Durable Engraftment and Long-Term Survival Following Fludarabine-Based Nonmyeloablative Hematopoietic Cell Transplantation (HCT) in Patients with ATG-Refractory Severe Aplastic Anemia (SAA) and Other Nonmalignant Hematological Disorders.

Abstract We evaluated the toxicity-profile, engraftment potential, and efficacy of fludarabine-based nonmyeloablative allogeneic HCT in patients with a variety of nonmalignant hematological disorders. Twenty three patients (median age 29 years; range 11–52) with nonmalignant hematological disorders including ATG refractory SAA (n=13), severe paroxysmal nocturnal hemoglobinuria (PNH: n=9), and pure red cell aplasia (PRCA; n=1) were transplanted from 5/99 – 8/2004 at the NHLBI. The majority of patients had an extensive transfusion history including 11/23 who had HLA allo-antibodies and 4/23 with allo-antibodies to RBCs. Conditioning with fludarabine (25 mg/m2 x 5 days), ATG (40mg/kg x 4 days) and cyclophosphamide (60mg/kg x 2 days) was followed by infusion of an un-manipulated G-CSF mobilized allograft from an HLA matched sibling (n=18), parent (n=2), or single antigen mismatched sibling (n=3). GVHD prophylaxis consisted of cyclosporine (CSA) either alone (n=2) or combined with mycophenolate mofetil (n=10) or mini-dose methotrexate (n=11). Despite a high prevalence of pre-transplant allo-immunization, all patients achieved sustained donor engraftment in both myeloid and T-cell lineages. Myeloid recovery (neutrophils >500cells/uL) occurred at a median 14 days post transplant (range 8–18 days). Conversion from mixed to full donor myeloid and T-cell chimerism occurred in all patients by 110 days post-transplant. CMV reactivation occurred in 11/21 patients at risk (KM probability 52%) without any cases of CMV disease. Grade II–IV and III–IV acute GVHD was the major transplant complication occurring in 13/23 (KM probability 60%) and 8/23 (KM probability 38%) patients respectively. Fourteen of 21 evaluable patients developed chronic GVHD (limited in 11 cases), which resolved completely with low-dose alternate day steroids and/or CSA in all but 1 case. One patient who received an allograft from his HLA matched father died 16 months post-transplant from complications related to chronic GVHD. With a median follow up of 25 months (range 1–64 months), 20/21 patients evaluable more than 100 days post-transplant survive in complete remission with full donor chimerism in all lymphohematopoietic lineages (KM probability of long-term survival 92.8 %-see figure ). Conclusion: Fludarabine-based nonmyeloablative transplantation achieves excellent donor engraftment and long-term disease free survival in heavily transfused and allo-immunized patients with ATG refractory SAA and other nonmalignant hematological disorders associated with bone marrow failure.

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Long-Term Survival In Patients With Acute Steroid Refractory Graft-Versus-Host-Disease (SR-GVHD) Treated With Infliximab Combined With Daclizumab

Blood ◽

10.1182/blood.v122.21.4624.4624 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4624-4624

Author(s):

Sanaz Nicky Soltani ◽

Ramaprasad Srinivasan ◽

Theresa Jerussi ◽

A. John Barrett ◽

Thomas E Hughes ◽

...

Keyword(s):

High Probability ◽

Chronic Gvhd ◽

Complete Response ◽

Cell Transplant ◽

Term Survival ◽

Hematopoietic Stem ◽

Long Term Survival ◽

Post Transplant

Acute SR-GVHD occurs in approximately 15% of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), and is associated with a 70-90% long-term mortality rate. We previously reported that concomitant blockade of TNF-α and IL-2 pathways with infliximab combined with daclizumab have a synergistic therapeutic effect, with a high probability of complete resolution of SR-GVHD. Although various treatment modalities are effective in the treatment of SR-GVHD, minimal long-term follow up data exists for complete responders to second line treatments. Here we report long-term outcomes in a cohort of 23 subjects developing SR-GVHD treated with infliximab/daclizumab. A consecutive series of 141 patients with a variety of hematological and non-hematological malignancies as well as nonmalignant hematological disorders including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria and pure red cells aplasia, underwent a reduced intensity allogeneic HSCT from an HLA identical or single antigen mismatched relative at a single institution between 2/2001 and 12/2008. Transplant conditioning consisted of cyclophosphamide (60 mg/kg days -7, -6) and fludarabine (25 mg/m2days -5 to -1) with or without equine ATG or 6-12 Gy of total body irradiation. GVHD prophylaxis was with cyclosporine with or without additional MMF or MTX. Twenty three patients (median age 35 years, range 13-65 years) developed SR-GVHD at a median of 28 days post transplant. SR-GVHD was defined as absence of response to at least 6 days of high dose methylprednisolone therapy. Following a diagnosis of SR-GVHD, patients received a combination of daclizumab (1mg/kg given on days 1, 4, 8, 15, 22), infliximab (10mg/kg given on days 1, 8, 15, 22), broad spectrum bacterial and anti-fungal prophylaxis, and had their methylprednisolone tapered to 1mg/kg/day. Combined cytokine blockade was highly active against SR-GVHD, with 21/23 (87.5%) patients achieving a complete response (CR), defined as total resolution of GVHD in all involved organ systems. All complete responders survived to hospital discharge. With a median follow-up of 9 years (range 5-10 years), 9/23 (39%) survive, including 6 patients without chronic GVHD whose immunosuppressive therapy (IST) has been discontinued and 3 patients with chronic GVHD (2 limited and 1 extensive) who continue to be tapered off IST. Fourteen of 21 patients with resolution of SR-GVHD died a median 173 days post transplant (range 67-1039 days), including 1 from complications related to recurrent SR-GVHD, 6 from progression of malignancy (all solid tumors), 2 from bleeding related to peptic ulcer disease and 5 from infectious complications including invasive fungal infection and CMV disease. A subgroup analysis showed 5/6 patients with SAA developing SR-GVHD had a complete response to combined infliximab/daclizimab. Remarkably, at a median 6 years follow up, 67% (4/6) of these SAA patients were long-term survivors. All these survivors have maintained normal blood counts and remained transfusion independent with 100% donor chimerism in myeloid and T-cell lineages. Conclusion Patients with SR-GVHD treated with infliximab combined with daclizumab had a high probability of achieving a complete response with nearly 40% of patients having long-term survival. This is the first report to show that long-term survival can be achieved in a substantial proportion of patients receiving combined IL-2 and TNF blockade for SR-GVHD. Disclosures: Off Label Use: Infliximab is FDA approved for the treatment of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Daclizumab gained FDA approval for use in transplant rejection.

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T-Cell–Depleted Reduced-Intensity Transplantation Followed by Donor Leukocyte Infusions to Promote Graft-Versus-Lymphoma Activity Results in Excellent Long-Term Survival in Patients With Multiply Relapsed Follicular Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.9100 ◽

2010 ◽

Vol 28 (23) ◽

pp. 3695-3700 ◽

Cited By ~ 109

Author(s):

Kirsty J. Thomson ◽

Emma C. Morris ◽

Don Milligan ◽

Anne N. Parker ◽

Ann E. Hunter ◽

...

Keyword(s):

T Cell ◽

Follicular Lymphoma ◽

Chronic Gvhd ◽

Mixed Chimerism ◽

Unrelated Donor ◽

Term Survival ◽

Long Term Survival ◽

Unrelated Donors ◽

Reduced Intensity

Purpose Follicular lymphoma (FL) is an indolent disorder that is treatable but considered incurable with chemotherapy alone. The curative potential of allogeneic transplantation using conventional myeloablative conditioning has been demonstrated, but this approach is precluded in the majority of patients with FL because of excessive toxicity. Thus, reduced-intensity conditioning regimens are being explored. Patients and Methods This study reports the outcome of 82 consecutive patients with FL who underwent transplantation using fludarabine, melphalan, and alemtuzumab for in vivo T-cell depletion. Patients were heavily pretreated, having received a median of four lines of prior therapy, and 26% had experienced treatment failure with previous autologous transplantation. Median patient age was 45 years, and 52% of patients received stem cells from unrelated donors. Results With a median follow-up time of 43 months, the nonrelapse mortality was 15% at 4 years (8% for sibling and 22% for unrelated donor transplantations), acute grade 2 or 3 graft-versus-host disease (GVHD) occurred in 13%, and the incidence of extensive chronic GVHD was only 18%. Although relapse risk was 26%, this was significantly reduced where mixed chimerism had been converted to full donor chimerism by the use of donor lymphocyte infusion (DLI; P = .03). In addition, 10 (77%) of 13 patients given DLI for relapse after transplantation experienced remission, with nine of these responses being sustained. Current progression-free survival at 4 years was 76% for the whole cohort (90% for those with sibling donors and 64% for those with unrelated donors). Conclusion The excellent long-term survival with associated low rates of GVHD and the frequency and durability of DLI responses make this an extremely encouraging strategy for the treatment and potential cure of FL.

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Long-Term Survival and Late Deaths in 2-Year Survivors of Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Hematologic Disorders.

Blood ◽

10.1182/blood.v114.22.520.520 ◽

2009 ◽

Vol 114 (22) ◽

pp. 520-520

Author(s):

John R. Wingard ◽

Navneet S. Majhail ◽

Ruta Bajorunaite ◽

Zhiwei Wang ◽

Kathleen A. Sobocinski ◽

...

Keyword(s):

Risk Factors ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Term Survival ◽

Long Term Survival ◽

Hematologic Disorders ◽

Allogeneic Hct ◽

Conditioning Regimens ◽

All Diseases

Abstract Abstract 520 Allogeneic hematopoietic-cell transplantation (HCT) is potentially curative therapy for a variety of hematologic disorders. Most deaths after HCT occur within the first 2-years, due to relapse, acute or chronic graft-versus-host disease (GVHD) or regimen-related toxicities. Among allogeneic HCT recipients who had survived in complete remission (CR) for at least 2-years following transplantation, we (1) investigated their long-term survival, (2) evaluated risk factors for late mortality, and (3) compared their long-term survival to that of the general population. Our study cohort consisted of 10,632 patients who received a myeloablative allogeneic HCT through 2003, surviving in CR for 2-years after transplant reported to the CIBMTR. The median followup of our cohort was 9 (range, 2-31) years; 37% of survivors were followed for ≥10-years and 12% for ≥15-years. Diagnoses included acute myeloid leukemia (AML, N=4,017), acute lymphoblastic leukemia (ALL, N=2,895), myelodysplastic syndrome (MDS, N=930), lymphoma (N=619) and severe aplastic anemia (SAA, N=2,171). Donors were HLA-identical siblings (72%), unrelated donors (22%) or other related donors (6%). Patients <20 years of age comprised 45% of our cohort and 17% were >40 years at HCT. Total body irradiation (TBI) based conditioning regimens were given to 60% of patients. Most frequent conditioning regimens were cyclophosphamide + TBI for AML, ALL and lymphoma, busulfan + cyclophosphamide for MDS and cyclophosphamide alone for SAA. Acute grade 2-4 GVHD had occurred in 39% and 43% patients experienced chronic GVHD by 2-years after HCT. Probability of overall survival at 10-years after HCT was 84% (95% CI, 82-85%) for AML, 84% (82-85%) for ALL, 80% (77-83%) for MDS, 84% (81-87%) for lymphoma and 92% (91-93%) for SAA. Disease relapse was the most common cause of death for AML, ALL, MDS, and lymphoma while GVHD was the most common cause of death for SAA. The cumulative incidence of relapse at 10-years post-HCT was 10% (9-11%) for AML, 9% (8-10%) for ALL, 10% (8-12%) for MDS and 6% (4-8%) for lymphoma. Older age at HCT and chronic GVHD were both associated with greater late mortality for all diseases in Cox-regression analyses that accounted for important patient, disease and transplant related factors (Table). Furthermore, some risk factors were associated with increased mortality for specific diseases only, including: more advanced disease (AML, ALL), peripheral blood as graft source (ALL), acute GVHD (MDS and SAA), unrelated donor (lymphoma) and longer time from diagnosis (SAA). Overall survival rates at 10-years post-HCT for patients with and without chronic GVHD were 79% and 89% for AML, 80% and 87% for ALL, 75% and 87% for MDS, 80% and 90% for lymphoma and 87% and 95% for SAA. At 15-years after HCT, the relative mortality of patients who had received HCT for AML, ALL, MDS and SAA remained significantly higher than in age-, race- and gender-matched normal populations. Mortality rates for lymphoma patients were not significantly different than those of the matched general population after 8-years post-HCT. Recipients of myeloablative allogeneic HCT for AML, ALL, MDS, lymphoma and SAA who remain in remission for at least 2-years have favorable subsequent long-term survival. Older age at HCT and chronic GVHD are important risk factors for late deaths in all diseases evaluated. Disclosures: No relevant conflicts of interest to declare.

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HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.

Blood ◽

10.1182/blood.v114.22.655.655 ◽

2009 ◽

Vol 114 (22) ◽

pp. 655-655 ◽

Cited By ~ 1

Author(s):

Steven M. Devine ◽

Robert J Soiffer ◽

Marcelo C. Pasquini ◽

Shelly Carter ◽

Parameswaran N Hari ◽

...

Keyword(s):

T Cell ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Abstract 655 Allogeneic hematopoietic cell transplantation (HCT) is the most effective means to prevent relapse in patients (pts) with AML in complete remission (CR). However, quality of life and overall survival (OS) are often affected by both acute and chronic graft versus host disease (GVHD). GVHD is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but has been limited in its use by logistical difficulties, lack of an FDA-approved method, and concerns regarding potential risk of graft rejection, post transplant infections, and leukemic relapse. Most reported TCD studies represent single centers, multiple disease types and processing methods with varying degrees of TCD, all of which affect outcome. Therefore we designed a trial using a single processing method providing extensive TCD that did not require post transplant GVHD prophylaxis involving adult pts with AML in first or second CR. We hypothesized that the undesired side effects of TCD HCT would be reduced if combined with a conditioning regimen that was highly immunosuppressive and anti-leukemic. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months (mos) post transplant that exceeded 75%. Secondary objectives included assessments of engraftment, transplant related mortality (TRM), GVHD, relapse, and performance of a single TCD method (CD34+ cell selection using the Miltenyi CliniMACS device) at participating centers. From 10/2005 to 12/2008, 47 pts were enrolled and 44 transplanted at 8 different centers. Median age was 48.5 years (range 21-59) with 28 female and 16 male pts. Of 37 AML CR1 pts, 49% had an unfavorable cytogenetic or molecular risk profile. The conditioning regimen consisted of hyperfractionated total body irradiation (1375cGy in 11 fractions) with partial lung shielding, thiotepa (10mg/kg), cyclophosphamide (120mg/kg), and rabbit antithymocyte globulin (2.5mg/kg). The donors, all HLA-identical siblings, were given G-CSF for mobilization and scheduled to undergo at least 2 leukapheresis procedures to ensure a graft with a high CD34+ cell content. All allografts were CD34-enriched and were targeted to contain ≥ 5×10e6 CD34+ cells/kg and < 1.0×10e5 CD3+ cells/kg. The median CD34+ and CD3+ doses achieved were 8.1 × 10e6/kg (range 2.4-46.2) and 0.07 × 10e5/kg (range 0.01-0.85), respectively. The majority (81%) of pts received the targeted CD34+ cell dose and no pt received > 1.0×10e5 CD3+ cells/kg. No pharmacological GVHD prophylaxis was given post transplant. There were no significant toxicities related to infusion of the CD34 enriched allografts. The most common grade 3-5 regimen-related toxicities included grades 3 or 4 mucositis (39%) and grades 3-5 pulmonary abnormalities (11%). Only 1 pt experienced hepatic veno-occlusive disease. All pts engrafted rapidly with a median time to neutrophil recovery (ANC > 500/ul) of 11 days (range 9-19). There was 1 secondary graft failure. The assessed outcomes are shown below.Estimate (95% Confidence Interval)Outcome100 Days6 Months12 MonthsAcute GVHD II-IV20.5% (8.7 – 23.3%)Acute GVHD III-IV4.5% (0 – 10.6%)Chronic GVHD17.7% (5.8-29.6%)Extensive Chronic GVHD7.6% (0-15.7%)TRM17.8% (5.8-29.8%)Overall Relapse18.2% (5.9-30.5%)Relapse 1st CR9.6% (0- 19.8%%)Relapse 2nd CR64.3% (27.5-100%)DFS81.3% (66.1-90.2%)64.0% (46.5-77.1%)DFS 1st CR89.2% (73.7-95.8%)72.1% (53.0-84.6%)OS74.3% (57.3-85.4%) The absolute peripheral CD4+ cell count remained on average below 200/ul until day +365. Donor cell chimerism increased in the CD3+ cell compartment through day +365. There were 14 deaths. The most common causes of death were relapse (N=5) and pulmonary toxicity (N=4). The median follow-up of survivors is 489 days (range 96-776). There was no difference in OS or DFS for pts above or below the median age of 48.5 years. We conclude that TCD HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a single TCD method without additional post transplant prophylaxis with excellent DFS and OS, consistent engraftment, low TRM, and low incidence of relapse even in pts with unfavorable risk AML in CR1. The low incidences of acute and chronic GVHD in the absence of post transplant prophylaxis were particularly encouraging. A follow-up study of TCD HCT in AML recipients of unrelated donor allografts is being planned by the BMT CTN Disclosures: No relevant conflicts of interest to declare.

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Preemptive interferon-α treatment could protect against relapse and improve long-term survival of ALL patients after allo-HSCT

Scientific Reports ◽

10.1038/s41598-020-77186-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sining Liu ◽

Xueyi Luo ◽

Xiaohui Zhang ◽

Lanping Xu ◽

Yu Wang ◽

...

Keyword(s):

Residual Disease ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Multiparameter Flow Cytometry ◽

Interferon Α ◽

Term Survival ◽

Hematopoietic Stem ◽

Long Term Survival

AbstractRelapse was the major cause of treatment failure in patients with acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the efficacy and safety of preemptive interferon-α (IFN-α) treatment in ALL patients who had minimal residual disease (MRD) after allo-HSCT. Multiparameter flow cytometry and polymerase chain reaction assays were applied for MRD monitoring. Recombinant human IFN-α-2b injections were administered subcutaneously twice weekly in every 4 weeks cycle. Twenty-four (35.3%), 5 (7.4%), 6 (8.8%), and 13 (19.1%) patients achieved MRD negativity at 1, 2, 3, and > 3 months, respectively, after treatment. Seven patients showed grade ≥ 3 toxicities after IFN-α treatment. The 4-year cumulative incidence of total acute graft-versus-host disease (aGVHD), severe aGVHD, total chronic GVHD (cGVHD), and severe cGVHD after treatment was 14.7%, 2.9%, 40.0%, and 7.5%, respectively. The 4-year cumulative incidences of relapse and non-relapse mortality after treatment was 31.9% and 6.0%, respectively. The 4-year probabilities of disease-free survival and overall survival after IFN-α treatment were 62.1% and 71.1%, respectively. Thus, preemptive IFN-α treatment could protect against relapse and improve long-term survival for ALL patients who had MRD after allo-HSCT. The study was registered at https://clinicaltrials.gov as #NCT02185261 (09/07/2014).

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Dose and Time-Dependent Association of Red Blood Cell Transfusion with Increased Risk of GvHD and Worse Survival after Allogeneic HSCT

Blood ◽

10.1182/blood.v124.21.1555.1555 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1555-1555

Author(s):

Sakura Hosoba ◽

Edmund K. Waller ◽

Sheilagh Barclay ◽

Kirk A Easley ◽

Neeta Shenvi ◽

...

Keyword(s):

T Cell ◽

Multivariable Analysis ◽

Time Dependent ◽

Univariable Analysis ◽

Term Survival ◽

Long Term Survival ◽

Post Transplant ◽

Rbc Transfusion ◽

Grade Iii

Abstract Background: Acute graft-versus-host disease (aGvHD) remains a critical barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nearly all patients who undergo allo-HSCT receive red blood cell (RBC) transfusions during the first 30 days post-transplant, but the long-term effects of transfusions on post-transplant outcomes remain unclear. Preclinical and clinical studies indicate that RBC transfusions can activate dendritic cells (DCs) sensitizing transplant recipients to minor histocompatibility antigens (miHA). Initial interactions between donor T cell and DC regulate donor T cell activation and proliferation. We hypothesized that RBC transfusion may contribute to aGvHD in allo-HSCT patients by activating DC and stimulating allo-reactive T cells or other inflammatory pathways. Methods: We conducted a retrospective study of 336 adult allo-HSCT patients at Emory University Hospital from 2007 to 2013. In cases involving multiple transplants, only data relevant to the first allo-HSCT was included. Graft sources were restricted to bone marrow and G-CSF mobilized peripheral blood (excluded cord blood and T cell depleted grafts). 181 patients (54%) were male and 155 (46%) were female. Patients received transplants from matched related donors (n=123, 37%) or matched unrelated donors (n=213, 63%) for treatment of AML (n=132), ALL (n=40), acute leukemia (n=5), MDS (n=41), CML (n=22), CLL (n=15), HD (n=6), NHL (n=33), AA (n=10), MM (n=7) or other diseases (n=25). aGvHD with onset of up to 150 days after allo-HSCT was the primary end-point. Leuko-reduced and irradiated RBC transfusions administered during the week prior to transplant and 30 days post-transplant (while patients were closely monitored at the transplant center) were provided by a single Blood Bank. The median follow up time was 14.6 months post transplantation (range, 0.3 to 65.1 months). The relationship of RBC transfusions to aGvHD was determined as a time-dependent variable or as a function of the total number of RBC units transfused. Results: 306 patients (91%) received RBC transfusions during the observation timeframe, while 30 (9%) did not require transfusion (median 6). 221 patients (66%) developed grade I-IV aGvHD with a distribution of 85 (25%), 72 (21%), 47 (14%), and 11 (3%) of patients with maximum grade of I, II, III and IV, respectively, while 115 (34%) patients did not show any signs of aGvHD. We compared transfusion history, prior to the diagnosis of GvHD, in patients who developed grade 0-II aGvHD (n=272, 81%) vs. grade III-IV aGvHD (n=64, 19%). Patients with grade III-IV aGvHD received more RBC units (median 8) than patients with grade 0-II aGvHD (median 4). In univariable Cox regression analysis, factors significantly associated with grade III-IV acute GvHD were HLA match (HR 2.22, p=0.004), number of RBC units per week (HR=1.26, p<0.001), cumulative number of RBC units (HR=1.09, p<0.0003), and maximum storage age of units transfused (HR per 5 days older =1.12, p=0.02). In multivariable analysis, HLA match (HR=2.148, p=0.008) and number of RBC units transfused weekly (HR=1.293, p=0.0001) were associated with development of grade III-IV aGvHD. Kaplan-Meier analysis showed significantly worse long-term survival for patients with grade III-IV aGvHD (p value from Log-rank test <0.0001). Increased numbers of transfused RBC units (HR per 2 units =1.17, p<0.0001) was also associated with worse long-term survival in univariable analysis, and patients who received 7 or more RBC units had poorer long-term survival (HR=3.56, p<0.0001). In multivariable analysis, grade III-IV aGvHD was associated with worse long-term survival. Conclusion: We have demonstrated a significant association of RBC transfusions with the subsequent development of grade III-IV aGvHD for allo-HSCT patients and shown that patients with grade III-IV aGvHD have poorer long-term survival. While RBC transfusions are associated with worse survival in univariable analysis, based on our multivariable analysis, increased RBC transfusions are only associated with poorer survival in the context of severe aGvHD. These data are consistent with preclinical observation that allogeneic RBC can initiate inflammatory reactions to miHA. The data suggest that new strategies to improve RBC transfusion methods for allo-HSCT patients are needed to help reduce the risk of severe aGvHD and improve survival rates. Disclosures No relevant conflicts of interest to declare.

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Long-term survival of patients with therapy-related myeloid neoplasms after allogeneic hematopoietic cell transplantation—more than just a myth

Bone Marrow Transplantation ◽

10.1038/bmt.2016.121 ◽

2016 ◽

Vol 51 (6) ◽

pp. 763-764 ◽

Cited By ~ 1

Author(s):

S Mukherjee ◽

A T Gerds

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Term Survival ◽

Long Term Survival ◽

Myeloid Neoplasms

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EXTH-13. LOCAL DELIVERY OF AN IL-15 SUPERAGONIST USING A REPLICATING RETROVIRUS SIGNIFICANTLY IMPROVES SURVIVAL AND LYMPHOCYTE INFILTRATION IN POORLY IMMUNOGENIC MURINE GLIOBLASTOMA MODELS

Neuro-Oncology ◽

10.1093/neuonc/noab196.652 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi166-vi166

Author(s):

Alexander Haddad ◽

Jordan Spatz ◽

Megan Montoya ◽

Sara Collins ◽

Sabraj Gill ◽

...

Keyword(s):

T Cell ◽

Median Survival ◽

T Cell Activation ◽

Term Survival ◽

Long Term Survival ◽

Immunosuppressive Cell ◽

Imaging Results ◽

Local Immunosuppression ◽

Inflammatory Changes

Abstract Glioblastoma (GBM) leads to severe systemic and local immunosuppression, and immunotherapies have had limited clinical success. Here, we evaluated the treatment efficacy of RLI, a superagonist of T-cell activator IL-15, delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the syngeneic murine SB28 and Tu2449 GBM models, which are both engineered to be poorly immunogenic with low-mutational burden and known resistance to immunotherapy, and hence more accurate biomimetic models of human GBM. RRV-RLI replicated and spread effectively in cultured murine GBM cells with robust production of functional RLI (165.4 ± 5.3 ng/mL). Stereotactic injection of RRV-RLI into pre-established intracerebral SB28 tumors significantly reduced tumor growth on bioluminescent imaging, and increased median survival compared to control mice (55 vs. 19 days, p=0.002), leading to long-term survival in 12% of treated mice. In the Tu2449 model, imaging results showed complete eradication of intracerebral tumors after RRV-RLI treatment, with long-term survival (median not reached) in > 85% of treated mice, compared to a median survival of 12.5 days in control mice (p=0.001). RRV-RLI treated tumors showed significantly increased CD8 T-cell infiltration, without altering immunosuppressive cell populations. Similarly, broad anti-tumor inflammatory changes, including increased expression of genes involved in T-cell activation and killing, were observed in the NanoString nCounter platform using a 770-gene panel representing various immune cell types. Notably, RLI was not detected in the blood of treated mice, and tumor-localized RRV-RLI gene delivery showed no adverse systemic immune effects in either model. In summary, RRV-mediated RLI immunotherapy results in immunostimulatory and pro-inflammatory changes to the tumor microenvironment and achieves a significant survival benefit in two poorly immunogenic syngeneic murine models of GBM. This tumor-localized immunomodulatory gene therapy has the potential to safely reverse the T-cell depleted immunophenotype of GBM.

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