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Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
S73
blood stem cells (PBSC) in 73.3%. 32.5% developed acute GVHD grade II- IV. With a median follow-up of 32 months, the treatment outcomes at 3 years are: Incidence of cGVHD 37.5% (95% conf. int. [CI] 32.6 – 42.3) Non-Relapse-Mortality (NRM) 22.1% (CI 18.4 -26.1) Overall survival (OS) 56.3% (CI 51.5- 61.2) Leukemia-Free-Survival (LFS) 46.5% (CI 41.7- 51.4) Relapse Incidence (RI) 31.4% (CI 26.9- 35.9)
Figure 2. CD4+ T-cell reconstitution after allo HCT in patients receiving busulfan (targeted to optimal exposure) and fludarabine (160mg/m2). Groups consist of patients in the highest quartile of F-ara-A AUC exposure (red) and the lower three quartiles (green).
Conclusions: High exposure to Flu significantly impairs CD4+ T-cell reconstitution and reduces survival chances after HCT. This is the first step in the definition of a target exposure for Flu in this setting. Dose individualization and/or TDM-based corrections towards the Flu target may reduce overexposure and improve survival chances after HCT.
73 Allogeneic Transplant for Mixed Phenotype Acute Leukemia (MPAL): Characteristics and Outcome in the ALWP-EBMT Database Reinhold Munker 1, Myriam Labopin 2, Jordi Esteve 3, Christoph Schmid 4, Arnon Nagler 5. 1 Tulane University, New Orleans, LA; 2 Hopital Saint-Antoine, Paris, France; 3 Hospital Clínic, Hematology department, IDIBAPS, Barcelona, Spain; 4 Department of Hematology and Oncology, Klinikum Augsburg, Ludwig-Maximilians-University, Munich, Germany; 5 The Bone Marrow Transplantation Department, Division of Internal Medicine, The Chaim Sheba Medical Center, TelHashomer, Israel Mixed phenotype acute leukemias (bearing markers of both myeloid and lymphoid lineages, MPAL) are rare (2- 3% of all acute leukemias) and considered puzzling due to their cell of origin. In the past, MPAL was considered as poor risk leukemia. The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers. The recommended treatment strategy involves induction regimens similar to acute lymphoblastic leukemia and consolidation by allogeneic transplant. Until recently, limited data were available validating this approach. The Center for International Blood and Marrow Transplant Research (CIBMTR) published a series of 95 cases of MPAL (median age 20 years) who underwent allogeneic transplant and found an encouraging long-term survival. In the present study, the Acute Leukemia Working Party (ALWP) of the EBMT database was queried for all consecutive patients with MPAL who received an allogeneic transplant for MPAL between 2000 and 2014 and were transplanted in complete remission (CR1; total of 519 patients). Cytogenetics were available in 203 patients. The median age was 38.1 years (range 18- 75). 54.5% of the patients were transplanted from a matched sibling donor, 45.5% were transplanted from a matched unrelated donor. Myeloablative conditioning (MAC) was used in 500 patients (77.1%, 140 chemotherapy-only, 260 chemotherapy with total body-irradiation [TBI]), reduced intensity in the remaining patients (22.9%). Bone marrow was used in 26.4%, peripheral
In univariate analysis, the age at transplant strongly impacted on LFS, NRM, RI and OS, with the age group 18- 35 having the best outcomes. Transplants done in the more recent period (2005- 2014 vs 2000-2004) had a lower NRM (20% vs 33.2%, P = .01) and a better OS (58.3 vs 44.7%, P = .04). No differences in outcomes were found between related and unrelated donors. Female donors for male recipients, no in vivo T cell depletion and PBSC were associated with more cGVHD. Use of MAC-TBI correlated with a lower RI and better LFS compared both to MAC-chemo and to RIC. In multivariate analysis, younger age and more recent year of transplant were statistically associated with a better LFS (P = .03 and P = .013) and OS (P = .006 and P = .004). MAC-TBI was associated with better LFS and a trend for higher OS. In conclusion, we confirm and extend the previous CIBMTR study in a large international database. Allogeneic transplant is a valid treatment option for MPAL (with a potential for cure) if a matched donor is available.
74 Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 Laura F. Newell 1, Todd E. Defor 2, Corey S. Cutler 3, Michael R. Verneris 4, Bruce R. Blazar 2, Joseph H. Antin 5, Alan Howard 6, Juan (Maggie) Wu 7, Margaret L. MacMillan 4, Angela Panoskaltsis-Mortari 4, Daniel J. Weisdorf 8, Shernan Holtan 9. 1 Oregon Health & Science University, Portland, OR; 2 University of Minnesota, Minneapolis, MN; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN; 5 Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 6 CIBMTR, National Marrow Donor Program, Minneapolis, MN; 7 The EMMES Corporation, Rockville, MD; 8 Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN; 9 Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN Introduction: Inflammation and tissue repair are linked processes influencing aGVHD after allogeneic HCT. In aGVHD, the balance between angiogenic factors (AF) contributing to tissue healing/repair (epidermal growth factor [EGF]) versus those associated with tissue damage/inflammation (follistatin [FS]) is dysregulated. Given that regimen-related tissue injury plays a role in NRM, we hypothesized that elevated levels of inflammation-associated AF would be associated with NRM even in patients without aGVHD. Methods: Levels of angiopoietin-2 (Ang2), EGF, FS, vascular endothelial growth factor (VEGF)-A and -B, endoglin (sEng), placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2 were quantified by MILLIPLEX magnetic bead panels, using plasma samples from patients enrolled on
S74
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
SESSION K: ALTERNATIVE DONORS, LATE EFFECTS/ QUALITY OF LIFE/PSYCHOSOCIAL ISSUES, AND GVH/GVL ALTERNATIVE DONORS
75
Figure 1. Adjusted Non-Relapse Mortality by Composite Score of log(sEng) + log(FS).
BMT CTN 0402. Factors associated with NRM were used to develop composite AF scores to predict NRM. In calculating the composite scores, we extrapolated the individual probabilities of 1 year NRM from regression models, and sorted the individual probabilities into 3 composite scores based on estimated probability of NRM: < 10%, between 10-19%, >20%. Results: 221 patients had pre-HCT and day +28 plasma samples available for analysis. Univariate analysis showed associations of Ang2, FS, sEng, and sVEGFR1 on day +28 with NRM. Of these, only higher levels of log-transformed FS (P = .01) and sEng (P = .04) showed a correlation with NRM, and these were selected for the final model. In multivariate analysis, patients with the highest levels of day +28 FS and sEng (score 3, n = 32, Figure 1) had a 4.6-fold higher relative risk (RR) of NRM (95% confidence interval 1.7-12.3, P < .01, Table 1). The prognostic value of the composite score was stronger than either individual factor alone (RR log[FS] = 2.1, P = .03, and RR log[sEng] = 2.3, P = .07). Grade III-IV aGVHD and patient age > 50 years were also independently associated with 1-year NRM. Conclusions: A composite score using day 28 plasma levels of FS and sEng predicts 1-year NRM after myeloablative HCT. Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicity implying defective capability for tissue repair and survival. We have previously shown that elevated levels of FS and sEng at the onset of aGVHD are associated with poor survival. Here, we show that these factors are predictive of NRM, independent of aGVHD. Measurement of these AF may highlight prospective opportunities to mitigate complications and improve survival after allogeneic HCT. Table 1 Multivariate Regression for 1-year Non-Relapse Mortality (NRM) NRM Factor Score 1* 2 3 Grade III-IV aGVHD No* Yes Age <35* 35-49 50+ * reference group.
N
RR (95% CI)
A Novel Pre-Transplant Immunosuppressive Preparative Regimen for Myeloablative Haploidentical and Unrelated Donor Hematopoietic Transplant in Hemoglobinopathies: A Safe and Effective Approach Sunil Bhat 1, Sonamani Ngangbam 2, Waseem Iqbal 2, Shobha Badiger 3, Sharat Damodar 4, K.S. Nataraj 2, Sohini Chakraborty 2, Ruchi Chaudhary 2. 1 Pediatric Hematology, Oncology and Bone Marrow Transplantation, Mazumdar Shaw Cancer Center, Narayana Health City, Bangalore, India; 2 Mazumdar Shaw Cancer Center, Narayana Health City, Bangalore, India; 3 Mazumdar Shaw Cancer Center, Narayana Health Center, Bangalore, India; 4 Department of Haematology, Mazumdar Shaw Cancer Center, Bengaluru, India Haplo-identical and unrelated donor carries high risk of developing serious regimen related toxicities and failure to sustain a durable engraftment, especially in hemoglobinopathies. We introduced a novel pre transplant preparative regimen incorporating cyclophosphamide (1000 mg/m2 × 1 day), Fludarabine (30 mg/m2 × 4 days) and dexamethasone (20 mg/m2 × 5 days), preceding myeloablative conditioning (FLU/BU/CY/ATG). Fifteen patients (class 1 thalassemia—3, class 2 thalassemia—6, class 3 thalassemia—4, Sickle cell disease—1, unstable Hemoglobin disease—1) received 2 or 3 cycles of pre transplant preparative regimen prior to HSCT. Seven patients underwent HSCT from haplo-identical donor (TCR α/β and CD 19 depleted graft—5, T cell replete graft—2) while eight patients received unrelated donor grafts (MUD—6, MMUD—2). The median age of the patient was 5 years (range 2-19 years). All the 15 patients exhibited a rapid engraftment with a median day of neutrophil engraftment on day 14 (range 9-20). Two patients developed secondary mixed chimerism on days 87 and 93 post transplantation necessitating withdrawal of immunosuppressants to regain full chimerism. Three patients developed moderate sinusoidal obstruction syndrome and recovered completely. Asymptomatic CMV reactivation occurred in 7 patients (47%), EBV infection in two patients and fatal disseminated adenovirus infection occurred in one patient who also had HHV6 encephalitis Grade II-IV acute GVHD occurred in 6, while grade IV acute GVHD was seen in 2 patients. None of the patients developed chronic GVHD. One patient with grade IV acute GVHD died of disseminated adenovirus infection and treatment related mortality was 7.3%. With a median follow-up of 12 months (range 2 to 19 months), the overall survival and disease free survival was 92.3% (SE 7.4). We conclude that this novel pre transplant preparative regimen prior to myeloablative conditioning is well tolerated, safe and can result in durable graft function in hemoglobinopathies.
P
76
123 66 32
1.0 1.8 (0.7-4.6) 4.6 (1.7-12.3)
193 28
1.0 3.1 (1.3-7.6)
0.01
53 120 48
1.0 5.8 (0.8-43.2) 10.2 (1.3-77.4)
0.08 0.02
0.26 <0.01
Haploidentical Bone Marrow Transplantation with PostTransplant Cyclophosphamide for 41 Children and Adolescents with Bone Marrow Failures Carmem Bonfim 1, Lisandro Ribeiro 1, Samantha Nichele 1, Marco Bitencourt 2, Cilmara Kuwahara 3, Ana Luiza Melo Rodrigues 3, Gisele Loth 1, Noemi F. Pereira 4, Alberto C.M. Lima 4, Mary Eapen 5, Ricardo Pasquini 2. 1 Pediatric Blood and Marrow Transplantation Service, Federal University of Paraná, Curitiba, Brazil; 2 Blood and Marrow
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blood stem cells (PBSC) in 73.3%. 32.5% developed acute GVHD grade II- IV. With a median follow-up of 32 months, the treatment outcomes at 3 years are: Incidence of cGVHD 37.5% (95% conf. int. [CI] 32.6 – 42.3) Non-Relapse-Mortality (NRM) 22.1% (CI 18.4 -26.1) Overall survival (OS) 56.3% (CI 51.5- 61.2) Leukemia-Free-Survival (LFS) 46.5% (CI 41.7- 51.4) Relapse Incidence (RI) 31.4% (CI 26.9- 35.9)
Figure 2. CD4+ T-cell reconstitution after allo HCT in patients receiving busulfan (targeted to optimal exposure) and fludarabine (160mg/m2). Groups consist of patients in the highest quartile of F-ara-A AUC exposure (red) and the lower three quartiles (green).
Conclusions: High exposure to Flu significantly impairs CD4+ T-cell reconstitution and reduces survival chances after HCT. This is the first step in the definition of a target exposure for Flu in this setting. Dose individualization and/or TDM-based corrections towards the Flu target may reduce overexposure and improve survival chances after HCT.
73 Allogeneic Transplant for Mixed Phenotype Acute Leukemia (MPAL): Characteristics and Outcome in the ALWP-EBMT Database Reinhold Munker 1, Myriam Labopin 2, Jordi Esteve 3, Christoph Schmid 4, Arnon Nagler 5. 1 Tulane University, New Orleans, LA; 2 Hopital Saint-Antoine, Paris, France; 3 Hospital Clínic, Hematology department, IDIBAPS, Barcelona, Spain; 4 Department of Hematology and Oncology, Klinikum Augsburg, Ludwig-Maximilians-University, Munich, Germany; 5 The Bone Marrow Transplantation Department, Division of Internal Medicine, The Chaim Sheba Medical Center, TelHashomer, Israel Mixed phenotype acute leukemias (bearing markers of both myeloid and lymphoid lineages, MPAL) are rare (2- 3% of all acute leukemias) and considered puzzling due to their cell of origin. In the past, MPAL was considered as poor risk leukemia. The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers. The recommended treatment strategy involves induction regimens similar to acute lymphoblastic leukemia and consolidation by allogeneic transplant. Until recently, limited data were available validating this approach. The Center for International Blood and Marrow Transplant Research (CIBMTR) published a series of 95 cases of MPAL (median age 20 years) who underwent allogeneic transplant and found an encouraging long-term survival. In the present study, the Acute Leukemia Working Party (ALWP) of the EBMT database was queried for all consecutive patients with MPAL who received an allogeneic transplant for MPAL between 2000 and 2014 and were transplanted in complete remission (CR1; total of 519 patients). Cytogenetics were available in 203 patients. The median age was 38.1 years (range 18- 75). 54.5% of the patients were transplanted from a matched sibling donor, 45.5% were transplanted from a matched unrelated donor. Myeloablative conditioning (MAC) was used in 500 patients (77.1%, 140 chemotherapy-only, 260 chemotherapy with total body-irradiation [TBI]), reduced intensity in the remaining patients (22.9%). Bone marrow was used in 26.4%, peripheral
In univariate analysis, the age at transplant strongly impacted on LFS, NRM, RI and OS, with the age group 18- 35 having the best outcomes. Transplants done in the more recent period (2005- 2014 vs 2000-2004) had a lower NRM (20% vs 33.2%, P = .01) and a better OS (58.3 vs 44.7%, P = .04). No differences in outcomes were found between related and unrelated donors. Female donors for male recipients, no in vivo T cell depletion and PBSC were associated with more cGVHD. Use of MAC-TBI correlated with a lower RI and better LFS compared both to MAC-chemo and to RIC. In multivariate analysis, younger age and more recent year of transplant were statistically associated with a better LFS (P = .03 and P = .013) and OS (P = .006 and P = .004). MAC-TBI was associated with better LFS and a trend for higher OS. In conclusion, we confirm and extend the previous CIBMTR study in a large international database. Allogeneic transplant is a valid treatment option for MPAL (with a potential for cure) if a matched donor is available.
74 Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 Laura F. Newell 1, Todd E. Defor 2, Corey S. Cutler 3, Michael R. Verneris 4, Bruce R. Blazar 2, Joseph H. Antin 5, Alan Howard 6, Juan (Maggie) Wu 7, Margaret L. MacMillan 4, Angela Panoskaltsis-Mortari 4, Daniel J. Weisdorf 8, Shernan Holtan 9. 1 Oregon Health & Science University, Portland, OR; 2 University of Minnesota, Minneapolis, MN; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN; 5 Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 6 CIBMTR, National Marrow Donor Program, Minneapolis, MN; 7 The EMMES Corporation, Rockville, MD; 8 Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN; 9 Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN Introduction: Inflammation and tissue repair are linked processes influencing aGVHD after allogeneic HCT. In aGVHD, the balance between angiogenic factors (AF) contributing to tissue healing/repair (epidermal growth factor [EGF]) versus those associated with tissue damage/inflammation (follistatin [FS]) is dysregulated. Given that regimen-related tissue injury plays a role in NRM, we hypothesized that elevated levels of inflammation-associated AF would be associated with NRM even in patients without aGVHD. Methods: Levels of angiopoietin-2 (Ang2), EGF, FS, vascular endothelial growth factor (VEGF)-A and -B, endoglin (sEng), placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2 were quantified by MILLIPLEX magnetic bead panels, using plasma samples from patients enrolled on
S74
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
SESSION K: ALTERNATIVE DONORS, LATE EFFECTS/ QUALITY OF LIFE/PSYCHOSOCIAL ISSUES, AND GVH/GVL ALTERNATIVE DONORS
75
Figure 1. Adjusted Non-Relapse Mortality by Composite Score of log(sEng) + log(FS).
BMT CTN 0402. Factors associated with NRM were used to develop composite AF scores to predict NRM. In calculating the composite scores, we extrapolated the individual probabilities of 1 year NRM from regression models, and sorted the individual probabilities into 3 composite scores based on estimated probability of NRM: < 10%, between 10-19%, >20%. Results: 221 patients had pre-HCT and day +28 plasma samples available for analysis. Univariate analysis showed associations of Ang2, FS, sEng, and sVEGFR1 on day +28 with NRM. Of these, only higher levels of log-transformed FS (P = .01) and sEng (P = .04) showed a correlation with NRM, and these were selected for the final model. In multivariate analysis, patients with the highest levels of day +28 FS and sEng (score 3, n = 32, Figure 1) had a 4.6-fold higher relative risk (RR) of NRM (95% confidence interval 1.7-12.3, P < .01, Table 1). The prognostic value of the composite score was stronger than either individual factor alone (RR log[FS] = 2.1, P = .03, and RR log[sEng] = 2.3, P = .07). Grade III-IV aGVHD and patient age > 50 years were also independently associated with 1-year NRM. Conclusions: A composite score using day 28 plasma levels of FS and sEng predicts 1-year NRM after myeloablative HCT. Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicity implying defective capability for tissue repair and survival. We have previously shown that elevated levels of FS and sEng at the onset of aGVHD are associated with poor survival. Here, we show that these factors are predictive of NRM, independent of aGVHD. Measurement of these AF may highlight prospective opportunities to mitigate complications and improve survival after allogeneic HCT. Table 1 Multivariate Regression for 1-year Non-Relapse Mortality (NRM) NRM Factor Score 1* 2 3 Grade III-IV aGVHD No* Yes Age <35* 35-49 50+ * reference group.
N
RR (95% CI)
A Novel Pre-Transplant Immunosuppressive Preparative Regimen for Myeloablative Haploidentical and Unrelated Donor Hematopoietic Transplant in Hemoglobinopathies: A Safe and Effective Approach Sunil Bhat 1, Sonamani Ngangbam 2, Waseem Iqbal 2, Shobha Badiger 3, Sharat Damodar 4, K.S. Nataraj 2, Sohini Chakraborty 2, Ruchi Chaudhary 2. 1 Pediatric Hematology, Oncology and Bone Marrow Transplantation, Mazumdar Shaw Cancer Center, Narayana Health City, Bangalore, India; 2 Mazumdar Shaw Cancer Center, Narayana Health City, Bangalore, India; 3 Mazumdar Shaw Cancer Center, Narayana Health Center, Bangalore, India; 4 Department of Haematology, Mazumdar Shaw Cancer Center, Bengaluru, India Haplo-identical and unrelated donor carries high risk of developing serious regimen related toxicities and failure to sustain a durable engraftment, especially in hemoglobinopathies. We introduced a novel pre transplant preparative regimen incorporating cyclophosphamide (1000 mg/m2 × 1 day), Fludarabine (30 mg/m2 × 4 days) and dexamethasone (20 mg/m2 × 5 days), preceding myeloablative conditioning (FLU/BU/CY/ATG). Fifteen patients (class 1 thalassemia—3, class 2 thalassemia—6, class 3 thalassemia—4, Sickle cell disease—1, unstable Hemoglobin disease—1) received 2 or 3 cycles of pre transplant preparative regimen prior to HSCT. Seven patients underwent HSCT from haplo-identical donor (TCR α/β and CD 19 depleted graft—5, T cell replete graft—2) while eight patients received unrelated donor grafts (MUD—6, MMUD—2). The median age of the patient was 5 years (range 2-19 years). All the 15 patients exhibited a rapid engraftment with a median day of neutrophil engraftment on day 14 (range 9-20). Two patients developed secondary mixed chimerism on days 87 and 93 post transplantation necessitating withdrawal of immunosuppressants to regain full chimerism. Three patients developed moderate sinusoidal obstruction syndrome and recovered completely. Asymptomatic CMV reactivation occurred in 7 patients (47%), EBV infection in two patients and fatal disseminated adenovirus infection occurred in one patient who also had HHV6 encephalitis Grade II-IV acute GVHD occurred in 6, while grade IV acute GVHD was seen in 2 patients. None of the patients developed chronic GVHD. One patient with grade IV acute GVHD died of disseminated adenovirus infection and treatment related mortality was 7.3%. With a median follow-up of 12 months (range 2 to 19 months), the overall survival and disease free survival was 92.3% (SE 7.4). We conclude that this novel pre transplant preparative regimen prior to myeloablative conditioning is well tolerated, safe and can result in durable graft function in hemoglobinopathies.
P
76
123 66 32
1.0 1.8 (0.7-4.6) 4.6 (1.7-12.3)
193 28
1.0 3.1 (1.3-7.6)
0.01
53 120 48
1.0 5.8 (0.8-43.2) 10.2 (1.3-77.4)
0.08 0.02
0.26 <0.01
Haploidentical Bone Marrow Transplantation with PostTransplant Cyclophosphamide for 41 Children and Adolescents with Bone Marrow Failures Carmem Bonfim 1, Lisandro Ribeiro 1, Samantha Nichele 1, Marco Bitencourt 2, Cilmara Kuwahara 3, Ana Luiza Melo Rodrigues 3, Gisele Loth 1, Noemi F. Pereira 4, Alberto C.M. Lima 4, Mary Eapen 5, Ricardo Pasquini 2. 1 Pediatric Blood and Marrow Transplantation Service, Federal University of Paraná, Curitiba, Brazil; 2 Blood and Marrow