Risk Factor Analysis for the Development of Large Granular Lymphocytosis after Allogeneic Hematopoietic Cell Transplantation: Randomized Stratification and Propensity Score Analysis

Abstract Introduction Large granular lymphocytes (LGL) are a morphologically recognizable subpopulation of lymphocytes comprising an immunophenotypically heterogeneous population of activated CD3+ T cells and CD3- natural killer (NK) cells that mediate non-MHC-restricted cytotoxicity. Increased number of circulating LGL can be found as a response to viral infections, autoimmune disease or malignant neoplasms, as a result of chronic antigenic stimulation. Of interest, LGL lymphocytosis has been reported to occur following hematopoietic cell transplantation (HCT), with a variable incidence of up to 20%. This population display improved transplant outcomes with a lower incidence of non-relapse mortality and relapse (Kim, BMT, 2013; Nann-Rütti, BBMT, 2012). The aim of the present study is to determine the risk factors associated with the development of LGL lymphocytosis after allogeneic HCT. Methods A total of 826 patients who underwent an allogeneic HCT at Princess Margaret Cancer Centre, Toronto, Canada from 2000 to 2012 were retrospectively analyzed. LGL lymphocytosis was defined as the presence of at least two of the followings: 1) Sustained peripheral blood lymphocyte count ≥3.0 x 109/L observed in at least three consecutive determinations over a period of 2-3 months; 2) Predominance (≥30%) of LGL lymphocytes in the peripheral blood, as assessed by morphologic or immunophenotypic criteria; 3) T-cell receptor monoclonality assessed by PCR. The patient population was divided into discovery and replication sets using 2 different methods: stratified randomization and propensity score matching, using relevant baseline variables such as donor type, CMV serostatus, conditioning, T-cell depletion. Results No significant imbalances were found between the discovery and replication sets in terms of relevant baseline characteristics and clinical outcomes, for both the randomly divided patients and the propensity score matched groups. The overall incidence of LGL lymphocytosis was 14.5% at 3 years. The incidence of LGL lymphocytosis was similar across all subgroups of patients, both for the randomly divided groups and the propensity score matching (P-value not significant). A multivariable analysis of the risk factors for the development of LGL lymphocytosis was performed, including the following variables: grades 3-4 acute graft-versus-host-disease (GVHD), chronic GVHD, CMV viremia, CMV serostatus of the recipient, donor type, transplant year and T-cell depletion (TCD) for GVHD prophylaxis. In the stratified randomization analysis, the following risk factors were identified: 1) Discovery set: chronic GVHD (Hazard Ratio: 8.3, 95% CI: 3.1-22.6, P<0.001), CMV viremia (HR: 2.7, 95% CI: 1.5-4.7, P<0.001) and use of an unrelated donor (HR: 2.1, 95% CI: 1.2-3.7, P=0.01). 2) Replication set: chronic GVHD (HR: 38.9, 95% CI: 5.3-284.9, P<0.001) and CMV viremia (HR 3.8, 95% CI: 2.2-6.6, P<0.001). For the propensity score matching analysis the risk factors for the development of LGL lymphocytosis were the following: 1) Discovery set: chronic GVHD (HR: 22.9, 95% CI: 3.2-169.3, P=0.002) and CMV viremia (HR: 2.2, 95% CI: 1.1-4.2, P=0.02). 2) Replication set: chronic GVHD (HR: 28.9, 95% CI: 3.9-212.5, P<0.001), CMV viremia (HR: 3.6, 95% CI: 1.9-6.7, P<0.001). Conclusions Chronic GVHD and CMV viremia are strongly associated with the development of LGL lymphocytosis following allogeneic HCT. This may reflect a chronic antigenic stimulation in the setting of GVHD and CMV infection, leading to the expansion of LGL. However, the underlying mechanisms of LGL activation and expansion in the allogeneic HCT setting still remain unclear. Thus, further investigations are needed to elucidate these mechanisms in particular in the setting of GVHD. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

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Incidence and Risk Factors of De Novo Skin Cancer in a Contemporary Cohort of Hematopoietic Cell Transplantation Survivors

Blood ◽

10.1182/blood-2019-124993 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2011-2011

Author(s):

Jennifer Berano Teh ◽

Farah Abdulla ◽

Kelly Peng ◽

Liezl Atencio ◽

Alicia Gonzales ◽

...

Keyword(s):

Risk Factors ◽

Skin Cancer ◽

Cell Carcinoma ◽

Cumulative Incidence ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

De Novo ◽

Chronic Gvhd ◽

Allogeneic Hct ◽

Skin Cancers

Introduction: Hematopoietic cell transplantation (HCT)-related factors, such as total body irradiation (TBI) used for conditioning, graft-versus-host disease (GvHD), and prolonged exposure to calcineurin-inhibitors, can result in high risk for subsequent skin cancers in long-term survivors. Previous studies examining skin cancers after HCT have largely focused on patients transplanted in earlier eras (<2000), which may not be as informative for providers caring for survivors treated with contemporary conditioning (e.g. less myeloablative) approaches or GvHD treatment regimens, and do not account for newer stem cell sources (e.g. cord, haploidentical) with their evolving immunosuppression risk. Additionally, due to registry reporting, past studies have largely focused on melanoma, which underestimates the burden due to more common skin cancers such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The current study describes the incidence and risk factors of melanoma and non-melanoma skin cancer in a large contemporary cohort of HCT survivors. Methods: 2338 consecutive patients who underwent a first HCT between 2005 and 2014 at City of Hope (COH) and survived ≥1 year, were included in the study. Patients with a history of skin cancer prior to HCT were excluded from the cohort. All skin cancers were validated using pathology reports, and physician notes (20%) whenever the former was not available. Skin cancers included SCC, BCC, melanoma, atypical fibroxanthoma, and merkel cell carcinoma. Patients were followed from HCT to death, second HCT, last known alive date, or December 31, 2018, whichever occurred first. Cumulative incidence of skin cancer was estimated taking into consideration competing risk of death. Fine-Gray sub-distributional hazard regression was used to calculate hazard ratio (HR) estimates, adjusted for relevant covariates. Results: Median age at HCT was 51.8y (range: 0.7-78.7); 57.6% were male; 56.5% were non-Hispanic white (NHW); 4.4% had a history of Pre-HCT cancer (antecedent to primary diagnosis); 47.7% underwent allogeneic HCT; 22.0% received myeloablative TBI (≥1200 cGy)-based conditioning. Among survivors of allogeneic HCT, 57.2% developed ≥moderate chronic GvHD (84% involving the skin); the most common immunosuppressive agents used for the management of ≥moderate chronic GvHD were tacrolimus (84.6%), followed by sirolimus (76.5%), and cyclosporine (28.4%). Burden of skin cancer over time: 179 survivors developed a total of 450 skin cancers after HCT; median time from HCT to first skin cancer was 2.8 years (range: 0.2-13.6). SCC was the most common subtype (59.1%), followed by BCC (31.3%), melanoma (5.1%), and other (4.4%); 43.4% of patients with SCC had invasive or high grade disease at presentation. The cumulative incidence of de novo skin cancer after HCT was 8.3% at 5 years, and 14.8% at 10 years (figure). Eighty-nine patients with skin cancer had a second skin cancer at a median of 0.5 years (range: 0.2 to 7.2) from the first; 55.1% were of a different histology. The cumulative incidence of a second skin cancer was 41.9% at 5-years (figure). Risk factors: Multivariate analysis revealed male sex (HR=1.7, p=0.0008), NHW race/ethnicity (HR=9.0, p<0.0001), older age HCT (≥50years at HCT, HR=2.4, p<0.0001), allogeneic HCT (HR=2.2, p<0.0001), and a history non-skin cancer prior to HCT (HR=1.7, p=0.04) to be significant and independent predictors of post-HCT skin cancer risk. Among allogeneic HCT patients, neither severity of chronic GvHD, location (e.g. skin), nor duration of post-HCT immunosuppression were associated with risk of de novo skin cancer, irrespective of skin cancer histology. Conclusions: This study confirms the higher risk of skin cancer by sex, race/ethnicity, and age at HCT, and highlights the greater than two-fold risk of skin cancer among allogeneic HCT survivors compared to autologous patients, a finding that is not entirely explained by GvHD and its treatment. Further, we identified a previously unreported association between pre-HCT (non-skin) cancer and post-HCT cancer risk, and describe the very high burden of multiple histologically distinct skin cancers over time. Taken together, these data set form the basis for implementation of updated risk-based screening and prevention practices in survivors at highest risk of skin cancer after HCT. Disclosures Abdulla: Johnson & Johnson: Research Funding; Elorac: Research Funding; Trillium: Research Funding; Stemline: Research Funding; MiRagen: Research Funding; Bionz: Research Funding; Mallinckrodt: Research Funding; Mallinckrodt: Consultancy; Mallinckrodt: Speakers Bureau. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

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The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Blood ◽

10.1182/blood.v114.22.3375.3375 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3375-3375

Author(s):

Julio Delgado ◽

Carme Canals ◽

Michel Attal ◽

Kirsty Thomson ◽

Antonio Campos ◽

...

Keyword(s):

T Cell ◽

Follicular Lymphoma ◽

Research Funding ◽

Alkylating Agent ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Off Label ◽

Reduced Intensity

Abstract Abstract 3375 Poster Board III-263 Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients. We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo. Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT. Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001). There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD. In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures: Delgado: Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.

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Impact of Allogeneic Hematopoietic Cell Transplantation (allo-HCT) on the Outcomes of Angioimmunoblastic T-Cell Lymphoma (AITL): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Blood ◽

10.1182/blood-2018-99-110469 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 969-969

Author(s):

Narendranath Epperla ◽

Kwang Woo Ahn ◽

Carlos Litovich ◽

Mohamed A Kharfan-Dabaja ◽

Sonali M. Smith ◽

...

Keyword(s):

T Cell ◽

Disease Control ◽

Cumulative Incidence ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Nk Cell ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Post Transplantation ◽

Significant Difference

Abstract Introduction: AITL is a distinct clinicopathologic entity among the mature T-cell and NK-cell lymphomas, accounting for approximately 1-2% of all non-Hodgkin lymphomas. Although autologous HCT (auto-HCT) provides high response rates, there is a high relapse risk associated with this procedure. Allo-HCT may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by alloreactive donor cells. The role of allo-HCT in AITL with advanced disease (prior auto-HCT failure, or chemorefractory state) is not well described. Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT. Methods: We evaluated 249 adult (≥18years) patients with AITL who received a first allo-HCT during 2000-2016. Patients receiving mismatched unrelated donor, cord blood or haploidentical donor transplantation were excluded due to small numbers. The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence of acute graft-versus-host disease (GVHD), chronic GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS). Results: Baseline patient characteristics are summarized in Table. The median patient age was 56 years (range=21-77 years). The graft source was mainly peripheral blood. Median follow-up of survivors was 49 months (range=4-170 months). The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42)% and 12 (95% CI=8-17)%, respectively. The cumulative incidence of chronic GVHD at 2 years was 58% (95% CI=51-64)%. The 1-year NRM was 19% (95% CI=14-24)%, while the 4-year R/P, PFS, and OS were 21% (95% CI=16-27)%, 49% (95% CI=42-56)% and 56% (95% CI=49-63)%, respectively [Figure]. On multivariate analysis, chemoresistant status at allo-HCT was associated with a significantly higher risk for progression (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (RR=3.46 95% CI=1.75 - 6.87). Subgroup analysis looking at the effect of prior auto-HCT (no prior auto-HCT vs prior auto-HCT), the 4-year PFS (50% vs 47%, p=0.60) and OS (57% vs 54%, p=0.70) were not significantly different. Similarly, on comparing the disease status at allo-HCT (CR1 vs CR>1 vs PR vs refractory), there was no significant difference in the 4-year PFS (58% vs 45% vs 47% vs 38%, p=0.41) or OS (70% vs 54% vs 50% vs 52%, p=0.27). The 1-year NRM was 24%, while the 4-year R/P, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. The most common cause of death was organ failure. Conclusion: In this largest series of mostly advanced AITL patients, allo-HCT was shown to provide durable disease control (4-year PFS=47%) with a clear plateau in relapse at 1-year post-transplantation. Allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting. Disclosures Kharfan-Dabaja: Alexion Pharmaceuticals: Speakers Bureau; Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria. Sureda:Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria. Hamadani:Merck: Research Funding; Celgene Corporation: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Takeda: Research Funding; Cellerant: Consultancy.

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Nonmelanoma Skin and Mucosal Cancers After Hematopoietic Cell Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.7052 ◽

2006 ◽

Vol 24 (7) ◽

pp. 1119-1126 ◽

Cited By ~ 116

Author(s):

Wendy Leisenring ◽

Debra L. Friedman ◽

Mary E.D. Flowers ◽

Jeffrey L. Schwartz ◽

H. Joachim Deeg

Keyword(s):

Risk Factors ◽

Cell Carcinoma ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Significant Risk ◽

Hematopoietic Cell ◽

Allogeneic Hct ◽

Increased Risk ◽

The Impact

Purpose To evaluate the incidence of and risk factors for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in survivors of hematopoietic cell transplantation (HCT). Patients and Methods The impact of patient-, disease-, treatment-, and toxicity-related factors on risk of BCC and SCC was determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT and who survived for at least 100 days. Results Among allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95). Twenty-year cumulative incidences of BCC and SCC were 6.5% and 3.4%, respectively. Total-body irradiation was a significant risk factor for BCC (P = .003), most strongly among patients younger than 18 years old at HCT (P = .02, interaction). Light-skinned patients had an increased risk of BCC (P = .01). Acute graft-versus-host disease (GVHD) increased the risk of SCC (P = .02), whereas chronic GVHD increased the risk of both BCC (P = .01) and SCC (P < .001). Conclusion This analysis suggests that immutable factors, such as age and complexion, have a significant impact on BCC and SCC. However, specific treatment (radiotherapy) and transplantation complications (GVHD) may modify that risk. These additional risk factors suggest the contribution of immunologic mechanism DNA and tissue repair in the development of BCC and SCC. We confirm previous reports that exposure to ionizing radiation increases the risk of BCC but not SCC. Survivors of HCT should be monitored for the development of BCC and SCC and use preventive strategies.

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Risk Factors for the Development of Cutaneous Melanoma after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2018-99-116261 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 249-249

Author(s):

Megan Herr ◽

Rochelle E. Curtis ◽

Margaret A. Tucker ◽

Heather R. Tecca ◽

Eric A. Engels ◽

...

Keyword(s):

Risk Factors ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Skin Involvement ◽

Melanoma Risk ◽

Allogeneic Hct ◽

Melanoma Diagnosis ◽

Conditioning Regimens

Abstract Introduction Advances in clinical practice for allogeneic hematopoietic cell transplantation (HCT), a potentially curative treatment most frequently indicated for hematologic malignancies, have led to substantial improvements in prognosis. HCT survivors are at risk for a number of post-transplant complications, including the development of new malignancies. Although cutaneous melanoma risk is known to be increased after HCT, no previous study has comprehensively investigated risk factors in order to identify patients at highest risk for melanoma development. The purpose of this study was to identify risk factors for developing melanoma after allogeneic HCT, specifically evaluating the relationship between melanoma and conditioning regimens as well as factors associated with immunosuppression and immune dysfunction. Methods We conducted a nested case-control study of melanoma within a cohort of 21,590 patients receiving a first allogeneic HCT during 1985-2012, as reported to the Center for International Blood and Marrow Transplant Research. Data on patient and transplant characteristics derived from standardized reports pre-HCT, 100 days and 6 months post-HCT, and annually thereafter or until death. The cohort was restricted to non-Hispanic Caucasians because melanoma is rare among other racial/ethnic groups. Among cases with a melanoma diagnosis reported by transplant centers (N=140), 82 (59%) were confirmed by pathology report review. Four controls were matched to each case on age at HCT (±3 years), sex, primary disease, and time since HCT (without a melanoma diagnosis). Conditional logistic regression was utilized to assess risk factors associated with melanoma development after allogeneic HCT. Multivariable models were adjusted for ambient ultraviolet radiation (UVR), estimated based on residence at the time of HCT, because of the known association between UVR and melanoma. Exploratory analyses were conducted to assess melanoma risk by age and time to melanoma development. Results Among the 140 melanoma cases, the median age at HCT was 46 years (range, 1-73 years), 56% were male, and median time from HCT to melanoma was 4 years (range <1-24 years). Patients were most frequently transplanted for chronic myeloid leukemia (24%) followed by acute myeloid leukemia (18%), acute lymphoblastic leukemia (18%), and non-Hodgkin lymphoma (12%). Multivariable analysis showed that melanoma risk was statistically significantly increased among HCT survivors who received myeloablative conditioning regimens with total body irradiation [odds ratio (OR), 95% confidence interval (95%CI): 1.8, 1.0-3.2] or reduced intensity conditioning regimens containing melphalan (OR, 95%CI: 2.6, 1.1-6.0) or fludarabine (OR, 95%CI: 2.7, 1.0-7.3) compared with those receiving a busulfan-containing myeloablative conditioning regimen; acute graft-versus-host disease (GvHD) with stage 2+ skin involvement (OR, 95%CI: 1.9, 1.2-3.1) versus no acute GvHD; chronic GvHD without skin involvement (OR, 95%CI: 1.9, 1.0-3.6) versus no chronic GvHD; and occurrence of keratinocytic carcinoma (OR, 95%CI: 2.4, 1.2-4.8; median time from keratinocyte carcinoma to melanoma: cases=3.5 years, controls=2.8 years). In exploratory analyses of these factors by patient subgroup, melanoma risks associated with acute GvHD stage 2+ skin involvement were especially increased among individuals of younger age at HCT (age<40 years: OR, 95%CI: 3.2, 1.4-7.4) but not among those of older age at HCT. In the multivariable model, no significant associations were observed with other patient and transplant characteristics, including graft source and ex-vivo or in-vivo T-cell depletion. Conclusion In the largest study to date of melanoma risk factors following allogeneic HCT, we report novel associations with specific conditioning regimens, occurrence of acute and chronic GvHD, and occurrence of keratinocyte carcinoma. Our results emphasize the importance of adherence to current surveillance guidelines for HCT recipients, specifically routine skin examination, heightened skin cancer awareness, and photoprotection recommendations, particularly for those survivors at highest risk. Disclosures No relevant conflicts of interest to declare.

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GvHD Prophylaxis with Everolimus and Mycophenolate in Allogeneic Hematopoietic Cell Transplantation - A Phase I/II Study.

Blood ◽

10.1182/blood.v114.22.4642.4642 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4642-4642

Author(s):

Reinhard Marks ◽

Alf Zerweck ◽

Razvan George Racila ◽

Hartmut Bertz ◽

Jürgen Finke

Keyword(s):

T Cells ◽

T Cell ◽

Research Funding ◽

Malignant Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Tolerance Induction ◽

Treg Function ◽

Gvhd Prophylaxis

Abstract Abstract 4642 Next to the control of malignant disease, tolerance induction of the grafted cells remain to be a critical issue for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are believed to be involved in the process of tolerance induction to solid organ grafts and in the regulation of alloreactivity, e.g. graft versus host disease (GvHD) and graft versus leukemia effect (GvL), after allogeneic HCT. Since GvHD causes substantial morbidity, medication with calcineurin inhibitors (CI) like cyclosporine are established prophylactic measures for the prevention of GvHD after HCT. Next to the substantial renal toxicity of CI, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. In contrast, data from in vitro and animal experiments suggest that inhibition of the mammalian target of rapamycin (mTOR) has not only an antiproliferative effect on many malignant cell lines but also results in an inhibition of proliferation of alloreactive T cells with sustained Treg function in a murine HCT model. Therefore we initiated a phase I/II, monocenter trial using everolimus and mycophenolate sodium (MMF-Na) as GvHD prophylaxis in patients undergoing allogeneic HCT with peripheral stem cell (PBSC) grafts after conditioning with fludarabine, melphalan, and BCNU (FBM). No additional T cell depleting agents were used for conditioning/GvHD prophylaxis. Enrolment was started in april 2008, and up to august 2009 10 patients were included (median age: 50.7 years, range: 26-64). The diagnoses included de novo AML (n=3), sAML (n=4), RAEB II (n=1), CML (n=1), T-PLL (n=1). 6/10 patients were regarded as high risk (not in CR1) for early relapse. PBSC grafts were obtained from unrelated (n=5) and related (n=5) HLA-matched donors. With no graft failures, engraftment kinetics for myeloid cells were normal, and reconstitution of the T cell compartment reached median cell counts of 251 CD4+ cells/μl and 163 CD8+ cells/μl at day +30. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow-up of 6 month two patients have died. The causes were acute GvHD, refractory to several lines of treatment, in a patient with CML, and severe pulmonary toxicity/BOOP in a patient with sAML. Out of 9 patients reaching CR after HCT, only one high risk patient relapsed after 6 month. In total 6 patients are alive and show complete donor chimerism for time periods of 1-14 months post transplant. The observed early recovery of T cell immunity correlated in 8/10 patients with an early brief period of acute GvHD, with 4 patients experiencing grade III/IV severities. Most of the cases could be controlled with steroids alone. Chronic GvHD could be observed in 6/7 patients, with mild to moderate forms in 5 cases, mainly involving skin, mucosa and liver. Interestingly, while early tapering of MMF-Na did not cause any problems, reduction of everolimus earlier as 6 month after HCT resulted in an induction of GvHD symptoms. Although viral reactivation (CMV, HHV6) did occur in patients receiving additional immunosuppression with steroids, no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of mild to moderate chronic GvHD. Since this sustained mild alloreactivity might reduce the risk of relapse, this GvHD prophylaxis could well be suited for patients undergoing HCT with advanced or uncontrolled malignant disease. Disclosures: Marks: Novartis: Research Funding. Off Label Use: Everolimus for prophylaxis of GvHD. Finke:Novartis: Research Funding.

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

Blood ◽

10.1182/blood.v114.22.520.520 ◽

2009 ◽

Vol 114 (22) ◽

pp. 520-520

Author(s):

John R. Wingard ◽

Navneet S. Majhail ◽

Ruta Bajorunaite ◽

Zhiwei Wang ◽

Kathleen A. Sobocinski ◽

...

Keyword(s):

Risk Factors ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Term Survival ◽

Long Term Survival ◽

Hematologic Disorders ◽

Allogeneic Hct ◽

Conditioning Regimens ◽

All Diseases

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

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Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A Single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint

Blood ◽

10.1182/blood.v128.22.4574.4574 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4574-4574

Author(s):

Melhem Solh ◽

Lawrence E. Morris ◽

H. Kent Holland ◽

Scott R. Solomon ◽

Stacey Brown ◽

...

Keyword(s):

Competing Risks ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Chronic Gvhd ◽

Composite Endpoint ◽

Allogeneic Hct ◽

Kaplan Meier ◽

Donor Type ◽

Grade 3

Abstract Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint Introduction The success of allogeneic HCT is based on long term survival, free of relapse or morbidity as commonly encountered when patients develop graft versus host disease (GVHD). The Bone marrow transplant clinical trials network (BMTCTN) recently incorporated a composite endpoint to determine success rate in ongoing clinical trials. The new composite endpoint of GVHD free, relapse free survival (GRFS) includes the factors of acute GVHD grade 3-4, relapse, death and chronic GVHD requiring systemic immunosuppression. As the decision to start patients on immunosuppression for chronic GVHD can be subjective and physician dependent, we elected to assess the success of allogeneic HCT using a more objective endpoint m-GRFS where the clinically significant negative events are acute GVHD grade 3-4, moderate-severe chronic GVHD, disease relapse and Death at 1 and 2-year post HCT. Methods Six hundreds and thirteen patients who underwent a first allogeneic HCT after a HLA-identical sibling (MRD, n=212), 10/10 matched unrelated donor (MUD, n=251) or T-replete haploidentical donor with post-transplant cyclophosphamide (HIDT, n=150) were included in this analysis. Patient, Disease and Transplant related variables were prospectively documented and obtained from our institutional database. The Kruksall-Wallis test was used to compare continuous variables and the Chi-squared test for categorical variables. OS, DFS and m-GRFS were estimated by the Kaplan-Meier (K-M) method. Log-log transformed confidence intervals for OS, DFS and GRFS were calculated. Comparison of m-GRFS between demographic subgroups and between clinical subgroups were evaluated using the log-rank test for the entire study period and using the Wald test for a select time point. Competing risks analysis was performed to disentangle the components of GRFS. Grade III/IV acute GVHD, mod-severe chronic GVHD, relapse and death were considered as competing risks and cumulative incidences of these endpoints were calculated. Patients were considered to have met the endpoint once any of the components occurred. Cox regression analysis was conducted to examine the impact of donor, demographic and clinical factors on the primary endpoint of modified GRFS. The proportional hazards assumption was checked by temporarily including and testing time-dependent variables and the variables in the final model passed the proportionality test. The adjusted GRFS for one characteristic was calculated as the average survival of the whole sample, assuming that everyone in the sample had this characteristic. Results The median follow-up was 50.2 months. Patients characteristics were as follows: median age 53 years (18-77), male 56%, reduced intensity/non-ablative 49%, AML 37%, ALL 13%, MDS/MPD 24%, bone marrow graft 19%, HCT-comorbidity index >=3 in 39%, and high/very high DRI 34%. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95%CI 32%-40%) and 28% (95%CI 25%-32%). The 2-year m-GRFS for MRD recipients was 30% (24-36%), MUD 24% (19-30%) and HIDT 33% (26-41%). The most common event at 2 years post HCT was chronic GVHD (39%) followed by relapse (31%), acute GVHD 3-4(20%) and death (10%). After adjusting for age, gender, diagnosis, conditioning intensity, donor type, cell source, HCT-CI, DRI , donor-recipient gender mismatch and year of transplant, the multivariate cox model on m-GRFS showed donor type, DRI risk , donor recipient sex mismatch and year of transplant to be significant predictors of m-GRFS (table 1). Patients who received a MUD had worse GRFS compared to MRD (HR 1.39, p=0.003) whereas HIDT had similar GRFS to MRD (HR 1.10, p=0.43). HIDT had better GRFS than MUD (HR 0.79, p=0.046). The adjusted 1- and 2- year m-GRFS showed donor type (MUD vs MRD), DRI, donor-recipient sex mismatch and transplant year to be associated with worse GRFS (table 2). Conclusions m-GRFS is a useful measure of transplant success. It appears to be significantly impacted by several modifiable factors including donor type, donor-recipient sex match and also by DRI. Adjusting donor choice and early referral of patients for transplant evaluation to improve DRI can potentially overcome the negative impact of these factors. Disclosures No relevant conflicts of interest to declare.

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Humoral Serologic Response to the BNT162b2 Vaccine Afterallogeneic Haematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2021-149979 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4876-4876

Author(s):

Moshe Yeshurun ◽

Oren Pasvolsky ◽

Liat Shargian ◽

Dafna Yahav ◽

Maly Rubinstein ◽

...

Keyword(s):

Immune Response ◽

Antibody Response ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Medical Center ◽

Severe Disease ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Allogeneic Hct

Abstract Objectives: Compared with the general population, patients after allogeneic hematopoietic cell transplantation (HCT) are at higher risk to develop severe disease or die from COVID-19. Immunosuppressive therapy and graft-vs-host disease (GVHD) may abrogate the ability of transplanted patients to mount an adequate immune response to vaccines. We assessed the immune response of patients after allogeneic HCT to the BNT162b2 vaccine (Pfizer-BioNTech) and identified patient and treatment-related factors that predict humoral response in this population. Methods: We conducted an observational prospective cohort study at Rabin Medical Center, Israel. Adult patients after allogeneic HCT were eligible if they had no history of SARS-CoV-2 infection and received the 2-dose BNT162b2 vaccine. The SARS-CoV-2 IgG II Quant (Abbott©,) assay was performed 4-6 weeks after the second vaccine for quantitative measurement of IgG antibodies to spike protein (S-IgG) of SARS-CoV-2. The assay result was considered positive if S-IgG level was ≥50 AU/ml. We used the likelihood ratio of the ROC curves to define the optimal cut-off for continuous variables, χ2 to compare variables on categorical scale and Mann-Whitney to compare medians. To predict seronegativity, we applied logistic regression with the exp(β) as an estimator of hazard-ratio (HR) and the 95% confidence interval (CI) around it. To predict S-IgG levels, we used linear regression. Results: Our cohort included 106 patients. Median age was 65 (range: 23-80) years and 59% were males. Median time from transplant to vaccination was 42 (range: 4-439) months. At time of vaccination, 49% of patients were receiving immunosuppression, while 51% were not. Overall, 14% (15/106) tested negative for S-IgG after vaccination, 27% (14/52) of patients on immunosuppression compared with only 1.8% (1/54) of patients off immunosuppression (p=0.0002). Based on ROC analysis we divided the cohort into patients who were transplanted within (57%) vs. beyond (43%) 4.5y (AUC 0.77, CI: 0.66-0.88). With this cut-off, the sensitivity was 0.93. In univariate analysis, patients vaccinated within 4.5y of HCT (HR: 13.7, 95% CI 1.8-108.5, p=0.013), or still receiving immunosuppression (HR: 9.8, 95% CI 2.1-44.7, p=0.004) and patients with moderate to severe chronic GVHD (HR: 5.9, 95% CI 1.2-29, p=0.03) were more likely to remain seronegative. Age, gender, type of disease and absolute-lymphocyte-count did not predict seronegativity. In MVA, only time, i.e. <4.5y from HCT remained predictive (HR: 10.8, 95% CI 1.2-93.2, p=0.03) (Table 2). Since 93% (14/15) of seronegative patients were transplanted <4.5y, we performed a subgroup analysis of the 57% (60/106) of patients that were transplanted within this time frame. Among these, patients receiving immunosuppression (65%, 39/60) were more likely to remain seronegative (HR: 10, 95% CI: 1.1-93, p=0.03); 36% (14/39) of patients on immunosuppression remained seronegative compared with none of the patients off immunosuppression (p=0.002). Among the 43% (46/106) of patients who were vaccinated >4.5y after HCT, 33% (15/46) were still receiving immunosuppression. Yet only 6.6% (1/15) in this subgroup tested negative. Titer levels in seropositive patients ranged between 60 and 80,000 AU/ml (median: 5319). Only a small fraction of this variance is explained by variables tested in this study. Older age (r 2=0.04, p=0.04), shorter time from transplantation (r 2=0.03, p=0.09), the use of corticosteroids (r 2=0.03, p=0.07) or calcineurin inhibitors (r 2=0.06, p=0.013) predicted lower S-IgG levels. The vaccine was well tolerated by most patients. No new cases of GVHD have been reported following vaccination. However, seven patients with chronic GVHD (mild=2; moderate=1; severe=4) reported that GVHD -related symptoms worsened within days following the first, second or both vaccines. Notably, one patient with chronic GVHD developed grade 4 steroid-refractory immune thrombocytopenia 2 weeks after the first vaccine. Conclusion: Overall, 14% of allogeneic HCT recipients had an inadequate antibody response to the BNT162b2 vaccine. It was only 6.5% among patients off immunosuppression and patients vaccinated >4.5y after HCT. However, inadequate antibody response rate was 36% among recipients vaccinated <4.5y from HCT who were still receiving immunosuppression. These patients should be recognised and instructed to take appropriate precautions. Figure 1 Figure 1. Disclosures Yeshurun: Astellas: Consultancy; Jannsen: Consultancy. Wolach: Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Neopharm: Consultancy.

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Largest Single Center Experience Using Dual T-Cell Depletion with ATG and Ptcy for Gvhd Prophylaxis in Peripheral Blood RIC Allo-HSCT

Blood ◽

10.1182/blood-2019-128639 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3344-3344

Author(s):

Maria Queralt Salas ◽

Arjun Law ◽

Wilson Lam ◽

Fotios V. Michelis ◽

Dennis Dong Hwan Kim ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

T Cell ◽

Chronic Gvhd ◽

Significant Risk ◽

Cell Depletion ◽

T Cell Depletion ◽

Single Center Experience ◽

Gvhd Prophylaxis ◽

Donor Type

Introduction: Dual T-cell depletion with ATG and PTCy combined with cyclosporine (CsA) in peripheral blood (PB) reduced intensity conditioning (RIC) allo-HSCT results in an impressive control of clinically relevant GVHD. We aim to share the largest and unique single center experience using this novel GVHD combination in allo-HSCT for hematological malignancies. Methods Between October 2015 and April 2019, 365 consecutive adult recipients underwent PB RIC allo-HSCT. Conditioning regimen consisted on fludarabine, busulfan and 200 cGy of total body irradiation. For GVHD prophylaxis all cases received ATG, PTCy (50mg/kg/24h x 2 doses on day +3 and +4) and CsA since day +5. Two hundred fifty-nine (71%) recipients, transplanted between 2015 and May 2018, received a total dose of 4.5mg/kg of rabbit-ATG (given on day -3,-2 and -1). In May 2018, the protocol was reviewed and refined decreasing the dose of ATG to a total of 2mg/kg (given on day -3 and -2). A total of 106 (29%) recipients received the lowered dose of ATG. Data was collected retrospectively and updated on July 2019. Cumulative incidence (Cum.Inc) of GVHD, CMV and EBV reactivation analysis was assessed accounting relapse and death as competing events. The multivariate analysis for OS and RFS was controlled by the following significant variables in the univariate analysis: age at transplant, disease risk index (DRI) (low and moderate v's high and very high), Karnofsky performance status (>80% v's ≤80%), HCT-CI score ≥3 and donor type. Results Baseline characteristics and main post-transplant information and outcome are summarized in Table 1 and 2. The cum.Inc of grade II-IV and grade III-IV at day +100 was respectively 14% (95 confidence interval (CI) 11.1-18.4) and 4.7% (95% CI 2.8-7.2). The cum.Inc of moderate and severe chronic GVHD at 1 year was 13% (95% CI 9.7-16.8). ATG dose and donor type did not influence acute/chronic GVHD rates (Table 3). The cum.Inc of CMV and EBV reactivation at day +180 was comparable between the two cohorts that received different dose of ATG (P>0.05). However, in the cohort that received a lower dose of ATG (2mg/kg), no CMV disease was documented and the percentage of probable or proven EBV-post-transplant lymphoprolipherative disease (P/P-PTLD) was only 3.7%. The percentages of CMV disease and P/P-PTLD in the group that received a dose of ATG of 4.5 mg/kg were respective 4.6% and 8.8%. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM) and the cumulative incidence (cumInc) of acute GVHD of the entire cohort and according to the ATG dose are shown in the Table 2 and the Table 3. OS and RFS curves of all 365 patients and stratified according to donor type are shown in the Plots 1 to 4. In the multivariate analysis, age at transplant [(HR 1 (95% CI 1.01-1.02); P=0.046], high and very high DRI score [HR 1.8 (95% CI 1.2-3.6); P=0.001], KPS ≤80% [HR 1.8 (95% CI 1.2-2.7); P=0.001], and HCT-CI score ≥3 [HR 1.4 (95% CI 1.01-2.09); P=0.042] were significant risk factors for worse OS. Donor type was not a significant parameter for OS (P>0.05). In the multivariate analysis of risk factors for RFS, high DRI score [HR 1.7 (95% CI 1.2-2.4); P=0.002], and a KPS ≤80% prior allo-HSCT [HR 2 (95% CI 1.4-2.8); P<0.001] were significant risk factors for worse RFS. To receive grafts from a 10/10 MUD was a significant parameter for better RFS [HR 0.6 (95% CI 0.4-0.9); P=0.046]. Conclusions Dual T-cell depletion with ATG and PTCy provides an impressive control of GVHD with acceptable relapse rates using PB stem cell grafts independently of the donor type. This observation suggests that the present combination overcomes the HLA-barrier and its effect on GVHD. Acute GVHD rates are effectively controlled with a dose of ATG of only 2mg/kg when it is combined with PTCy and CsA. Further investigations need to be done to better define the efficacy of a lower dose of ATG controlling chronic GVHD in this setting. Further investigations and refinements need to be done to improve survival rates in those recipients with higher DRI score and worse KPS ≤80% prior transplantation. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Therakos: Honoraria; Celgene: Honoraria.

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