Second Blood or Marrow Transplant (BMT) for Relapse: Mismatch Haplotype Switch May Improve Outcome

Abstract Introduction: With improvements in supportive care, including graft-versus-host disease (GVHD) control, relapse has become the major complication of allogeneic BMT. The use of haploidentical donors often allows the potential to select a different donor for the second transplant. We examined the outcomes of patients who underwent a second BMT for relapse at Johns Hopkins between 2005 and 2014. We hypothesized that if loss of heterozygosity is a mechanism for relapse after haploBMT, then utilizing a donor that recognizes the other shared haplotype could improve antitumor activity and thus overall survival (OS). In the case of a failed matched transplant, recognition of a non-shared haplotype on the tumor by the second allograft would be beneficial. Methods: We identified all patients who received a second transplant for relapse of a hematologic malignancy between 2005 and 2014. Acute GVHD (aGVHD) is reported as Glucksberg grades 1-4; chronic GVHD (cGVHD) is reported as limited or extensive. GVHD and non-relapse mortality (NRM) was calculated via cumulative incidence (CI) with competing risk analysis. OS was calculated as the time from second transplant to death or last known follow-up and estimated using the Kaplan Meier method. Differences in time to death between patient groups were estimated using Cox proportional hazards models. Non-relapse mortality was estimated using Fine and GrayÕs method. Results: Between 2005 and 2014, 40 patients received a second BMT for a relapsed hematologic malignancy (Table 1). The median age at second transplant was 43.9 (range 1 to 74); 14 (35%) were female. Fifteen (41%) received myeloablative conditioning for their first transplant, and 35 (92%) received high dose post-transplant cyclophosphamide (PTCy) as part of their GVHD prophylaxis. The incidence of grade 2-4 aGVHD after the first transplant was 13%, and limited cGVHD was 13%. There was no extensive cGVHD. Re-induction therapy and second allograft characteristics (Table 2): Refractory or progressive disease at the time of second transplant was present in 20% of patients, and 7/40 (18%) had their second transplant within 1 year. After a first failed HLA-matched transplant, 15 received a haploidentical graft, and 4 received a second HLA-matched graft. Among the 21 who relapsed after a haploBMT, 7 received an HLA-matched allograft, and 14 received a haploidentical graft; 6 out of those 14 used a donor that switched the shared haplotype. Most (81%) received PTCy with the second BMT. Median follow up is 598 days. Median OS in the cohort is 911 days (95% CI 602 Ð NR); 4 year OS is 38%. The CI of NRM by 2 years was 29% - 4 patients died of complications of GVHD (only one of whom received post-transplant Cyclophosphamide), 3 associated with prolonged cytopenias, 1 within a month of BMT, and 3 of pneumonia. Grade 2-4 aGVHD occurred in 11 pts (28%), grade 3-4 in 5 (13%). Extensive cGVHD was seen in 7 (18%). Median OS for the patients who relapsed after initial haploBMT who were then retransplanted with an HLA-haploidentical donor with a different shared haplotype has not been reached, versus a median OS of 501 [317-2950+] days among the 15 who did not receive a graft with an alternate shared haplotype (HR 0.21 [0.03, 1.61]; p=0.06). If the 19 patients who received a matched allograft at first transplant are included, median OS is 552 days in the group transplanted with a second graft with the same shared haplotype(s), and 1308 days (Figure 1) in the group whose allograft contained a different non-shared haplotype (HR 0.39 [0.16, 0.98]; p=0.04). OS was better when the second transplant was performed more than one year after the first (HR 0.30 [0.11, 0.80]; p=0.03). A trend towards improved OS was associated with disease status at time of second transplant (remission or chemo-responsiveness versus progressive or refractory disease; HR 0.41 [0.16, 1.03]; p=0.07). Source of graft (BM versus peripheral), conditioning intensity, era of transplant (2005-2010 versus 2010-2015), same versus different donor, and age group (<25, 25-60, 60+) did not significantly influence OS. Conclusion: Second transplants are feasible in all age groups and provide a reasonable chance of long-term survival. GVHD rates using PTCy are low, and similar to that seen with first BMTs. An allograft sharing a different haplotype in the case of relapse after haploBMT, or a haploidentical donor after failure of a matched graft, may be beneficial. OS by Second Donor Haplotype OS by Second Donor Haplotype Figure 1 Figure 1. Disclosures Brodsky: Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Achillion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Haploidentical Transplantation Using High Dose Post-Transplant Cyclophosphamide for Patients with Aplastic Anemia : The European Group for Blood and Marrow Transplantation Experience

Blood ◽

10.1182/blood-2018-99-114033 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 486-486

Author(s):

Pedro H Prata ◽

Boris Afanasyev ◽

Dirk-Jan Eikema ◽

Frans Smiers ◽

Cora Knol ◽

...

Keyword(s):

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Advisory Committees ◽

Platelet Recovery ◽

Post Transplant ◽

Haploidentical Transplantation ◽

Grade Iii

Abstract The outcome of patients with severe aplastic anemia (SAA) has greatly improved in recent years but is still poor for patients who failed or relapsed after immunosuppressive therapy (IST) and don't have a matched donor. Recent use of eltrombopag shows blood count improvements in 40% of cases, but most patients refractory to immunosuppressive therapy, are also unresponsive to eltrombopag. In this situation, hematopoietic stem cell transplantation (HSCT) using alternative donor sources (mismatched unrelated donors, cord blood, and haploidentical family donors) may be curative but are also associated with a high risk of morbidity and mortality. Moreover, ethnic minorities have limited access to an alternative donor, especially in the adult population. Haploidentical transplantation using post-transplant cyclophosphamide (Haplo-PTCy) has been shown to facilitate engraftment and shows GvHD rates comparable to those of matched sibling HSCT in hematologic malignancies. However, few papers have been published on Haplo-PTCy in the context of aplastic anemia. We conducted a retrospective analysis of 36 patients (72% male), who received an haplo-PTCy for aplastic anemia in 22 EBMT centers from June 2010 to March 2017. Haplo-PTCy was the first transplantation for 81% patients (second, 11%; third, 8%). The non-myeloablative preparatory regimen included anti-thymocyte globulin in 33% of patients and low dose TBI in 58% of patients. Donors were father (n=12, 35%), mother (n=12, 35%), brother (n=5, 15%), sister (n=3, 9%), cousin (n=1, 3%) and daughter (n=1, 3%). The stem cell source was mainly bone marrow (55%). All patients received cyclophosphamide 50mg/kg/day IV on days +3, and +4 post-transplant and 75% received tacrolimus or cyclosporine plus mycophenolic acid. The primary endpoint was the probability of OS. Secondary study endpoints included probability of neutrophil recovery (ANC 500/ μL for at least 3 consecutive days), platelet recovery (platelets 20 000/ μL for at least 3 consecutive days, and 7 days after the last transfusion), cumulative incidences of acute and chronic GVHD and relapse-free survival without Grade III-IV acute GvHD and without extensive chronic (GRFS). Thirty-two patients were diagnosed with moderate (7%), severe (52%) or very severe idiopathic aplastic anemia (41%), while 4 patients were transplanted for congenital aplastic anemia (3 Fanconi Anemia and 1 Diamond Blackfan). The median age was 19.4 years (range 2.5-45.4 years; 58% adults). Median disease duration before haplo-PTCy was 11.3 months (1.9-201.2). Thirty patients (83%) received pretreatment (77% anti-thymocyte globulin plus cyclosporine, 12% eltrombopag, and 1 patient (3%) received androgens). Cumulative incidence (CI) of neutrophil recovery at day 60 was 78% (64-91) with a median time of 21 days (18-26). Cumulative incidence (CI) of platelet recovery at day 60 was 60% (44-76) with a median time of 31 days (22-185). The CI of grade II-IV acute GvHD was 26% (12-41%) (grade II 19% (7-32%), grade III 6% (0-13%) and no grade IV). CI of chronic GvHD was 17% (5-30) at 1 year (6% (0-13%) extensive) and a CI of 22% (7-37) at 2 years (only limited, there was no new case of extensive cGvHD after one year). With a median follow-up of 24.6 months (15.9 - 38.2), the estimated probability of overall survival (OS) was 78% (64-91) at 1 year and 74% (60-89) at 2 years. Of note, among the 4 patients with inherited disorders, 2 died [1 infection (Diamond Blackfan) and 1 aGvHD (Fanconi Anemia)] and 2 are alive at month 12 and month 15 of follow-up, respectively. Nine patients died during the study. The main cause of death was infection (n=6, 67%). Finally, the GRFS (alive, full donor chimerism, without previous grade III-IV GvHD and without extensive cGvHD) was 58% (41-75) at 2 years. In conclusion, with a median follow-up of 2 years, Haplo-PTCy leads to 74% overall survival in 36 patients with aplastic anemia, with almost 60% of the patients being free from GvHD complication. In a population with no other therapeutic options, our data suggests haplo-PTCY is a feasible option. However, prospective well-designed trials are urgently needed before the inclusion of Haplo-PTCy in the treatment strategy of aplastic anemia. Disclosures Bloor: Janssen: Research Funding; AbbVie: Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Russell:Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy. Kerre:Celyad: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

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Donor Lymphocyte Infusion for Primary Cutaneous T Cell Lymphomas: A Study from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and the French Study Group on Cutaneous Lymphomas (GFLEC)

Blood ◽

10.1182/blood-2018-99-119566 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3341-3341 ◽

Cited By ~ 1

Author(s):

Sarah Faiz ◽

Henry Abi Rached ◽

Edouard Forcade ◽

Noel Milpied ◽

Marie Beylot-Barry ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Advisory Committees ◽

Post Transplant ◽

T Cell Lymphomas ◽

Cutaneous Lymphomas

Abstract Introduction: Primary cutaneous T cell lymphomas (PCTCL) including Mycosis fungoides (MF) and Sézary syndrome (SS) account for 75% of primary cutaneous lymphomas. The 5-year survival is 18-40% in patients with advanced-stage PCTCL. Management strategies and prognosis of PCTCL depend on the disease stage (affected body surface area, blood, visceral and nodal involvement). Allogeneic hematopoietic cell transplantation (allo-HCT) can be used to treat advanced stages in young adults who are otherwise in good health. However, post-transplant relapse is still an issue with no clear guidelines regarding its management. Here we describe the largest study investigating donor lymphocyte infusions (DLI) in patients who relapsed after allo-HCT for PCTCL. Patients and methods: We conducted an observational, retrospective, French multicenter study. Between January the 1st 2000 and December the 31st 2017, all patients who underwent an allo-HCT for PCTCL regardless of the subtype and who received DLI for a post-transplant relapse were included. Data were collected using the ProMISE database. As needed, centers were asked to provide additional data. Statistical analyses were carried out by the Lille University Hospital (CHRU Lille) Biostatistics Methodology Unit and were performed using SAS software (SAS Institute version 9.4). Results: All 13 patients who received DLI after allo-HCT for a PCTCL in France were enrolled in the study (Figure 1). Mean duration of follow-up was 718 days. See table 1 for study population characteristics. Four patients (30%) presented acute graft versus host disease (GVHD) following allo-HCT, of which no incidences were superior to grade 2. Those four patients relapsed at day 342, 463, 499 and 659 after allo-HCT. Five patients (38%) presented chronic GVHD of which three had an extensive presentation. Those three patients relapsed at day 1082, 1568 and 1861. Table 2 details relapses and relapse management in our cohort. Table 3 shows parameters relative to allo-HCT, post-therapeutic management, and follow-up. Objective response rates to DLI was 62% (n=8). Five patients (38%) showed complete response and three patients exhibited partial response (32%). Five patients (38%) did not respond to DLI. The median best response duration to DLI was 181 days. Six out of the eight patients who responded to DLI relapsed (75%); the median time before the relapse after DLI was of 405 days. The two patients who have received DLI and did not relapse on January the 1st 2018 had 321 and 1350 days follow-up. Progression-free survival (PFS) was 46% at 1 year and 19% at 5 years (Figure 2). Overall survival rates were 100% at 1 year and 59% at 5 years (Figure 3). Six patients (46%) presented GVHD after DLI of which three cases were chronic GVHD. Two of them was an extensive presentation. One patient had received an allo-HCT from a female donor. One patient received bone marrow transplant carrying a 9/10 mismatch. All other patients received peripheral blood stem cell (PBSC) transplantation; two of them received a geno-identical stem cell transplantation from sibling donors and three patients received non-sibling donor HSCT with a 10/10 mismatch. Only three patients received DLI following SFGM-TC guidelines. Four patients died before January the 1st 2018 in our cohort. One patient died because of direct complications of the HSCT and related treatments. Two patients died because of a disease relapse. One patient died from unrelated cause (severe pulmonary). Conclusion: With a 5-year survival rate of 59% from the date of post-transplant relapse, DLI appears to be an effective treatment in cases of patient relapse after allo-HCT for PCTCL. DLI should be considered in the management of post-transplant relapse whenever possible. To our best knowledge, this is the largest study cohort investigating DLI in the post-transplant setting Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Peffault De Latour:Amgen Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding.

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Comparison of Peripheral Blood Stem Cells (PBSC) to Bone Marrow (BM) for T-Replete HLA-Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v128.22.683.683 ◽

2016 ◽

Vol 128 (22) ◽

pp. 683-683 ◽

Cited By ~ 3

Author(s):

Asad Bashey ◽

MeiJie Zhang ◽

Shannon R. McCurdy ◽

Stefan O. Ciurea ◽

Andrew St. Martin ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Mortality Risks ◽

Post Transplant

Abstract T cell-replete haploidentical donor transplants (HAPLO-HCT) using post-transplant cyclophosphamide for control of alloreactivity is now being increasingly utilized. HAPLO-HCTs were originally performed using BM grafts. However, recently, a few single center studies have reported good outcomes using G-CSF mobilized PBSC grafts for HAPLO-HCT. No prospective randomized comparisons of BM to PBSC grafts for HAPLO-HCT have been performed. Therefore, we analyzed outcomes for 687 adults (496 BM, 191 PBSC) who received HAPLO-HCT for hematologic malignancies using post-transplant cyclophosphamide + mycophenolate + calcineurin inhibitor for GVHD prophylaxis between 2009 and 2014 in the United States. The primary outcome was overall survival. The characteristics of recipients of BM and PBSC were similar except BM recipients were older, more likely to have a performance score ≥90, HCT-CI index ≤2, be CMV seronegative, have a lymphoid malignancy and receive reduced-intensity conditioning. Most PBSC transplants occurred between 2012 and 2014. The median follow-up was 35 and 20 months for recipients of BM and PBSC grafts, respectively. Cox regression models were built to study the effect of graft type adjusted for other significant factors on overall mortality, non-relapse mortality, relapse and graft-versus-host disease (GVHD) and outcomes censored at 2-years to accommodate differential follow-up between treatment groups (Table 1). After adjusting for age, CMV serostatus, disease risk index (disease type/disease status for myeloid and lymphoid malignancy and cytogenetic risk for acute leukemia and myelodysplastic syndrome) and transplant conditioning regimen there were no significant differences in risks for overall mortality (HR 1.00, p= 0.98; 2-year overall survival: 54% and 57%) or non-relapse mortality (HR 0.92, p=0.74; 2-year non-relapse mortality: 17% and 16%) after transplantation of BM compared to PBSC, respectively. However, relapse risks were higher after transplantation of BM compared to PBSC (HR 1.49, p=0.009; 2-year relapse: 45% and 28%). Subset analyses explored the effect of graft type separately for myeloablative and reduced intensity conditioning regimen adjusting for age, CMV serostatus and disease risk index. Consistent with the main analysis there were no differences in overall or non-relapse mortality risks and relapse risks were higher with BM compared to PBSC with myeloablative regimens (Table 1). Although this may in part be explained by lower chronic GVHD risks with transplantation of BM grafts, chronic GVHD was not significantly predictive of relapse risk when modeled as a time-dependent covariate (HR= 0.73, p=0.49). Grade II-IV acute GVHD risks (HR 0.45, p<0.001; 22% and 37%), adjusted for conditioning regimen were lower after transplantation of BM compared to PBSC. Chronic GVHD risks adjusted for age and performance score were also lower after transplantation of BM compared to PBSC (HR 0.35, p<0.001; 20% and 41%) but rates of moderate and severe chronic GVHD were not significantly different (28% and 32%). There were no differences in incidence of hematopoietic recovery by graft type. In conclusion, compared to BM grafts HAPLO-HCT with PBSC are associated with similar overall survival and non-relapse mortality risks but lower relapse risks with myeloablative conditioning regimens. Longer follow up is needed to ascertain whether survival differences may occur later. The observed adverse effect of BM grafts on relapse with myeloablative regimens must be studied further in the setting of carefully controlled trials. Table 1. Table 1. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Hamadani:Takeda: Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees. Wingard:Ansun: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

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Long-Term Follow up of a Comparison of Non-Myeloablative Allografting with Autografting for Newly Diagnosed Myeloma

Blood ◽

10.1182/blood.v116.21.525.525 ◽

2010 ◽

Vol 116 (21) ◽

pp. 525-525 ◽

Cited By ~ 1

Author(s):

Benedetto Bruno ◽

Barry Storer ◽

Francesca Patriarca ◽

Marcello Rotta ◽

Roberto Sorasio ◽

...

Keyword(s):

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

New Drugs ◽

High Dose ◽

Advisory Committees ◽

Term Survival ◽

High Dose Melphalan

Abstract Abstract 525 Background: Role and timing of allografting in myeloma are hotly debated. Before the introduction of new drugs, we carried out a trial where the treatment assignment was based only on the presence/absence of an HLA-identical sibling (Bruno et al, N Engl J Med 2007). Methods: Overall, 162/199 (81%) of patients with at least one sibling were HLA-typed. First-line treatments included induction with VAD-based regimens and a cytoreductive autograft, followed by a nonmyeloablative allograft (Tandem auto-allo) or a second melphalan-based autograft (Double-auto). We now report an update at a median follow up of 7.1 years. Results: Response rates [complete (CR) and partial remissions (PR)] at the time and after the non-myeloablative allograft and at the time and after the second autograft did not differ between the two cohorts: 76% and 86%, and 76% and 91% respectively (p=1 and p=0,54). However, CR rate was significantly higher after the non-myeloablative allograft than after the second autograft: 55% versus 26% (p=0,0026). At a median follow up of 7.1 years (range 2.5 – 10.7+), by intention-to-treat analysis, median overall survival (OS) and event free survival (EFS) were significantly longer in patients with HLA-identical siblings (No.80) as compared with those without (No.82): not reached vs. 4.25 years (HR 0.51, CI 95% 0.34–0.76, p=0.001) and 2.8 vs. 2.4 years (HR 0.62, CI 95% 0.44–0.87, p=0.005). By multivariate analysis, independent of age, gender, myeloma protein isotype, Durie&Salmon stage, and disease status at the first autograft; the presence of an HLA-identical sibling was significantly associated with longer OS (HR 0.5, CI 95% 0.3–0.8, p=0.001) and EFS (HR 0.63, CI 95% 0.4–0.9, p=0.01). At a median follow up of 7.3 (range 5.4 – 10.7+ years), median OS was not reached in the 58 patients who received a non-myeloablative allograft and 5.3 years in the 46 who received a second high-dose melphalan autograft (HR 0.55, CI 95% 0.32–0.94, p=0.02), whereas EFS was 39 months and 33 months (HR 0.62, CI 95% 0.40–0.96, p=0.02) respectively. Cumulative incidence of transplant related mortality was 11% and 2% at 2 years respectively. At median follow-ups of 7.3 years from diagnosis (range 5.4 – 10.4+) and 6.5 years from the allograft (range 4.2 – 9.4+), and 7.4 years from diagnosis (range 5.6 – 10.7+) and 6.2 years from the second autograft (range 4.7 – 9.1+), 30/58 (52%) and 37/46 (80%) patients, respectively, were treated for disease relapse/progression. Salvage therapies included bortezomib- or thalidomide-containing regimens in most patients of both cohorts. After 1–3 lines of therapy, 22/30 (73%) had a response, including 5 CR and 17 PR, in the tandem auto-allo group, whereas 21/37 (54%) had a response, including 4 CR and 16 PR after the second autograft. Of note, at a median follow up of 3.9 years from the start of the first salvage therapy, OS was not reached and was 1.7 years in patients who had relapsed/progressed after the allograft and the second high-dose melphalan (HR 0.44, CI 95% 0.24–0.82, p=0.01) respectively. Conclusions: In this study, allografting conferred a long term survival advantage over standard autografting. Salvage therapy was associated with longer OS perhaps due to a synergistic effect between new drugs and residual graft-vs.-myeloma effects. In prospective clinical trials, the combination of graft-vs.-myeloma effects with “new drugs” should be explored and may increase the cure rate of myeloma patients. Disclosures: Bringhen: Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Blood ◽

10.1182/blood-2021-153560 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2188-2188

Author(s):

Louis Terriou ◽

Christopher J. Patriquin ◽

Morag Griffin ◽

Jong Wook Lee ◽

Philippe Gustovic ◽

...

Keyword(s):

Rare Disease ◽

Board Of Directors ◽

Survival Probability ◽

Advisory Committees ◽

Term Survival ◽

Treatment Status ◽

History Of ◽

Baseline Characteristics

Abstract Background Eculizumab, the first C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH), transformed PNH treatment by improving survival to that of an age- and sex- matched general population. Previous analyses demonstrating the survival benefit of eculizumab in patients with PNH leveraged historical data and were limited by small patient numbers and short follow-up durations; few evaluated survival of patients receiving eculizumab compared with untreated patients. The objective of the current analysis was to describe the baseline characteristics and overall survival of a large international cohort of eculizumab-treated patients compared with a contemporaneous untreated cohort using data from the prospective, observational International PNH Registry (NCT01374360). Methods Data from patients enrolled in the Registry after March 16, 2007 with complete information for birth date, sex, enrollment date, and treatment status were included (database cut-off, April 12, 2021). Ever-treated patients were those who received eculizumab for a minimum treatment period of 35 days while enrolled in the Registry; never-treated patients did not receive eculizumab at any time before or during Registry participation. Univariate and multivariate analyses were performed using a Cox proportional hazards that incorporated the following parameters at baseline as covariates: treatment status, presence of high disease activity (HDA), age, sex, history of bone marrow failure (BMF), history of thrombotic events (TE), transfusion dependence, and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2. HDA was defined as lactate dehydrogenase (LDH) ratio ≥1.5 × upper limit of normal (ULN) and ≥1 of the following: history of major adverse vascular events (including TE); anemia (hemoglobin <10 g/dL), or physician-documented abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction at any time before and including baseline. Baseline was defined as the date of eculizumab treatment initiation (ever-treated patients) or date of Registry enrollment (never-treated patients). Survival time was analyzed using a left-truncation approach that mapped time in patients' survival based on disease start date, defined as the earliest date of first-reported PNH diagnosis, PNH symptom, or first consistent flow cytometry result. Results Baseline characteristics of the 4627 patients included in the analysis (mean [SD] age at disease start, 40.2 [18.71] years; 53% female; 75% white) were comparable between the ever-treated and never-treated groups (n=1892 and n=2735, respectively). Compared with never-treated patients, more ever-treated patients had LDH ≥1.5 × ULN (90% vs 35%), and fewer had <10% PNH granulocytes (3% vs 57%) or history of BMF (45% vs 76%). The univariate Cox proportional hazard ratio (HR) for mortality in ever-treated vs never-treated patients was 0.48 (95% CI, 0.39-0.60; P<0.0001), indicating a 52% increase in survival in the treated group (Table). Among ever-treated patients, those with HDA at baseline experienced the largest reduction in mortality risk (HR [95% CI], 0.46 [0.33-0.64]; n=174); however, decreased mortality was also evident in ever-treated patients without HDA (HR, 0.65 [0.39-1.10]; n=212) or with unknown HDA status (HR, 0.50 [0.32-0.76; n=120) at baseline. Overall survival probability by treatment status was consistently greater in ever-treated vs never-treated patients through 20 years of follow-up; survival probability at 20 years was 82% (ever-treated) vs 69% (never-treated). Although long-term survival probability was greatest throughout follow-up in ever-treated patients with HDA at baseline, increased survival among ever-treated patients was evident in all 3 HDA status groups (Figure). Conclusion In this analysis of Registry data, treatment with the C5 inhibitor eculizumab improved patient survival compared with a never-treated cohort at a comparable time point in their disease course. Covariates were assessed at baseline only and competing risks and time on treatment were not controlled for, which are potential limitations. Survival benefits conferred by eculizumab treatment were observed regardless of HDA status at baseline, were more pronounced in treated patients with HDA vs those without HDA, and were maintained through 2 decades of real-world follow-up. Figure 1 Figure 1. Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin: Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Szer: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Allogeneic Stem Cell Transplantation Is Associated with Prolonged Disease Control in Chemosensitive Aggressive Histology Lymphoma Patients When Done Early

Blood ◽

10.1182/blood.v118.21.4525.4525 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4525-4525

Author(s):

Auro Viswabandya ◽

Tony Panzarella ◽

Dennis Dong Hwan Kim ◽

Vikas Gupta ◽

Jeffrey H. Lipton ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Aggressive Histology ◽

Grade 3

Abstract Abstract 4525 Introduction Allogeneic stem cell transplantation (Allo-SCT) is a treatment option in aggressive histology lymphoma (AG-NHL) patients who have either failed or relapsed after autologous SCT (ASCT) or if the potential for long term disease control after ASCT is limited. There is limited data in literature regarding the long term outcome of allo-SCT in AG-NHL. Methods We did a retrospective analysis of all aggressive histology patients who underwent Allo-SCT between 1989 and 2009 at our centre. A total of 41 patients with AG-NHL [diffuse large B cell lymphoma (DLBCL) and variants, follicular lymphoma grade 3 (FL3), biopsy proven aggressive transformation of indolent lymphoma (TRIL)] underwent Allo-SCT. All patients were in a chemosensitive remission at time of transplantation. The conditioning regimen was BU-CY in the majority (36 or 88%) of patients and 3 patients had reduced intensity transplantation (RIC) with fludarabine-based regimens. GVHD prophylaxis was cyclosporine and methotrexate until 2009 and was cyclosporine and mycophenolate mofetil after that. Alemtuzumab was used in matched unrelated donor (MUD) transplants in 5 (12%) cases. Results There were 22 (54%) males and 19 (46%) females. The median age at BMT was 48 years (range: 20–65). Fifteen (37%) had DLBCL, 19 (46%) had TRIL and 7 (17%) had FL3. Fifteen (37%) patients had received 2 or less lines of chemotherapy and 26 (63%) had received more than 2 lines of therapy at time of transplantation. The median number of chemo regimens was 3 (range: 1–7). The chemotherapy regimens included prior anthracyclines in 40 (98%), prior platinum in 26 (63%) and prior mini BEAM in 19 (46%). Six (15%) patients had received Rituximab and 9 (22%) had received prior RT. Seven (17%) patients had prior ASCT. Thirty-five (85%) of patients received matched related donor transplant whereas 5 (12%) received MUD transplant. The graft source was bone marrow in 33 (80%) and peripheral blood stem cells in 8 (20%). Grade 1–2 acute GVHD was seen in 53% and grade 3–4 in 9%. Chronic GVHD was seen in 51% patients. With a median follow up of 49 months and 96 months in those who are alive, five (12%) patients have relapsed, 20 (49%) patients are alive and in remission. Non relapse mortality (NRM) was 16/41 (39%) and predominantly related to infection. The overall survival (OS) and progression free survival (PFS) of the entire cohort at 60 months was 55% (Fig-1). Patients, who had achieved CR pre-allo-SCT (compared to PR) had a statistically significantly improved PFS and OS (100% survival for those who were in CR). In multivariate analysis, number of chemotherapy regimens (≤2) was associated with improved OS (p=0.015) and presence of chronic GVHD showed a trend towards significant OS (p=0.052) Conclusions With a median follow up of 96 months in survivors, myeloablative allo-SCT is associated with durable remission in patients with chemosensitive AG-NHL. Results are less favourable in patients who have received multiple prior regimens. NRM remains a significant concern with myeloablative regimens. We believe there is a role for myeloablative regimens and research should focus on ways to reduce NRM in this setting. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Stable Factor IX Activity Following AAV-Mediated Gene Transfer in Patients with Severe Hemophilia B

Blood ◽

10.1182/blood.v120.21.752.752 ◽

2012 ◽

Vol 120 (21) ◽

pp. 752-752

Author(s):

Andrew Davidoff ◽

Edward GD Tuddenham ◽

Savita Rangarajan ◽

Cecilia Rosales ◽

Jenny McIntosh ◽

...

Keyword(s):

Gene Transfer ◽

Board Of Directors ◽

Normal Values ◽

Factor Ix ◽

Hemophilia B ◽

High Dose ◽

Severe Hemophilia ◽

Advisory Committees ◽

Short Course

Abstract Abstract 752 Introduction: We are conducting a phase I/II clinical trial of factor IX gene transfer for severe hemophilia B. In the trial we are using a serotype-8 pseudotyped self-complementary adeno-associated virus (scAAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). We have previously reported the early safety and efficacy of our novel gene transfer approach in six patients with severe hemophilia B following a single peripheral vein infusion of one of three vector doses (low [2×1011 vector particles (vp)/kilogram weight (kg)], intermediate [6×1011 vp/kg], or high dose [2×1012 vp/kg]) (Nathwani et al, NEJM 365:2357–65, 2011). AAV-mediated expression of FIX at 1–6% of normal was established in all six participants with an initial follow-up of between 6–14 months following gene transfer. We now report longer follow-up of these participants, as well as data from two additional participants recently enrolled at the high dose level. Methods: We have now infused scAAV2/8-LP1-hFIXco in eight subjects with severe hemophilia B (FIX activity, <1% of normal values). Vector was administered without immunosuppressive therapy, and participants have now been followed for 3 months to 2½ years. FIX activity, serum transaminases, vector genomes in secretions/excretions, antibodies to FIX and AAV8, and AAV8 capsid-specific T-cells were monitored during the follow-up. Results: Each of the participants currently has AAV-mediated activity of FIX at 1 to 6% of normal levels. These levels have been stable in each during the follow-up period which is now greater than 1½ years for the first six participants. Five of the eight participants have discontinued FIX prophylaxis and remain free of spontaneous hemorrhage; in the other three, the interval between prophylactic injections has increased. None of the participants in the low or intermediate dose cohorts had evidence of transaminitis; each currently has FIX activity of 1–3% for over 1½ years. Of the four participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; two others had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these three participants received a short course of glucocorticoid therapy, which rapidly normalized their aminotransferase levels and maintained FIX levels in the range of 4 to 6% of normal values. The fourth participant has not had transaminitis three months after vector administration. Conclusions: This represents the first successful, long-term, gene therapy-mediated expression of a therapeutic protein from an AAV vector delivered to human liver. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. Larger numbers of patients followed for longer periods of time are necessary to fully define the benefits and risks and to optimize dosing. However, this gene therapy approach, even with its risk of mild, transient transaminitis, has the potential to convert the bleeding phenotype of patients with severe hemophilia B into a mild form of the disease or to reverse it entirely for a prolonged period of time following vector administration. (ClinicalTrials.gov number, NCT00979238). Disclosures: Chowdary: Novo Nordisk: Consultancy. High:Amsterdam Molecular Therapeutics: ; Baxter Healthcare: Consultancy; Biogen Idec: Consultancy; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees; Genzyme, Inc.: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: ; Sangamo Biosciences: ; Shire Pharmaceuticals: Consultancy.

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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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