-200621,076 (46.8%)9,185 (47.2%)7,185 (46.0%)3,854 (46.6%)852 (49.3%)2007-201124,003 (53.2%)10,291 (52.8%)8,429 (54%)4,408 (53.4%)875 (50.7%)Household income$59.157$60,254$66,540$45,237$46,633<0.001Adults with at least bachelor degree29.7%32.8%31.6%19.7%24.3%<0.001Disease0.46Multiple Myeloma44,749 (99.3%)19,327 (99.3%)15,498 (99.3%)8,212 (99.2%)1,712 (99.1%)Plasma Cell Leukemia330 (0.7%)149 (0.7%)116 (0.7%)60 (0.8%)15 (0.9%)Table 2 –Multivariate analysis of factors associated with survival in MMFactorReferenceHR95% C.I.PModel 1Year of diagnosisPer year0.9630.959-0.968<0.001Age at diagnosisPer year1.0421.041-1.044<0.001FemaleMale0.900.89-0.93<0.001Plasma Cell LeukemiaMultiple Myeloma2.942.60-3.31<0.001Race-ethnicity<0.001AIANNHW1.040.87-1.260.65APINHW1.030.97-1.090.32HispanicNHW1.141.09-1.19<0.001NHBNHW1.111.07-1.15<0.001Distance to advanced care<0.00120 - 70 miles<20 miles0.960.93-0.990.00570-200 miles<20 miles1.101.06-1.14<0.001>200 miles<20 miles1.101.03-1.170.004Model 2Year of diagnosisPer year0.9630.959-0.968<0.001Age at diagnosisPer year1.0421.041-1.044<0.001FemaleMale0.910.89-0.93<0.001Plasma Cell LeukemiaMultiple Myeloma2.942.60-3.31<0.001Race-ethnicity<0.001AIANNHW1.040.86-1.250.68APINHW1.061.00-1.120.04HispanicNHW1.151.10-1.20<0.001NHBNHW1.081.05-1.12<0.001Household incomePer $10,0000.980.96-0.990.001% adults with bachelor degreePer % point0.9940.992-0.996<0.001 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Implementation of an evidenced based nutrition support pathway for haematopoietic progenitor cell transplant patients

The type of nutrition support given during haematopoietic progenitor cell transplantation (HPCT) varies greatly between transplant units and often includes enteral nutrition (EN) and/or parenteral nutrition (PN). The aims of this study were to develop an evidenced based nutrition support pathway for HPCT patients and then evaluate changes in nutrition support practices post implementation of the pathway into clinical practice. A retrospective audit of 66 consecutive patients who underwent HPCT during the six months prior to the development of the pathway was undertaken, followed by a prospective audit of 61 consecutive patients undertaking HPCT during the six months post implementation. Data collected included type and timing of nutrition support given. Post implementation of the pathway the use of PN for allogeneic HPCT patients reduced significantly from 86% to 50% (p < 0.001) and use of oral nutrition support increased significantly from 14% to 45% (p = 0.003). Autologous HPCT recipients had shorter lengths of inadequate intake with only 30% of patients having a poor intake for greater than one week compared to 72% prior to implementation of the pathway (p = 0.02). Implementation of a nutrition support pathway impacts significantly on appropriate use of nutritional support in recipients of HPCT.

Trends in Utilization and Outcomes of Autologous Transplantation as Early Therapy for Multiple Myeloma

The impact of novel drugs for treating multiple myeloma (MM) on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients who underwent AHPCT within 12 months of diagnosis of MM in the United States and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts reflecting the increasing availability of novel drugs: 1995 to 1999 (n = 2226), 2000 to 2004 (n = 6408), and 2005 to 2010 (n = 11,644). In the United States, the number of AHPCTs performed increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3 MM, and more likely to have received previous thalidomide, lenalidomide, or bortezomib. On multivariate analysis, AHPCT in the 2000 to 2004 cohort (HR = 0.77) or in the 2005 to 2010 cohort (HR = 0.68) were associated with lower risk of death. Survival at 60 months post-AHPCT improved from 47% in 1995 to 1999 to 55% in 2000 to 2004 and to 57% in 2005 to 2010, owing less to improvement in progression-free survival (50% versus 55% versus 57% at 24 months) than to postrelapse/progression survival (58% versus 65% versus 72% at 24 months). AHPCT and new biological agents are complementary, nonredundant therapies and should be combined in the management of MM in suitable patients.

Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia

Collection of hematopoietic progenitor cells (HPC) after previous autologous hematopoietic progenitor cell transplant (aHCT) was studied in 221 patients with multiple myeloma (MM). With a total of 333 collections, the median number of CD34+ cells collected was 4.7 × 10(6) CD34+ cells/kg, and 74% of the patients collected ≥ 2.5 × 10(6) CD34+ cells/kg. Among 26 variables examined, the strongest predictor for poor collection was a platelet count <100 × 10(6)/l before mobilization (P<0.001). A subsequent aHCT was performed in 154 of the 221 patients. Sole use of HPC procured after aHCT in 86 patients was associated with delayed platelet recovery (P<0.001) and linked to development of myelodysplastic syndrome (MDS)-associated cytogenetic abnormalities (MDS-CA; P=0.027, odds ratio (OR) 10.34) and a tendency towards clinical MDS/acute myeloid leukemia (AML; P=0.091, OR 3.57). However, treatment-related mortality (P=0.766) and time to absolute neutrophil count recovery ≥0.5 × 10(9)/l (P=0.879) were similar to when a pre-aHCT graft was used. Indeed, adding HPC collected before any aHCT neutralized the risk of MDS-CA or MDS/AML. Therefore, we advise generous initial HPC collection to broaden the salvage armamentarium for patients with MM.