scholarly journals Results of a Phase II Study of PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Gabriela S. Hobbs ◽  
Cansu Cimen Bozkus ◽  
Martha Wadleigh ◽  
Lonette Sandy ◽  
Mikaela Doughtery ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Post Treatment ◽  
Phase 2 ◽  
Hematopoietic Stem ◽  
Grade 3

Background: Myelofibrosis (MF) is a hematopoietic stem cell neoplasm characterized by abnormal JAK-STAT signaling, increased inflammation, and evolution to acute myeloid leukemia. Most patients harbor a phenotypic driver mutation- JAK2, CALR or MPL. In the last decade, two JAK2 inhibitors have been approved, however, outside of hematopoietic stem cell transplantation (HSCT), there are no medications that meaningfully modify MF disease biology. Thus, additional treatments are needed. We previously demonstrated the presence of multiple immunosuppressive mechanisms in MPN patients, including expanded myeloid derived suppressor cell (MDSC) populations and elevated expression of immune checkpoint receptors, particularly PD1, on T cells from MPN patients compared to healthy donors (Cimen Bozkus, Cancer Discovery 2019). Therefore, we conducted a multi-center, open-label, phase 2, single-arm study of pembrolizumab in patients with primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) (NCT03065400). Methods: Patients with intermediate-2/high DIPSS MF, ineligible for or previously failed ruxolitinib were eligible. Pembrolizumab was administered at the FDA-approved dose of 200 mg every 3 weeks for 6 cycles. The study was a Simon two-stage design, 9 patients enrolled in the first arm. The study was terminated after completion of this arm due to the lack of responses. Response assessment was conducted after 6 cycles utilizing the International Working Group (IWG-MRT) criteria. In addition, patients with accelerated or blast phase (MPN-AP/BP) could enroll as a separate, ten patient, exploratory cohort. Results: 9 patients enrolled in the MF cohort and 1 in the BP cohort between 6/2017 and 3/2020. Baseline characteristics are summarized in Table 1. Median weeks on treatment were 14.7 (range 4-20). All 9 MF patients were evaluable for response as they received at least 1 dose of pembrolizumab. Of the 9 patients who were evaluable for response, all had SD, 4 (44%) patients discontinued therapy prior to the end of cycle 6. Reasons for discontinuation were adverse events (n=1), patient decision (n=1), physician decision (n=2). Grade 3/4 AEs included anemia (n=3), thrombocytopenia (n=2), leukopenia (n=1), hyperglycemia (n=2), hyperuricemia (n=1), dyspnea (n=1), headache (n=1). No grade 3/4 immune related AEs occurred (Table 2). The effects of pembrolizumab on the immune suppressive milieu observed in MPN were analyzed. PD-1 was detected on peripheral blood T cells by flow cytometry at baseline, but not post-treatment, likely due to receptor occupancy by pembrolizumab. In all patients analyzed, the levels of soluble PD1 in the plasma by Olink assay were significantly higher post-treatment. Other soluble factors associated with T cell activation such as class I-restricted T cell-associated molecule (CRTAM) and CD27 were also elevated after pembrolizumab administration. Furthermore, ARG1, a molecule that mediates T-cell suppression by MDSC, was significantly reduced in the plasma of treated patients. An increase in peripheral blood T cell frequencies was observed in a subset of patients after two cycles. Discussion: Pembrolizumab did not demonstrate clinical activity in this phase 2 trial. The relevance of the preliminary correlative findings will be further confirmed by in situ gene profiling of immune cells and their microenvironment. The complete results will be available at the meeting. These results suggest that pembrolizumab may promote a phenotypical and soluble signature suggestive of a restored immune response. The fact that these molecular changes were not associated with clinical responses indicate that pembrolizumab alone may not be sufficient to reverse the multifactorial causes of immune tolerance in MPN. Disclosures Hobbs: Constellation: Honoraria, Research Funding; Bayer: Research Funding; Jazz: Honoraria; Incyte: Research Funding; Novartis: Honoraria; Merck: Research Funding; Celgene/BMS: Honoraria. Stone:Syndax: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Takeda: Other: DSMB; Syntrix: Other: DSMB; Arog: Consultancy, Research Funding; Jazz: Consultancy; Trovagene: Consultancy; Syros: Consultancy; Abbvie: Consultancy, Research Funding; Biolinerx: Consultancy; Argenix: Other; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Other; Agios: Consultancy, Research Funding; Gemoab: Consultancy; Janssen: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Aztra-Zeneca: Consultancy; Macrogenics: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.

Evaluation Of Immunocompentence In Tolerant Chimeric Recipients Of Hematopoietic Stem Cell/Renal Transplants

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4483-4483
Author(s):  
Joseph Leventhal ◽  
Larry D Bozulic ◽  
Mark D. Badder ◽  
Mary Jane Elliott ◽  
Michael N Issa ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
High Frequency ◽  
Blood Type ◽  
Phase 2 ◽  
Hematopoietic Stem ◽  
Tcr Repertoire

A phase 2 protocol was developed to attempt to induce donor-specific tolerance to renal allografts in related and unrelated donor/recipient combinations (IND 13947 phase 2). Subjects were conditioned with fludarabine (days -5, -4, -3), cyclophosphamide (50 mg/ky days -3 and +3), and 200 cGy total body irradiation. The kidney transplant was performed day 0. G-CSF mobilized peripheral blood stem cells processed to remove GVHD-producing cells and retain graft facilitating cells (FC) was administered on day +1. The conditioning was well tolerated and the subjects were managed as outpatients after post-operative day 2. This has resulted in high levels of durable chimerism and immunosuppression-free graft survival without GVHD or engraftment syndrome in mismatched related and unrelated recipients of living donor FC/hematopoietic stem cell/kidney allografts. Nine subjects are completely off immunosuppression from 2 months to 3 years. A number of others are in the process of tapering. In the present study, we have prospectively analyzed recovery of immune function, persistence of vaccination memory, and response to vaccination in subjects who exhibit high levels of chimerism. Chimerism testing was performed using molecular short tandem report (sensitivity ±5%). Three of four subjects who had been vaccinated to hepatitis B prior to transplantation and whose donors had not been vaccinated retained their immunity following transplantation. All subjects tested exhibited memory for varicella and the majority did as well for measles (9/11), mumps (8/11), and rubella (5/10). A blood group disparity was present in 9 chimeric donor/recipient pairs. One chimeric subject converted to donor blood type, 3 exhibited mixed donor/host RBC chimerism, and 5 retained their own blood type. Six chimeric subjects have been immunized with pneumococcal vaccine after transplantation. All generated an immune response to vaccination, confirming immunocompetence to generate an antibody response to antigen. Notably, recovery of CD8+ and CD4+ central memory, naïve, and effector memory T cells occurred within one year post-transplantation to levels that were not significantly different from pre-transplantation. In addition, CD31+/CD45RA+ CD8+ and CD4+ T cells representative of recent thymic emigrants were present by 3 months, demonstrating de novo thymic production of T cells after transplantation. Four patients were randomly selected for study of Tcell repertoire (TCR) generation after transplantation. Two had achieved durable full donor chimerism and the other two did not have durable chimerism. Peripheral blood samples freshly obtained from donors and recipients and T cell subsets were isolated using MACs microbead system. DNA was extracted and sequenced by ImmunoSeq (Adaptive Biotech, Seattle, WA) to evaluate TCR clonal repertoires in recipients. Although clonal diversity in TCR repertoire was reduced in post-Tx recipients (0.9 ± 0.05 pre-Tx vs. 0.79 ± 0.09 post-Tx), the repertoire was diverse enough to suggest recovery of immune competence. Interestingly, at least 97% of the unique sequences observed in post-Tx recipient were not present in either donor or recipient pre-Tx. Within the pool of shared sequences, full chimerism correlated with a shift towards homology with the donor, while loss of chimerism correlated with recipient pre-Tx. In addition, the chimeric patients also exhibited reduced diversity of TCR sequences and increased clonality. Top 20 “high frequency” clones are most stably expressed. CD8+ cells had the highest number of “high frequency” clones. Notably, the pattern of “low frequency” clones was highest in the CD127-CD4+CD25+ regulatory T cell subset, indicating an extensive and rapidly changing TCR repertoire. Taken together, these data suggest that immunologic recovery is robust in these nonmyeloablatively conditioned tolerant chimeric subjects. Disclosures: Bozulic: Regenerex, LLC: Employment. Badder:Regenerex, LLC: Employment. Ildstad:Regenerex, LLC: Equity Ownership.

Thymic Dendritc Cells Generated Ex Vivo Induce Donor Regulatory T Cell Differentiation and Hasten Immune Reconstitution After Hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1905-1905
Author(s):  
Mari Hashitate Dallas ◽  
Deanna Langfitt ◽  
Kenneth Busby
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Control Group ◽  
Hematopoietic Stem

Abstract Abstract 1905 Dendritic cells (DCs) are the first committed cells to engraft in the thymus after hematopoietic stem cell transplantation (HSCT). The critical role of thymic DCs in ensuring efficient tolerance and selection has been well demonstrated, however its role in facilitating donor engraftment has not been reported. Here we show DCs accelerates thymic reconstitution by inducing regulatory T cells (Tregs) differentiation and enhancing T cell recovery after HSCT. Lethally irradiated CD45.2 C57BL/6 control group received 103 CD45.1 lin−sca-1+c-kit+ (LSK) hematopoietic stem cell progenitors while the DCs group received 103 CD45.1 LSK cells along with 103 CD45.2 GFP+ DCs. DCs were generated ex vivo using bone marrow from CD45.2 GFP+ CD57BL/6 mice and cultured for 7 days with GMCSF. At 4 and 7 days after HSCT, the thymus of DC group contained 1.8 and 4.2- fold higher number of thymocytes (p<0.05) and a 3.2 and 7.4-fold, respectively, higher number of donor derived thymoctyes compared to the control group (p<0.05). Moreover, thymuses of the DCs group had GFP+ CD11c+ cells present in the medulla and 5.6-fold increase in the number of donor derived FoxP3+ Tregs compared to control confirmed by immunohistochemistry (IHC). Furthermore, thymic recovery scored by a pathologist blinded to the groups found significant increase in lymphoid regeneration (H&E) and higher number of CD3+ lymphoid aggregates (IHC) in the DC group compared to control group that had severe, diffuse lymphoid depletion. Lastly, at 2 and 4 weeks after HSCT, peripheral blood of DCs group contained 2.6 and 4.8-fold, respectively, higher numbers of CD3+ cells derived from donor LSK cells compared to the control group (p<0.05). Here, we demonstrate that donor DCs efficiently migrate and home to the thymic medulla and hasten thymic recovery as demonstrated by the higher number of total thymoctyes. Furthermore, DCs facilitate thymic engraftment as shown by increase number of donor derived FoxP3+ Tregs and thymocytes. Lastly, recipients of DCs have earlier generation of de-novo donor derived CD3+ T cells in the peripheral blood. By using the GFP+ cells along with donor LSK cells, we were able to confirm that the facilitation of early thymic recovery was due to the increased engraftment of the donor cells rather than autologous recovery of the host. In conclusion, this study demonstrates that DCs committed prior to thymic entry maintains the ability to home to the medullary region and facilitate thymic recovery by enhancing Tregs differentiation. Thus, ex vivo generation of donor DCs to augment a HSC graft may Disclosures: No relevant conflicts of interest to declare.

scholarly journals Direct evidence for new T-cell generation by patients after either T-cell–depleted or unmodified allogeneic hematopoietic stem cell transplantations

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2235-2242 ◽  
Author(s):  
Sharon R. Lewin ◽  
Glenn Heller ◽  
Linqi Zhang ◽  
Elaine Rodrigues ◽  
Eva Skulsky ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Opportunistic Infections ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
The Difference ◽  
T Cell Phenotypes

Abstract Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution of normal T-cell immunity. Recipient thymic activity, biologic features of the allograft, and preparative regimens all contribute to immune reconstitution. We evaluated circulating T-cell phenotypes and T-cell receptor rearrangement excision circles (TRECs) in 331 blood samples from 158 patients who had undergone allogeneic HSCTs. All patients had received myeloablative conditioning regimens and were full donor chimeras in remission. Younger patients exhibited more rapid recovery and higher TRECs (P = .02). Recipients of T-cell–depleted allografts initially had lower TRECs than unmodified allograft recipients (P < .01), but the difference abated beyond 9 months. TREC level disparities did not achieve significance among adults with respect to type of allograft. Measurable, albeit low, TREC values correlated strongly with severe opportunistic infections (P < .01). This finding was most notable during the first 6 months after transplantation, when patients are at greatest risk but before cytofluorography can detect circulating CD45RA+ T cells. Low TRECs also correlated strongly with extensive chronic graft-versus-host disease (P < .01). Recipients of all ages of either unmodified or T-cell–depleted allografts therefore actively generate new T cells. This generation is most notable among adult recipients of T-cell–depleted allografts, most of whom had also received antithymocyte globulin for rejection prophylaxis. Low TREC values are significantly associated with morbidity and mortality after transplantation. T-cell neogenesis, appropriate to age but delayed in adult recipients of T-cell– depleted allografts, justifies interventions to hasten this process and to stimulate desirable cellular immune responses.

Berkeley Sickle Mice Demonstrate CD8- and NK1.1-Dependent Increased Rejection of Allogeneic Hematopoietic Stem Cell Transplants.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2332-2332
Author(s):  
Leslie Kean ◽  
Kelly Hamby ◽  
Jennifer Perry ◽  
Christian Larsen ◽  
David Archerq
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
Increased Risk

Abstract While hematopoietic stem cell transplantation (HSCT) represents the only curative therapy for sickle cell disease, sickle patients undergoing HSCT face many complications, including an increased risk of graft rejection compared to non-sickle patients. We have used the Berkeley sickle mouse model to study the potential mechanisms underlying this increased risk of rejection. Using a CD28/CD40 costimulation-blockade-based non-myeloablative HSCT regimen, we transplanted Berkeley sickle mice with fully allogeneic SJL bone marrow. While the vast majority (&gt;85%, n=25) of control C57BL/6 animals became stably chimeric and immunologically donor-tolerant with this transplant regimen, sickle mice were much more prone to reject the transplant (~20% graft acceptance, n=25). Both CD8+ cells and NK1.1+ cells were found to contribute to this rejection, as depletion of either of these cell populations led to a marked increase in the percent of engrafted mice (&gt;85% graft acceptance, n=15–25), while depletion of CD4+ cells led to the opposite effect, with 0% (n=25) animals engrafted in this depletion cohort. The increased propensity of HSCT rejection in the Berkeley sickle mice may, in part, be explained by the presence of increased numbers of donor-reactive T cells (5–10-fold compared to C57BL/6 controls) in naïve sickle mice, despite their lack of exposure to donor antigens, and their housing in a Specific-Pathogen-Free environment. We speculate that these increased numbers of anti-donor T cells may occur as a result of heightened inflammation in the context of active sickle cell disease, which could lead to increased expansion and persistence of a T cell repertoire containing anti-donor heterologous T cell immunity. This heterologous immunity may have a profound effect on the success of HSCT for sickle cell disease, especially when non-myeloablative regimens are employed.

Hematopoietic Stem Cell Differentiation Pathway in Humans Deduced From the Lineage Diversity of PNH-Type Cells in Patients with Bone Marrow Failure.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1489-1489
Author(s):  
Takamasa Katagiri ◽  
Zhirong Qi ◽  
Yu Kiyu ◽  
Naomi Sugimori ◽  
J. Luis Espinoza ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Bone Marrow Failure ◽  
Stem Cell Differentiation ◽  
Refractory Anemia ◽  
Hematopoietic Stem

Abstract Abstract 1489 Poster Board I-512 The hematopoietic stem cell (HSC) differentiation pathway in humans remains largely unknown due to the lack of an appropriate in vivo assay allowing the growth of HSCs as well as of clonal markers that enable the tracing of their progenies. Small populations of blood cells deficient in glycosylphosphatidylinositol-anchored proteins (GPI-APs) such as CD55 and CD59 are detectable in approximately 50% of patients with aplastic anemia (AA) and 15% of patients with refractory anemia (RA) of myelodysplastic syndrome defined by the FAB classification. Such blood cells with the paroxysmal nocturnal hemoglobinuria (PNH) phenotype (PNH-type cells) are derived from single PIGA mutant HSCs and their fate depends on the proliferation and self-maintenance properties of the individual HSCs that undergo PIG-A mutation by chance (Blood 2008;112:2160, Br J Haematol 2009 in press) Analyses of the PNH-type cells from a large number of patients on the diversity of lineage combination may help clarify the HSC differentiation pathway in humans because PIG-A mutant HSCs in patients with bone marrow failure appear to reflect the kinetics of healthy HSCs. Therefore, different lineages of peripheral blood cells were examined including glycophorin A+ erythrocytes (E), CD11b+ granulocytes (G), CD33+ monocytes (M), CD3+ T cells (T), CD19+ B cells (B), and NKp46+ NK cells (Nk) from 527 patients with AA or RA for the presence of CD55−CD59− cells in E and G, and CD55−CD59−CD48− cells in M,T, B, Nk with high sensitivity flow cytometry. Two hundred and twenty-eight patients (43%) displayed 0.003% to 99.1% PNH-type cells in at least one lineage of cells. The lineage combination patterns of PNH-type cells in these patients included EGM in 71 patients (31%), EGMTBNk in 43 (19%), EG in 37 (16%), T alone 14 (6%), EGMBNk in 11 (5%), G alone in 10 (4%), GM in 10 (4%), EGMNk in 7 (3%), EGMT in 7 (3%), EGMB in 6 (3%), EM in 5 (2%), EGMTB in 3 (1%), EGNk in 1 (0.4%), EGMTNk in 1 (0.4%), GMTB in 1 (0.4%), and GT in 1 (0.4%) (Table). All patterns included G or M, except for 14 patients displaying PNH-type T cells alone. No patients showed TB or TBNk patterns suggestive of the presence of common lymphoid progenitor cells. Peripheral blood specimens from 123 patients of the 228 patients possessing PNH-type cells were examined again after 3 to 10 months and all patients showed the same combination patterns as those revealed by the first examination. PIG-A gene analyses using sorted PNH-type cells from 3 patients revealed the same mutation in G and Nk for 1 patient and in G and T for 2 patients. These findings indicate that human HSCs may take a similar differentiation pathway to that of murine HSCs, the ‘myeloid-based model’ that was recently proposed by Kawamoto et al. (Nature 2008; 10:452), though the cases with PNH-type T cells alone remain to be elucidated. Table. Lineages of cells containing PNH-type cells in patients with AA or RA. The number in the parenthesis denotes the proportion of patients showing each combination pattern in the total patients possessing PNH-type cells. (+ ; presence of PNH-type cells) Disclosures No relevant conflicts of interest to declare.

Interruption of IFNγR Signaling Results in Altered T Cell Trafficking in Vivo and Abrogation of GvHD While Maintaining a Robust Gvl Response

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 455-455
Author(s):  
Jaebok Choi ◽  
Edward Dela Ziga ◽  
Julie Ritchey ◽  
Lynne Collins ◽  
Julie Prior ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Trafficking ◽  
Hematopoietic Stem ◽  
T Cell Trafficking ◽  
Target Organs ◽  
Donor T Cells

Abstract Abstract 455 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia, and marrow failure states such as myelodysplasia and aplastic anemia. However, allo-HSCT is complicated by allogeneic donor T cell-mediated graft-versus-host disease (GvHD) which can be life-threatening especially in recipients of unrelated or HLA-mismatched hematopoietic stem cell products. These same alloreactive donor T cells also mediate a beneficial graft-versus-leukemia (GvL) effect. Thus, the clinical goal in allo-HSCT is to minimize GvHD while maintaining GvL. Recent studies have suggested that this might be achieved by infusing regulatory T cells (Tregs) which in some preclinical models suppress GvHD-causing alloreactive donor T cells but have only limited effects on GvL-promoting alloreactive donor T cells. Unfortunately, Tregs exist in low frequency in the peripheral blood, are costly to purify and expand, and after expansion are difficult to isolate due to the lack of cell surface markers, all of which prevent their routine use in the clinic. Thus, alternative therapeutic approaches that do not require Tregs are needed. We have found that interferon gamma receptor deficient (IFNγR−/−) allogeneic donor T cells induce significantly less GvHD in both a MHC fully-mismatched (B6 (H-2b) → Balb/c (H-2d)) and a minor-mismatched (B6 (H-2b) → B6×129(H-2b)) allo-HSCT models compared to WT T cells. In addition, IFNγR−/− donor T cells maintain a beneficial GvL effect, which has been examined in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c. We find that IFNγR−/− T cells migrate primarily to the spleen while WT T cells to GI tract and peripheral lymph nodes (LNs) using bioluminescence imaging (BLI), suggesting that altered T cell trafficking of IFNγR−/− T cells to GvHD target organs might be the major reason for the reduced GvHD. We further demonstrate that the IFNγR-mediated signaling in alloreactive donor T cells is required for expression of CXCR3 which has been implicated in trafficking of T cells to areas of inflammation and target organs, commonly known to be the sites of GvHD. Indeed, CXCR3−/− T cells recapitulate the reduced GvHD potential of IFNγR−/− T cells. In addition, forced overexpression of CXCR3 in IFNγR−/− T cells via retroviral transduction partially rescues the GvHD defect observed in IFNγR−/− T cells. We next examine if inhibition of IFNγR signaling using a small molecule inhibitor can recapitulate the anti-GVHD effects seen in IFNγR−/− T cells. We find that INCB018424, an inhibitor of JAK1/JAK2 which are the mediators of IFNγR signaling, blocks CXCR3 expression in vitro. Most importantly, in vivo administration of INCB018424 after allo-HSCT alters T cell trafficking and significantly reduces GvHD. Thus, the IFNγR signaling pathway represents a promising therapeutic target for future efforts to mitigate GvHD while maintaining GvL after allo-HSCT. Moreover, this pathway can be exploited in other diseases besides GvHD such as those from organ transplantation, chronic inflammatory diseases and autoimmune diseases. Disclosures: DiPersio: genzyme: Honoraria.

Subsequent Hematopoietic Stem Cell Transplantation in Belinostat-Treated Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5438-5438
Author(s):  
Andrei R. Shustov ◽  
Haifa Kathrin Al-Ali ◽  
Gerald Wulf ◽  
Pamela Hsu ◽  
Mi Rim Choi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Hematopoietic Stem

Abstract Background: PTCL is a heterogeneous group of hematologic malignancies associated with a poor prognosis for most subtypes. In the relapsed setting, hematopoietic stem cell transplantation (HSCT) is the only potentially curative option for patients with PTCL. However, many patients are not able to achieve an adequate response to allow for HSCT. Belinostat (Beleodaq) is a potent pan-histone deacetylase inhibitor that was recently approved in the US for the treatment of patients with R/R PTCL. Approval was based on data from the pivotal Phase 2 BELIEF study that enrolled 129 patients with R/R PTCL (N = 120 evaluable), and demonstrated durable clinical benefit and tolerability. This analysis presents data for 12 of the enrolled patients (9 evaluable) who proceeded to HSCT following belinostat treatment. Methods: Patients with R/R PTCL received belinostat as a 1000 mg/m2IV infusion on Days 1-5 of a 21-day cycle. The primary endpoint of the study was Objective Response Rate (ORR; Complete Response [CR] + Partial Response [PR]) determined by an Independent Review Committee (IRC). We present efficacy and safety data for the subset of 12 patients who subsequently went on to HSCT. Results: Among 12 patients who subsequently proceeded to HSCT, 4 went on to receive an autologous HSCT and 8 received an allogeneic HSCT; 8 patients (67%) were female and 4 (33%) were male, and the median age was 54.5 (range 31-71) years. The median number of prior anticancer therapies was 2 (range 1-8), including 3 patients with prior autologous HSCT. The median number of belinostat treatment cycles was 2.5 (range 1-14) compared to the median of 2.0 (range 1-8) in the overall study population. Most patients in this subgroup had PTCL-Not Otherwise Specified (58.3%), angioimmunoblastic T-cell lymphoma (16.7%), or anaplastic large cell lymphoma (16.7%); 41.7% of patients had Stage IV disease. Three of the 12 patients were not evaluable for response due to insufficient histological material for confirmation by central pathologic analysis. The IRC-confirmed ORR for the 9 evaluable patients was 33.3% vs 25.8% in the study overall, and included 2 CRs, 1 PR, 2 patients with stable disease (SD) and 3 patients with progressive disease (PD). Duration of Response after transplant ranged from 41-261 days for the 3 belinostat responders. At last study contact, 2 patients had died from cardiac events (unrelated to belinostat) and 10 remained alive, with Overall Survival (OS) ranging from 8-23+ months. Most adverse events (AEs) were Grade 1-2, with two treatment-related Grade ≥3 AEs (neutropenia and prolonged QT interval); 3 serious AEs (arthralgia, lower limb fracture, and pyrexia) were reported in this subgroup. Conclusions: Belinostat was well tolerated in previously treated patients with R/R PTCL and enabled some patients to proceed to HSCT. Three patients responded and went on to HSCT following belinostat; the remaining patients had HSCT following SD (2), PD (4) or were not evaluable (3). OS was prolonged when compared to historical controls. Summary of Patients Treated with Belinostat Who Subsequently Went on to Hematopoietic Stem Cell Transplantation Sorted by Subtype and Response Table 1PatientSubtype(Stage)Prior RegimensECOGPSBelinostat CyclesIRC ResponseOS(months)DoR(days) Evaluable Patients931-003^PTCL-NOS (IIIB)3114CR11.56261907-006PTCL-NOS (IIA)5 + auto SCT02SD13.93-907-007^PTCL-NOS (IVA)402SD12.09-907-005^PTCL-NOS (IIIA)202PD13.63-140-002PTCL-NOS (IVA)817PD17.64-914-006PTCL-NOS (IIIA)4 + auto SCT02NE13.73-245-001AITL (UNK)106PR19.9141221-003ALCL ALK– (IA)2 + auto SCT011CR20.4173907-001ALCL ALK– (IVA)204PD22.87- Non-Evaluable Patients*914-002PTCL-NOS (IVB)102PD7.75-147-002^AITL (IIIB)221NE9.43-147-001Hepatosplenic TCL (IVA)103NE10.22- AITL = angioimmunoblastic T-cell lymphoma; ALCL = anaplastic large cell lymphoma; ALK = alkaline phosphatase; auto = autologous; CR = complete response; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; IRC = independent review committee; NE = not evaluable; NOS = not otherwise specified; OS = overall survival; PD = progressive disease; PR = partial response; PS = performance status; PTCL = peripheral T-cell lymphoma; SCT = stem cell transplantation; SD = stable disease; TCL = T-cell lymphoma *Lack of central pathologic confirmation resulted in exclusion from the evaluable population ^Autologous hematopoietic SCT Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Choi:Spectrum Pharmaceuticals: Employment. Allen:Spectrum Pharmaceuticals: Employment. Visser:Sanofi: Membership on an entity's Board of Directors or advisory committees. Horwitz:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jannsen: Consultancy.

Favorable Immune Reconstitution Profile after Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2236-2236
Author(s):  
Omer Hassan Jamy ◽  
Ayman Saad ◽  
Rachael Orlandella ◽  
Samantha B Langford ◽  
Ravi K. Paluri ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Research Funding ◽  
Immune Reconstitution ◽  
First Year ◽  
Gvhd Prophylaxis ◽  
One Year

Abstract Background: The administration of post-transplant high-dose cyclophosphamide (PTCy) has been shown to be an effective strategy for GvHD prophylaxis following allogeneic peripheral blood stem cell transplantation(PBSCT) from alternative donors. PTCy is toxic to allogeneic activated proliferating T lymphocytes, such as effector T cells. Conversely, it may not materially affect memory T cells. Methods: We evaluated immune reconstitution profile and transplant outcome in patients who received PBSCT with and without PTCy. PTCy was given on day +3 and +4 following haploidentical transplant (HAPLO), or only on day +3 following HLA-matched unrelated donor (MUD) transplant. No PTCy was given to patients with HLA-matched related donors (MRD). All patients received GvHD prophylaxis as tacrolimus (day +5 to +180) and MMF (day +5 to +35). Preparative regimens were myeloablative regimens (fludarabine/busulfan, fludarabine/TBI 12 Gy, or CY/TBI 12) in all patients except 4 patients (received fludarabine/melphalan). Immune reconstitution profile (IRP) was tested via serial flow cytometry analysis of peripheral blood lymphocytes after transplant were done on days +30, +100, and +180. Results: Data of 70 patients who underwent allogeneic PBSCT in our institution were analyzed in 3 groups; MRD (n=22), MUD (n=35), and HAPLO (n=13). The total cohort had 33 males (47%), and had median age of 52 years (range 20-70). All patients had hematological malignancy except one patient with HLH. The median duration of follow up was 6 months (range 1-17). The median day of neutrophil and platelet engraftment were 13, 12, 17 and 18, 15, 22 days for MRD, MUD and HAPLO groups respectively. The one-year overall survival of the whole group was 67% (95% confidence interval: 48-80) with no difference in OS among the 3 cohorts (log rank P value 0.4) (Figure 1). Lymphocyte and lymphocyte subset (T, B, NK) count recovery for MUD and HAPLO was significantly less (p<0.05) than MRD during the first month post-HSCT but these differences were statistically insignificant by day +60 and remained so through day +365. Recovery of both CD4+ and CD8+ naïve T cell (CD45RA+CD27+CD197+) population was generally slower for HAPLO patients during the first year and significantly less through day+ 180 for CD4+ T cells. As predicted, central memory (CD45RA-CD27+CD197+) CD4+ and CD8+ T cells remained proportionately equivalent at 40% and 28% respectively for all groups during the first year. The effector memory (CD45RA-CD27+CD197-) population was also proportionately consistent at 25% of total for both CD4+ and CD8+ subsets. Interestingly, the effector T cell population (CD45RA+CD27-CD197-) trended higher for all three recipient groups at each time point for both CD4+ and CD8+ populations increasing from 20% at one month to over 40% at one year. Conclusion: Post-PBSCT survival was not significantly different from alternative donor graft recipients and those that received MRD PBSCT. Lymphocyte recovery was impaired for the PTCy groups in the immediate post-PBSCT period but quickly recovered to that seen in MRD recipients. Figure 1 Figure 1. Disclosures Saad: Spectrum: Honoraria; American Porphyria foundation: Research Funding; Astellas: Research Funding; Alexion: Honoraria. Lamb:Incysus, Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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