scholarly journals Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 456-463 ◽  
Author(s):  
Yoshihiro Inamoto ◽  
Mary E. D. Flowers ◽  
Stephanie J. Lee ◽  
Paul A. Carpenter ◽  
Edus H. Warren ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Study Cohort ◽  
Recurrent Malignancy ◽  
Time Varying Covariates ◽  
Risk Of Relapse

AbstractThis study was conducted to elucidate the influence of immunosuppressive treatment (IST) and GVHD on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). The study cohort included 2656 patients who received allogeneic HCT after high-intensity conditioning regimens for treatment of hematologic malignancies. Rates and hazard ratios of relapse and mortality were analyzed according to GVHD and IST as time-varying covariates. Adjusted Cox analyses showed that acute and chronic GVHD were both associated with statistically similar reductions in risk of relapse beyond 18 months after HCT but not during the first 18 months. In patients with GVHD, resolution of GVHD followed by withdrawal of IST was not associated with a subsequent increase in risk of relapse. In patients without GVHD, withdrawal of IST was associated with a reduced risk of relapse during the first 18 months, but the risk of subsequent relapse remained considerably higher than in patients with GVHD. In summary, the association of GVHD with risk of relapse changes over time after HCT. In patients without GVHD, early withdrawal of IST might help to prevent relapse during the first 18 months, but other interventions would be needed to prevent relapse at later time points.

scholarly journals Genetic Associations with Immune-mediated Outcomes after Allogeneic Hematopoietic Cell Transplantation

2022 ◽  
Author(s):  
Paul J. Martin ◽  
David Levine ◽  
Barry E Storer ◽  
Cassandra L. Sather ◽  
Stephen R. Spellman ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Increased Risk ◽  
Recurrent Malignancy

Previous studies have identified more than 200 genetic variants associated with acute or chronic graft-versus-host disease (GVHD) or recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). We tested these candidate donor and recipient variants in a cohort of 4270 HCT recipients of European ancestry and in sub-cohorts of 1827 sibling and 1447 unrelated recipients who had 10/10 HLA-A, B, C, DRB1, DQB1-matched donors. We also carried out a genome-wide association study (GWAS) for these same outcomes. The discovery and replication analysis of candidate variants identified a group of closely linked recipient HLA-DPB1 single-nucleotide polymorphisms (SNPs) associated with an increased risk of acute GVHD and a corresponding decreased risk of recurrent malignancy after unrelated HCT. These results reflect correlation with the level of HLA-DPB1 expression previously shown to affect the risks of acute GVHD and relapse in unrelated recipients. Our GWAS identified an association of chronic GVHD with a locus of X-linked recipient intron variants in NHS, a gene that regulates actin remodeling and cell morphology. Evaluation of this association in a second replication cohort did not confirm the original replication results, and we did not reach any definitive conclusion regarding the validity of this discovery. The cohort used for our study is larger than those used in most previous HCT studies but is smaller than those typically used for other genotype-phenotype association studies. Genomic and disease data from our study are available for further analysis in combination with data from other cohorts.

Treosulfan-Based Myeloablative Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation Is Associated with Reduced Toxicity without Increased Risk of Relapse.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1152-1152
Author(s):  
Sebastian Giebel ◽  
Jerzy Wojnar ◽  
Malgorzata Krawczyk-Kulis ◽  
Iwona Wylezol ◽  
Miroslaw Markiewicz ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Platelet Recovery ◽  
Grade Ii ◽  
One Year ◽  
Reduced Toxicity ◽  
Risk Of Relapse

Abstract The goal of this study was to evaluate toxicity and efficacy of allogeneic hematopoietic cell transplantation (alloHCT) with Treosulfan (alkylyting agent, soluble Busulfan-derivative)-based conditioning as a preparative regimen. The outcome of 27 patients (CML-15, AML-9, ALL-1, SAA-2) given Treosulfan 3x14 g/m2 + Fludarabine 5x30 mg/m2 (n=15) or cyclofosfamide (CTX) 120 mg/kg (n=12) was compared with that of 146 patients treated with Busulfan 16 mg/kg + CTX 120 mg/kg between 2000–2004. In case of unrelated donor (URD)-HCT patients were additionally given anti-thymocyte globulin. GVHD prophylaxis consisted of cyclosporin A and short-course Methotrexate. The indications for alloHSCT were comparable for both subgroups. The patients age was 35(14–56)y and 30(14–55)y, the proportion of URD-HCT was 55% and 45%, peripheral blood was used as a source of stem cells in 33% and 11% of cases, and the proportion of patients with advanced disease (AML and ALL >CR1; CML > CP1) equaled 26% and 19%, respectively. The cumulative incidence of non-relapse mortality at one year was 8% for the Treosulfan (EBV-LPD n=1, cerebral hemorrhage n=1) and 32% for the Busulfan group (p=0.11). Grade II-IV neutropenic infections occurred in 5% and 13% (p=NS) and grade II-IV mucositis in 9% and 61% of patients (p<0.001), respectively. Other serious adverse events were infrequent. Both subgroups did not differ in terms of time to neutrophil and platelet recovery, as well as for need of RBC and platelet transfusions. Median hospital stay since the date of alloHCT was shorter after Treosulfan- compared to Busulfan-based conditioning (31 (21–55) d. vs. 40.5 (21–153) d., p<0.001). The overall survival and disease-free survival at one year equaled 92% vs. 67% (p=0.11), and 92% vs. 66% (p=0.09) for the Treosulfan group and the Busulfan group, respectively. None of the patients experienced hematologic relapse among Treosulfan- compared to 3% among Busulfan-treated alloHCT recipients. However, in two CML patients given Treosulfan-based regimen, the immunosuppression taper and interferon or imatinib therapy was neccessary to establish complete chimera. We conclude that Treosulfan + Fludarabine (or CTX) +/− ATG conditioning regimen is characterized by reduced toxicity resulting in shorter hospital stay and low transplat-related mortality. The pattern of hematopoietic recovery is similar to that of Busulfan + CTX indicating myeloablative character of the Treosulfan-based regimen. The risk of relapse is low and comparable for both kinds of treatment.

The Effect of In Vivo T-Cell Depletion with Alemtuzumab on Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3014-3014
Author(s):  
Julio Delgado ◽  
Srinivas Pillai ◽  
Reuben Benjamin ◽  
Dolores Caballero ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Lymphocytic Leukemia ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mixed Chimerism ◽  
Allogeneic Hct ◽  
Reduced Intensity

Abstract Reduced-intensity allogeneic hematopoietic cell transplantation (HCT) is increasingly considered as a therapeutic option for young patients with advanced chronic lymphocytic leukemia (CLL). We report 59 consecutive CLL patients who underwent allogeneic HCT following fludarabine and melphalan conditioning at four different institutions. For graft-versus-host disease (GVHD) prophylaxis, 38 patients (Cohort 1) received alemtuzumab (20–100 mg) and cyclosporine; and 21 patients (Cohort 2) received cyclosporine plus methotrexate or mycophenolate. Donors were 47 HLA-matched siblings and 12 unrelated volunteers, 6 of whom were mismatched. Median age at transplant was 53 (range, 34–64) years and median number of previous chemotherapy regimens was 3 (1–6), with 39% of patients being refractory to fludarabine. Nine patients had previously failed an autologous HCT. Fluorescent in-situ hybridization and IgVH mutation status data were available in 33 (56%) and 31 (53%) patients, respectively, being unfavorable (17p- or 11q-) in 22 (67%) and unmutated in 24 (77%) of them. All but 1 patient engrafted, and the median interval to neutrophil recovery (> 0.5 × 109/l) was 14 (range, 10–36) days. Twenty patients (34%), mostly from Cohort 1, received escalated donor lymphocyte infusions due to mixed chimerism or disease relapse. The overall complete response rate among 53 patients with measurable disease at the time of transplantation was 70%, whereas 21% had stable disease. Grade II-IV acute GVHD was observed in 14 (37%) and 12 (57%) patients from Cohorts 1 and 2, respectively (P = 0.17). Extensive chronic GVHD was observed in 3 (8%) and 10 (48%) patients from Cohorts 1 and 2, respectively (P < 0.01). The incidence of cytomegalovirus reactivation was not significantly different between cohorts (67% vs 47%, P = 0.23). With a median follow-up of 36 (range, 3–99) months for survivors, 18 (30%) patients have died, 3 of progressive disease and 15 of transplant-related complications. The 3-year overall survival (OS), progression-free survival (PFS) and non-relapse mortality were 66% (95% CI 48–84%), 38% (20–56%) and 21% (8–34%), respectively, for Cohort 1 and 65% (44–86%), 54% (32–76%) and 29% (10–48%) for Cohort 2 (P = 0.66; P = 0.33; and P = 0.53). Despite low patient numbers, alemtuzumab seemed particularly effective for unrelated donor recipients, with a 3-year OS and PFS of 54% and 40% for Cohort 1; and 33% and 0% for Cohort 2 (P = 0.02 and P = 0.07). In conclusion, results with reduced-intensity allogeneic HCT are promising for these poor-prognosis patients. Furthermore, the alemtuzumab-based regimen was effective in reducing the chronic GVHD rate with no negative effect on NRM, PFS or OS.

Salvage Allogeneic Hematopoietic Cell Transplantation with Fludarabine and Total Body Irradiation (3 or 4 Gy) after Failure of First Allografts.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3272-3272
Author(s):  
Boglarka Gyurkocza ◽  
Thai M. Cao ◽  
Rainer F. Storb ◽  
Thoralf Lange ◽  
Wendy Leisenring ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Umbilical Cord ◽  
Total Body Irradiation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Unrelated Donor ◽  
Idiopathic Myelofibrosis ◽  
Total Body

Abstract We analyzed data from 38 patients (median age = 56, range: 8 – 68 years) with acute leukemia (n=15), chronic idiopathic myelofibrosis (n=6), myelodysplastic syndrome with or without myeloproliferative disorder (n=5), chronic myeloid leukemia (n=4), non- Hodgkin lymphoma (n=4), aplastic anemia (n=2), multiple myeloma (n=1) and renal cell carcinoma (n=1), who underwent salvage allogeneic hematopoietic cell transplantation (HCT) for allograft failure. In 14 cases the original donors were used for second HCT, while in 24 cases different donors were identified (Table 1). Conditioning regimens for first HCTs included total body irradiation (TBI; 2 Gy) with or without fludarabine (Flu; n=28), myeloablative regimens (busulfan-cyclophosphamide, n=6; cyclophosphamide-TBI, n=2); and other, cyclophosphamide-anti-thymocyte globulin-based regimens (n=3). Conditioning for salvage HCT consisted of Flu 30 mg/m2/day on days -4 to -2 followed by TBI of 3 (n=24) or 4 (n=14) Gy on day 0. Cyclosporine and mycophenolate mofetil were used for postgrafting immunosuppression. The median time between first and salvage HCTs was 91 (range, 29 to 1004) days. Sustained second grafts were achieved in 34 patients (89%), while grafts failed in 4 patients (11%), all of whom had idiopathic myelofibrosis. With a median follow-up among surviving patients of 2.0 (range, 0.3 to 7.8) years, the 2 and 4 year Kaplan-Meier survival estimates were 49% (95% CI: 31%, 66%) and 42% (95% CI: 23%, 61%), respectively. The 2 year relapse-rate and non-relapse mortality were 36% (95% CI: 20%, 52%) and 25% (95% CI: 11%, 41%), respectively. The cumulative incidences of grades 2–4 acute and moderate-severe chronic graft-versus-host disease (GVHD) at 2 years were 42% and 41%, respectively. Four patients with chronic GVHD discontinued systemic immunosuppressive therapy at a median of 2.5 years. Within the limitations of the small patient numbers studied, TBI dose (3 vs. 4 Gy), same vs. different donors for salvage HCT, donor type (related, unrelated, HLA-haploidentical related vs. double umbilical cord), and HCT comorbidity scores did not appear to affect outcomes. Based on this retrospective multicenter analysis, we conclude that graft failure following allogeneic HCT can be effectively overcome by second transplantation using conditioning with Flu and low dose TBI (3 or 4 Gy), which should be further investigated in a prospective manner. Table 1. Donors in 1st and 2nd HCTs. HLA-MURD: HLA-matched unrelated donor; HLA-MMURD: HLA-mismatched unrelated donor, UCB: umbilical cord blood. 2nd HCT Different Donor 1st HCT Same Donor HLA-MURD HLA-MMURD Double UCB HLA-haploidentical HLA-identical sibling 11 11 - - - - HLA-MURD 17 3 10 4 - - HLA-MMURD 8 - 1 7 - - Double UCB 2 - - - 1 1

Validation of Favourable Impact of Large Granular Lymphocytosis after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3936-3936
Author(s):  
Marc Poch Martell ◽  
Jieun Uhm ◽  
Naheed Alam ◽  
Vikas Gupta ◽  
Jeffrey H. Lipton ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Predictive Factors ◽  
Lymphocyte Count ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Persistent Elevation

Abstract Introduction: We previously reported on the incidence of large granular lymphocytosis (LGL) following allogeneic hematopoietic cell transplantation (allo-HCT), its favorable impact on outcome and the predictive factors associated with its development (D Kim, BMT, 2013). In the current study we aimed to validate our previous findings in an independent set of patients. Methods:All 408 patients undergoing allo-HCT at Princess Margaret Cancer Centre, Toronto, from 2007 to 2012 (replication set) were included retrospectively. Data from the previously reported set of patients undergoing allo-HCT from 2000 to 2007 (n = 418) (original set) were updated. Results:There were significant differences between original and replication sets in baseline characteristics (age, underlying disease, conditioning, GvHD prophylaxis, graft source, donor type, and incidences of GvHD and CMV viremia) in accordance to the changes over a decade in allo-HCT procedures. The cumulative incidence of LGL lymphocytosis at 3 years was 21.8% in the original set and 11.7% in the replication set (P<0.001). The median onset of LGL lymphocytosis was 362 days after HCT in the original set and 223 days in the replication set. Patients with LGL lymphocytosis showed a persistent elevation of lymphocyte count compared to patients without LGL lymphocytosis (P<0.001). Patients with LGL lymphocytosis showed a higher overall survival (OS) (86.4% vs 46.1%, P<0.001, Fig. A) and lower non-relapse mortality (NRM) (10.5% vs 36.3%, P<0.001, Fig. B) at 3 years. No significant difference was found in relapse incidence according to the development of LGL lymphocytosis (13.9% vs 19.6%, P=0.25). Multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS (HR 0.30, P=0.02) and a trend towards lower NRM (HR 0.27, P<0.001, original set; HR 0.50, P=0.22, replication set). No effect of LGL lymphocytosis on relapse incidence was demonstrated (HR 1.24, P=0.37, original set; HR 0.53, P=0.29, replication set). Patients with LGL lymphocytosis showed a trend towards a higher incidence of IST cessation after cGvHD: 63.6% at 7 years vs 53.4% in patients without LGL lymphocytosis, P=0.07. The previously identified predictive factors for the development of LGL lymphocytosis were replicated: higher incidence of LGL lymphocytosis with 1) CMV seropositive recipients (29.6% vs 5.1%, P < 0.001); 2) CMV viremia (31.0% vs 8.9%, P<0.001) and 3) chronic GvHD (28.2%, vs 5.0%, P<0.001). Conclusions: The favorable impact of LGL lymphocytosis following allo-HCT in OS and NRM, as well as the predictive factors for the development of LGL lymphocytosis were successfully validated in an independent cohort of patients. No impact of LGL lymphocytosis on relapse incidence was noted. The difference in transplantation procedures between the two cohorts, such as GvHD prophylaxis/T-cell depletion, may explain the lower incidence of LGL lymphocytosis in the replication cohort. Patients with LGL lymphocytosis showed a trend towards a higher incidence of IST cessation after cGvHD, which may explain the lower NRM. Patients with LGL lymphocytosis showed a persistent elevation of lymphocyte count and had an indolent course. OS and NRM according to the development of LGL lymphocytosis Disclosures No relevant conflicts of interest to declare.

scholarly journals Total Body Irradiation without Chemotherapy as Conditioning for an Allogeneic Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sultan Altouri ◽  
Mitchell Sabloff ◽  
David Allan ◽  
Harry Atkins ◽  
Lothar Huebsch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Unrelated Donor ◽  
Relapsed Disease ◽  
Acute Myeloid

Current therapies for acute myeloid leukemia (AML), failing induction, are rarely effective. We report our experience in 4 patients with AML who received 16 Gy TBI prior to allogeneic hematopoietic cell transplantation (alloHCT), between June 2010 and May 2011. Patients were 20 to 55 years of age, 2 with relapsed disease and 2 with AML failing induction. An HLA-matched graft from related or unrelated donor was infused on day 0. All but one, who received a CD34+-selected graft, received methotrexate and tacrolimus +/− antithymocyte globulin, as GVHD prophylaxis. The other patient received tacrolimus alone. Neutrophil and platelet engraftment occurred at a median of 18 and 14 days, respectively. Patients were discharged at a median of 28 days. There were no unexpected toxicities in the first 30 days. One patient had cytomegalovirus (CMV) viremia and anorexia, at two months. One patient had grade 2 acute GVHD of the skin. One patient developed chronic GVHD of the eyes, mouth, skin, joints, and lung at 4 months. Two patients died from relapse of their leukemia at days 65 and 125. Two patients remain in remission beyond day 1500. 16 Gy TBI followed by an alloHCT for AML, failing induction, is feasible and tolerable.

scholarly journals Pre-Engraftment Gut Colonization with Enterococcus Casseliflavus Improves Survival after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 813-813
Author(s):  
Armin Rashidi ◽  
Maryam Ebadi ◽  
Robin Shields-Cutler ◽  
Todd E. DeFor ◽  
Dan Knights ◽  
...  
Keyword(s):  
Immune System ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Tryptophan Metabolism ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Gut Colonization ◽  
Metabolism Enzymes

Abstract Introduction: Gut bacteria modulate the immune system and influence outcomes of allogeneic hematopoietic cell transplantation (allo-HCT). The presence of Blautia, butyrate-producing Clostridia, and Eubacterium limosum in the stool has been associated with lower mortality after allo-HCT. We previously reported an unexpected association between pre-HCT gut colonization with intrinsically vancomycin-resistant enterococci (iVRE: E. gallinarum and E. casseliflavus) and improved overall survival (OS) due to decreased non-relapse mortality (NRM). In an expanded cohort, now also including patients who were iVRE-colonized early post-HCT (before day +14), we demonstrate that the iVRE association with improved OS is specific to E. casseliflavus. Patients and Methods: We studied allo-HCT recipients at our institution who had at least 1 positive rectal swab or stool culture for iVRE between days -14 and +14. New admissions for HCT were screened for gut VRE colonization weekly until discharge. SpectraTM VRE chromogenic agar medium (ThermoFisher Scientific) was used for species-level identification. Antimicrobial prophylaxis consisted of levofloxacin, acyclovir, and an azole. Cefepime was our empiric antibiotic for neutropenic fever. Results: 66 (23 with E. casseliflavus and 43 with E. gallinarum) of the 873 allograft recipients between 2011-2017 met our inclusion criteria. As expected from the constitutive, rather than acquired, vancomycin resistance of iVRE, the groups did not differ in their prior exposure to different classes of antibiotics. There were no significant differences between the groups in patient-, disease-, or transplant-related characteristics, except a higher frequency of sirolimus-based GVHD prophylaxis in the E. casseliflavus group (35% vs. 12%, P = 0.05). With a median follow up of 30 months, OS was significantly better in patients with E. casseliflavus (91% vs. 62% at 3 years, P = 0.04), due to lower NRM (0 vs. 18% at 3 years, P = 0.05) (Figures 1A and 1B). Only 2 patients with E. casseliflavus died within 3 years post-HCT, both due to relapse. In contrast, 14 patients with E. gallinarum died within 3 years post-HCT: 7 (50%) due to relapse, and 7 (50%) from NRM (4 GVHD, 1 infection, 1 graft failure, and 1 veno-occlusive disease). In multivariable analysis, E. casseliflavus gut colonization was significantly associated with reduced all-cause mortality (hazard ratio 0.20, 95% confidence interval 0.04-0.91, P = 0.04). There were no significant differences between the groups in 180-day acute grade II-IV GVHD (P = 0.19), 1-year chronic GVHD (P = 0.56), 100-day bacteremia (P = 0.59), or 100-day Clostridium difficile infection (P = 0.79). To probe the mechanism of this protection against mortality, we mined 15 E. casseliflavus and 8 E. gallinarum sequenced genomes for 14 shikimate and tryptophan metabolism enzymes. This analysis predicted that E. casseliflavus encodes a larger number of enzymes in the tryptophan metabolism pathway (Figure 1C). Several compounds in this pathway are ligands for the aryl hydrocarbon receptor (AhR). Signals downstream of AhR augment the gut barrier and modulate the immune system, potentially reducing pathogenic injury and inducing protective immune responses. Conclusions: Pre-engraftment gut colonization with E. casseliflavus, but not E. gallinarum, improves survival after allo-HCT. Future mechanistic studies of the interactions between E. casseliflavus and the host can guide the development of novel microbiota-oriented therapeutics in this high-risk patient population. Disclosures Weisdorf: Seattle Genetics: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy.

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