Risk-Adapted Intensive Chemotherapy for Primary ACUTE Myeloid Leukemia during the Last 25 YEARS: Increase in Complete Remission RATE, Hematopoietic Cell Transplantation Access and Decrease in Relapse Incidence Have LED to Improved Survival

BACKGROUND: The progress in the understanding of pathophysiology of AML has allowed the identification of genetic and immune abnormalities with prognostic impact on outcome and suitable as therapeutic targets. The genetic abnormalities are essential for risk allocation and risk-adapted treatment included the indication of hematopoietic cell transplantation. In the last decade, several studies have shown that persistence of measurable residual disease (MRD) after chemotherapy increases relapse incidence and the probability of leukemia recurrence and survival. Therefore, MRD has been progressively incorporated in prognosis estimation. In the last 25 years the CETLAM cooperative group has promoted 4 consecutive trials for AML patients fit for intensive chemotherapy and eventually HCT. Post-remission treatment was based on genetics of the disease and more recently on MRD. The aim of this study has been to investigate if the survival of patients has improved and, if so, to identify the factors that have influenced on the better outcome. METHODS: We included all patients with primary AML up to the age of 60 years enrolled in 4 consecutive Spanish CETLAM group trials. In brief, induction chemotherapy included idarubicin, cytarabine and etoposide in AML-94, AML-99 and AML-03 protocols and without etoposide in the AML-12. G-CSF priming was allowed in the two more recent trials. Post remission therapy included 1 to 3 consolidations including intermediate or high dose cytarabine. Hematopoietic transplantation indication was based on availability of an HLA-compatible donor, genetic findings and more recently MRD. Follow-up was extended to June 2020. The survival and relapse incidence analyses were censored at 5 years. Informed consent was obtained in all cases and the institutional review boards approved the protocols. RESULTS: Between 1994 and 2019, 1755 primary AML patients between 18 and 60 years-old fulfilled the inclusion criteria. The main characteristics of patients appear in table 1. Median age of the whole group was 46 years old. Overall survival (OS) in the whole group was 45% at 5 years, being significantly better in AML-03 and AML-12 than in AML-94 and AML-99 (image 1). Event free survival (EFS) in the whole group was 37% at 5 years, with also significant differences between trials. Also, the cumulative incidence of relapse (CIR) was 39% in the whole group with less relapses in the two more recent trials (image 2). To understand these findings, we analyzed first the CR rate over time that was higher in the AML-03 and AML-12 protocols (table 2). The results were different depending on genetics of AML with highest CR rate in patients with CBF AML and in those with intermediate-risk cytogenetics and favorable molecular findings; in contrast, patients with adverse cytogenetics had the lowest CR rate mainly because frequent refractoriness to therapy. According to outcomes in each MRC cytogenetic group 5y-OS was: 69±3% (63-76) in favorable group, 46±2% (43-49) in intermediate and 21±3% (16-27) in adverse group (p<0.001). 5y-EFS was 57±3% (51-64), 38±1% (35-41) and 15±2% (11-20) (p<0.001), and 5y-CIR was 30±3% (24-37), 39±2% (36-43) and 51±4% (43-59) (p<0.001), respectively (table 3). Referent to feasibility of allogeneic HCT, there was an increased access to the procedure over the years. A higher proportion of patients allografted in AML-03 and AML-12, 32% and 41% of patients in CR, respectively, compared to 16% in AML-94 and 19% in AML-99. A shortening of the interval between CR and transplantation has been observed in recent years; 3.9 months (mo) in AML-94, 2.7 mo in AML-99, 2.9 mo in AML-03 and 2.2 mo in AML-12. CONCLUSIONS: In adults with primary AML and age up to 60 years-old have improved over the last 25 years. During this period, the CETLAM group has refined the biological characterization of AML patients and tailored the post-remission therapy based on genetic markers with prognostic impact. The increased feasibility of allogeneic HCT may also justify the better results in more recent trials. Even though, there is substantial room for improvement, particularly in patients with AML and adverse genetic features. Disclosures Salamero: Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Daichii Sankyo: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Moraleda:Takeda: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Ribera:Pfizer, Amgen: Research Funding; Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau. Sureda Balari:Roche: Honoraria; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Speakers Bureau; Celgene: Consultancy, Honoraria. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽

10.1182/blood-2019-130338 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5742-5742

Author(s):

Han Bi Lee ◽

Jae-Ho Yoon ◽

Gi June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Establishment of Subspecialized Care in Hematologic Malignancies and a Hematopoietic Cell Transplantation Program

Blood ◽

10.1182/blood.v128.22.3580.3580 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3580-3580

Author(s):

Edward A. Copelan ◽

Jonathan M. Gerber ◽

Saad Z Usmani ◽

Michael R. Grunwald ◽

Nilanjan Ghosh ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hematologic Malignancies ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Transplantation Program ◽

Disease Specific

Abstract Introduction Access to appropriate healthcare close to home is a national and global problem with huge geographic variation in availability of subspecialized care and specific therapies, as illustrated by hematopoietic cell transplantation rates [Gratwohl, et al. Lancet Hematol, 2015]. Disease-specific physician specialization appears to improve outcomes in hematologic malignancies [Go, et al. Mayo Clin Proc, 2015]. Charlotte is the 2nd largest city in the Southeastern United States and 17th largest in the US, yet subspecialized care in hematologic malignancies including a leukemia unit and hematopoietic cell transplantation (HCT) program were non-existent 3 years ago. The closest HCT program was a 90-minute drive from Charlotte. Many patients lacked the resources or willingness to travel to a transplant center and died of potentially curable diseases. Establishment of a transplantation program, in particular, requires a substantial upfront investment, broad infrastructure and highly specialized interdisciplinary care. Better transplant outcomes have been associated with higher numbers of procedures [Loberiza, et al. Blood, 2005], but programs established over the last decade have struggled to attract adequate numbers of patients to support the required investment. Methods In 2011 Carolinas HealthCare System (CHS), which serves as a healthcare safety net for the region, decided to develop the Levine Cancer Institute as a primary through quaternary referral and treatment center, integrated through more than 12 sites, with a key focus being a program in HCT. The Department of Hematologic Malignancies and Blood Disorders was established in September 2012. We envisioned that the development of specialized care in leukemia, lymphoma, and plasma cell disorders, as well as more complex non-malignant hematologic disorders, would improve the quality of care for patients with those diseases, attract larger volumes of patients, and serve to identify patients appropriate for HCT in a timely manner. A 16 bed hematologic malignancies unit housed in a protected environment was constructed and completed in January 2014. Results Starting with 4 general hematologists, the department has grown over 4 years to include 23 faculty members, 14 of whom provide subspecialized care in hematologic malignancies and HCT. Patient volumes have grown more than six-fold during this time. The HCT Program performed its first transplant in March 2014, with a total of 60 transplants performed in 2014 and 81 in 2015. The HCT Program is on pace to perform over 100 transplants in 2016. The program received FACT accreditation in 2016, a little more than 2 years after the first HCT was performed. The age range of patients undergoing transplantation is from 22 to 76 (median 58) years. Sixty-nine percent of transplants have been autologous and 31% allogeneic, of which 65% were from haploidentical related donors. The proportion of transplants which are allogeneic is steadily increasing. More than 90% of patients who have undergone transplantation were referred through a disease-specific section. Non-relapse mortality (NRM) at 1 year is 1.8% for autologous transplants and 9.4% for allogeneic transplants, with survival rates at 1 year of 95.6% and 80.8% respectively. Notably, there is no difference in NRM (P=0.86), relapse-free survival (P=0.85), or overall survival (P=0.47) between HLA-identical and haploidentical transplant recipients. Conclusions Three years ago, for patients in Charlotte, access to subspecialized care in hematologic malignancies and HCT required significant travel. The development and growth of a program that provides disease-specific care in hematologic malignancies has overcome this barrier and has provided a base for growth of a newly established program in HCT. These developments have elevated the quality of care in hematologic malignancies in the Charlotte area and permit patients to receive appropriate and complex care close to home. Disclosures Gerber: Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Usmani:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Novartis: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Array: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grunwald:Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees. Ghosh:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Endocyte: Consultancy; Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy. Raghavan:Gerson Lehrman: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Comparison of 5-Azacytidine Versus Allogeneic Hematopoietic Cell Transplantation In Elderly (≥ 60 years) Patients with De Novo High-Risk MDS - a Retrospective Matched Pair Analysis

Blood ◽

10.1182/blood.v116.21.3500.3500 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3500-3500

Author(s):

Uwe Platzbecker ◽

Johannes Schetelig ◽

Juergen Finke ◽

Rudolf Trenschel ◽

Bart Lee Scott ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

De Novo ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Disease Stage ◽

Advisory Committees ◽

Allogeneic Hct

Abstract Abstract 3500 Background: Myelodysplastic syndromes (MDS) are a disease of the elderly in whom until recently, allogeneic hematopoietic cell transplantation (HCT) has not been considered a reasonable therapeutic option. Best supportive care (BSC), only including transfusion support, has been the standard of care for the majority of these patients (pts). However, innovations in transplant protocols have changed that approach resulting in an increased frequency of allogeneic HCT. Further, several innovative non-transplant therapeutic modalities for MDS pts have been developed. In fact, treatment with DNA-methyltransferase inhibitors (MTI) such as 5-azacytidine (5-aza) has changed the natural course of the disease and prolonged median survival by an average of 9 months compared to BSC. However, allogeneic HCT is currently still the only modality with proven curative potential, although there has been no true randomized trial comparison of HCT to 5-aza therapy only. Methods: Consequently, we performed a retrospective analysis in 126 pts, 60 –77, (median 64) years of age with de novo high-risk MDS according to FAB classification (RAEB n=88, RAEB-t n=20, CMML n=18) undergoing allogeneic HCT at a median of 9 months from initial MDS diagnosis. Cytogenetics were available in 108 pts (good: n=63, intermediate: n=18, poor: n=27), resulting in IPSS classification (in 107 pts) of INT-1 (n=28), INT-2 (n=45) or HIGH (n=34). The ECOG was available in 125 pts, and was either 0 (19%), 1 (66%) or >1 (15%). Prior to HCT, most pts had progressed to a higher stage than present at diagnosis (RAEB n=45, RAEB-t n=10, CMML n=10, AML n=61), the median blast count in the marrow being 12%. Patients were prepared for HCT with one of several reduced (RIC, n=78) or more conventional intensity (n=48) conditioning regimens followed by stem cells from either related (n=50) or unrelated (n=76) donors. The outcome of this high-risk MDS cohort was compared to patients from the French (GFM) 5-aza patient registry matched for age, gender, prior induction chemotherapy, time from diagnosis to therapy (either HCT or 5-aza), disease stage and cytogenetics at diagnosis as well as at start of therapy. The groups could be well matched except for age (median age 5-aza: 67 vs. HCT: 64; p=0.001). Further, the HCT group included more pts with a higher ECOG score (ECOG>0: 81% vs. 59%; p=0.05) prior to start of therapy. Results: With a median follow-up of 20 months for surviving pts from the start of therapy the estimated 3-year overall survival (OS) was 39% (95% CI, 30% to 48%) for HCT and 7% (95% CI, 0 to 16%) for 5-aza, respectively. In multivariate Cox regression analysis, ECOG score (p<0.001), disease stage p=0.021), cytogenetic risk group (p=0.002) and type of treatment (5-aza vs. HCT HR: 1.8; p=0.003) were associated with survival. Conclusion: These retrospective data suggest that allogeneic HCT from related or unrelated donors, using various conditioning approaches, might offer a meaningful survival benefit compared to 5-aza in patients with high-risk MDS, even in the 7th decade of life. There is a need for prospective clinical trials in order to determine the place of this approach within the growing therapeutic opportunities for pts with MDS. Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ades:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Panobinostat As a Maintenance Therapy after Autologous Hematopoietic Cell Transplantation for Patients with Multiple Myeloma

Blood ◽

10.1182/blood-2019-131451 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3189-3189

Author(s):

Taiga Nishihori ◽

Rachid Baz ◽

Leonel Ochoa ◽

Omar Alexis Castaneda Puglianini ◽

Kenneth H. Shain ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Autologous Hct ◽

Autologous Hematopoietic Cell Transplantation

Background: Autologous hematopoietic cell transplantation (HCT) followed by maintenance therapy with an immunomodulatory agent or a proteasome inhibitor remains an important strategy for upfront treatment in multiple myeloma (MM) with progression-free survival (PFS) and overall survival (OS) advantage. We designed a two-arm, open-label prospective study to examine the safety and tolerability of two different dosing schedules of an oral pan-histone deacetylase inhibitor, panobinostat (pano) as an alternative maintenance therapy option in patients with MM (NCT02722941). Methods: A total of 30 MM patients who underwent autologous HCT within the preceding 90 to 180 days were enrolled at Moffitt Cancer Center using a sequential alternating allocation to starting dose of either Cohort A: 20 mg PO 3/week, q 2 weeks on a 28-day cycle, or Cohort B: 10 mg PO daily for 7 days, q 2 weeks on a 28-day cycle, for 12 cycles. Dose level -1 was cohort A: 15 mg 3/week; and cohort B: 10 mg 4/week. Patients with clinically significant cardiac diseases, bradycardia, QTc > 470 msec, bifascicular block were ineligible. EKG was performed on pre- and post-dose on day 1 & 5 of cycle 1, and pre-dose on day 1 of cycles 2-4. Relative dose intensity (RDI), a ratio of amount of drug actually delivered in mg over the amount of planned dose in mg, was calculated to evaluate the treatment feasibility as a surrogate measure. Results: The median age of the entire cohort was 60 (range, 40-73) years with a male/female = 18/12. Disease characteristics are summarized in the Table. Patients initiated pano maintenance at a median of 131 (range 91 - 178) days after autologous HCT. As of 8/1/2019, 16 patients (8 in each cohort) completed full 12 cycles of pano. The RDI for the entire cohort, cohort A, and cohort B was 94.1% (33,750mg/35,860, 98% (16,350mg/16,680mg), and 90.7% (17,400mg/19,180mg), respectively. One patient in cohort A had dose reduction, and 6 patients in cohort B had dose reductions with cytopenias (43%) and GI toxicities (43%) being the most common reasons. No patients required dose modifications due to QT prolongation thus far. There were 3 possibly treatment-associated serious adverse events (pneumonia=2; colitis=1) but all patients successfully resumed pano. Three patients progressed while on pano maintenance. No mortality has been observed thus far. Ten patients are still on pano treatment. The median follow-up is 11 (range, 1-29) months. Conclusions: RDI is 90% overall and panobinostat as a single oral maintenance agent either at 20 mg three times per week or 10 mg po daily for 7 days on alternating weeks appears to be overall well tolerated. There were more dose reductions required in the 10 mg starting dose (cohort B). Panobinostat is a safe alternative for maintenance therapy after autologous HCT. Longer follow-up is needed to confirm the utility of this approach and updated results will be presented at the meeting. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Baz:Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shain:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Panobinostat single agent maintenance therapy after autologous hematopoietic cell transplantation for multiple myeloma

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Outcomes of Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Conditioning Regimen in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide for Acute Lymphoblastic Leukemia: ALWP of the EBMT Study

Blood ◽

10.1182/blood-2019-122258 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 320-320 ◽

Cited By ~ 1

Author(s):

Bhagirathbhai Dholaria ◽

Myriam Labopin ◽

Emanuele Angelucci ◽

Johanna Tischer ◽

Mutlu Arat ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Disease Status ◽

Advisory Board ◽

Hematopoietic Cell ◽

Advisory Committees

Background The intensity of a conditioning regimen has significant impact on outcomes of allogeneic hematopoietic cell transplantation in acute leukemia. In acute lymphoblastic leukemia (ALL) patients undergoing matched donor transplant, total body irradiation (TBI)- based myeloablative conditioning (MAC) regimen was associated with improved leukemia free survival (LFS) compared to chemotherapy (CT)-based MAC (Eder S. et al. 2017). Haploidentical hematopoietic cell transplantation(haplo-HCT) with post-transplant cyclophosphamide (PTCy) has emerged as a safe alternative in absence of a matched donor. The optimal MAC in haplo-HCT setting is yet to be defined. We studied the outcomes of TBI- vs. CT-based MAC in ALL patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 427 ALL (B-ALL-75%) patients, that underwent haplo-HCT with PTCy during the years 2010-2018, following TBI- (n=188, 44%) or CT- (n=239, 56%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose <9 mg/kg or TBI dose ≤6 Gy were excluded. All disease status were included (CR1=208, CR2+=135; advanced=84). Ninety-one (27%) patients had Philadelphia+ disease. Graft source was bone marrow in 229 (54%) patients. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most common TBI and CT-based regimens, respectively. Cyclosporin with mycophenolate was used as GVHD prophylaxis in 64% of patients. The patients, disease, and transplant related characteristics were similar in both cohorts. Median patient age was 32 yrs and the median follow ups for TBI and CT cohort were 20.7 (IQR-11.7-35.3) and 26.2 (IQR-10.2-41) months, respectively. Results In univariate analysis, day 100 incidences of acute GVHD II-IV and III-VI were 38% vs. 30% (p-0.07) and 19% vs. 13% (p-0.14) for TBI and CT cohort, respectively. Two-year overall and severe chronic GVHD incidences were 34% vs. 30% (p-0.51) and 17% vs. 12% (p-0.18) for TBI and CT cohort, respectively. Graft failure was reported in 6 (3%) and 19 (8%)(p-0.09) patients who received TBI and CT-based MAC, respectively. Death from veno-occlusive disease was reported in 4 (5%) TBI patients and 8 (7%) CT patients. There was no difference in reported deaths due to infection (28%) or interstitial pneumonitis (4%) among study cohorts. In multivariate analysis, TBI was associated with significant improvement in nonrelapse mortality (NRM) [HR=0.51, 95% CI:0.32-0.83, p<0.01] and LFS [HR=0.71, 95% CI:0.52-0.97, p-0.03] and higher incidence of aGVHD II-IV [HR=1.5, 95% CI:1.02-2.19, p-0.04]. Finally, relapse incidence (RI), acute GVHD (aGVHD) III-IV, OS and GVHD free relapse free survival (GRFS) did not differ between the groups. Two-year NRM, LFS and OS of TBI and CT cohort were 21% vs. 31% (p<0.01); 45% vs. 37% (p-0.05) and 51% vs. 47% (p-0.18), respectively (Figure 1). Other factors negatively impacting OS were disease status (CR2, HR=1.69, p-0.01 or advance, HR=2.62, p<0.01) and use of peripheral blood as graft source (HR=1.49, p-0.02). Interestingly, peripheral blood graft source also negatively impacted LFS (HR=1.44, p-0.02), aGVHD II-IV (HR=1.58, p-0.02 and GRFS (HR=1.54, p<0.01). Philadelphia+ disease was associated with reduced RI (HR=0.39, p-0.01) but had no impact on LFS (HR=0.80, p-0.29) or OS (HR=0.81, p-0.34)(Table 1). In a subgroup univariate analysis of patients <40 yrs old, TBI was associated with reduced 2-year NRM (19% vs. 28%, p-0.04) without impacting other outcome measures. In patients with pre-HCT disease status CR2 or advance disease, improvement in 2-year NRM (22% vs. 36%, p-0.02) was observed with TBI but no interaction was seen with other endpoints. Conclusions TBI based MAC resulted in significant reduction of NRM, translating into a better LFS without impacting aGVHD III-IV, chronic GVHD, RI or OS when compared to CT based MAC. Non-significant difference in OS between TBI and CT cohorts might be related to lower number of events, short follow-up and/or salvage therapies after relapse. These novel findings based on a large cohort of ALL patients, support the use of TBI based MAC and bone marrow graft in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

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A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation: A Retrospective Study from the CIBMTR

Blood ◽

10.1182/blood-2021-146957 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2890-2890

Author(s):

Esteban Arrieta-Bolanos ◽

Pietro Crivello ◽

Meilun He ◽

Tao Wang ◽

Shahinaz M. Gadalla ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Patent Application ◽

Multivariable Analysis ◽

Significant Proportion ◽

Cell Epitope ◽

Hematopoietic Cell ◽

Advisory Committees

Abstract Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes. Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the "classical" TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption. Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These "core" alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into "core" (N=930) and "non-core" (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B). Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and "core"/"non-core" TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with "core" TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), "non-core" TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, "core" vs. "non-core" HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The "core"/"non-core" TCE3 model was also associated with TRM with alloHCT from "core" TCE3-permissive donors showing lower risks of TRM than "non-core" TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002). Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of "core" TCE3-permissive donors might reduce patient morbidity after transplantation. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

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Dynamic Easix Scores Closely Predict Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-125834 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1971-1971

Author(s):

Mariam T. Nawas ◽

Miriam Sanchez-Escamilla ◽

Sean M. Devlin ◽

Molly A. Maloy ◽

Sergio A Giralt ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Ex Vivo ◽

Hematopoietic Cell ◽

Categorical Variable ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Over Time

Background: Endothelial Activation and Stress Index (EASIX) was developed as a simple surrogate of endothelial dysfunction and when evaluated pre-allogeneic hematopoietic cell transplantation (allo-HCT), is one of the strongest tools for predicting non-relapse mortality (NRM). In several datasets, we have found that high EASIX scores at days +30 and +100 post allo-HCT and at the onset of graft-versus-host disease (GVHD) are associated with higher NRM and poorer overall survival (OS) (data unpublished). These data demonstrate that EASIX analyzed as a categorical variable at specific landmarks is associated with outcomes after allo-HCT. However, the trend of EASIX scores has never been evaluated as a continuous variable over time. We hypothesized that defining the natural history of changes in EASIX post-HCT would help us identify an optimal time point at which EASIX has the highest discrimination for NRM. We also sought to determine whether changes in EASIX over time may be a more informative marker of NRM. Methods: We evaluated 509 adult patients who received an unmodified or ex-vivo CD34+-selected allo-HCT between April 2008 and December 2016. One hundred and forty-nine patients underwent unmodified, reduced intensity or nonmyeloablative allo-HCT with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose methotrexate. Three hundred and sixty patients underwent myeloablative allo-HCT with ex-vivo CD34+ selection (CliniMACS® CD34 Reagent System) as GVHD prophylaxis. The EASIX score (LDH*creatinine/platelet count) was calculated at continuous timepoints from baseline [day -30 to day -10] until 1-year post-HCT. For each longitudinal evaluation, the concordance of EASIX was estimated for NRM events occurring in the subsequent 180 days. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Disease relapse or death were considered competing risks for NRM. Results: Patient and HCT characteristics are detailed in Table 1. Median age at HCT was 56 years (range 19-78) and 59% of patients were males. The majority of unmodified allo-HCT were done for non-Hodgkin lymphoma (69%), while the majority of CD34-selected allo-HCTs were done for acute leukemia (61%). Most patients had sensitive disease at time of HCT (CR=61%; PR=13%). All patients except two received peripheral blood mobilized allografts. HCT-CI was 0 in 24% of patients, 1-2 in 32% and ≥ 3 in 44%. Sixty-eight patients experienced NRM within 1-year post-HCT. Causes of death in these patients were infection (41%), GVHD (29%), toxicity/organ failure (24%) and other (6%). Among all patients, EASIX scores rise rapidly early post-HCT and peak day +8 followed by sharp decline until day +40. Thereafter, EASIX scores tend to downtrend, but remain above baseline for the duration of the first year post-HCT (Figure 1). EASIX discrimination of 180-day NRM increases from time of allo-HCT until day +180 to +210, when concordance is highest (concordance index=0.85) (Figure 2). Overall, the ability of the EASIX score to discriminate NRM event times is similar when EASIX is analyzed as a categorical variable at landmark timepoints and as change from pre-HCT baseline EASIX score. In the first days post-HCT, EASIX values rise to a similar degree in patients regardless of whether they experience NRM or relapse in the following 180 days. Later in the post allo-HCT course, patients who do not experience NRM, including patients who relapse, have consistently lower EASIX scores compared to those who experience NRM in the following 180 days (Figure 3). Conclusions: Our data are the first to characterize the continuous trend of EASIX scores after allo-HCT, demonstrating that EASIX scores are highly dynamic and have variable concordance with NRM when analyzed longitudinally. While pre-HCT EASIX can be used to help guide allo-HCT treatment decisions prior to allo-HCT, evaluation of the dynamic changes in EASIX scores may better predict risk of NRM over time as patients acquire additional endothelial injury and toxicities after HCT. Assessment of dynamic EASIX scores may be useful in guiding novel investigative approaches to reduce the risk of toxicities and NRM along the allo-HCT journey. Disclosures Giralt: Actinium: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Takeda: Consultancy, Research Funding; Kite: Consultancy; Miltenyi: Research Funding. Perales:Miltenyi: Research Funding; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy.

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Effect of Vancomycin-Resistance Enterococci Colonization Status Prior to Allogeneic Hematopoietic Cell Transplantation on Transplant Outcomes: A Single Center Retrospective Experience

Blood ◽

10.1182/blood-2018-99-117646 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3386-3386

Author(s):

Amandeep Salhotra ◽

Dongyun Yang ◽

Bernard Tegtmeier ◽

Sally Mokhtari ◽

Justine Abella Ross ◽

...

Keyword(s):

Overall Survival ◽

Risk Factor ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Advisory Committees

Abstract The prevalence of vancomycin-resistance Enterococci colonization (VRE-C) in patients undergoing allogeneic hematopoietic cell transplantation (aHCT) is between 23-40%. Pre-HCT VRE-C is shown to be associated with high risks of VRE bloodstream infection (VRE-BSI), non-relapse mortality (NRM) and lower overall survival. Recent studies investigating the association between VRE-C and risk of acute graft-versus-host disease (aGVHD) after aHCT has demonstrated conflicting results, possibly due to the heterogeneous transplant conditioning and GVHD prophylactic regimens. Here, we sought to examine the VRE-C prevalence and determine its impact on aHCT outcomes, in patients receiving tacrolimus and sirolimus (T/S) as aGVHD prophylaxis. To explore the association between pre-HCT VRE-C and transplant outcomes, we retrospectively reviewed medical records of a cohort of 1074 consecutive patients who underwent aHCT at City of Hope from 2014 to 2017. Patients with stool culture screening within 30 days pre-aHCT (n=862) were identified from the microbiology database and were grouped as VRE-C and non-colonized (VRE-NC). Data was not available on VRE-C in 185 patients and they were not included in analysis. Overall survival (OS) and progression-free survival (PFS) were examined by Kaplan-Meier curves and log-rank tests. Non-relapse mortality (NRM), VRE-BSI, and GVHD rates of the 2 groups were compared by cumulative incidence rates and Gray's test. Multivariate analyses were performed when adjusting for prognostic factors. Two-sided P value of ≤0.05 was considered significant. Of the 862 evaluated patients, 68 had VRE-C (7.9% prevalence). Median age of patients in VRE-C and VRE-NC groups were 53 and 55 years, respectively. Gender distribution, transplant indications, stem cell source, proportion of unrelated donors, GVHD prophylaxis with T/S and other clinical variables including intensity of conditioning regimen and HCT-CI were similar between the two groups (Table 1) . Karnofsky performance status (KPS) of 90-100 and 70-80 were seen in 40% and 53% of patients with VRE-C compared to 47% and 48% of VRE-NC patients (p=0.12). Overall, VRE-BSI episodes were rare (n=7) with 4 patients in VRE-C (6.1%) and 3 patients in VRE-NC (0.4 %); p <0.001. All 3 patients in the VRE-NC group developed bacteremia within the first 100 days (range 2-97) but VRE-BSI was not the eventual cause of death. The median onset of VRE-BSI in the VRE-C group (n=4) was only 6 days (range: 2-12) with 1 surviving patient and 3 who died of non VRE-BSI related causes. No statistical significance was detected in rates of non-VRE BSI (24.1% in VRE-C Vs. 19.2% in VRE-NC; p=0.30) and fungemia (1.5% in VRE-C vs 1.2% VRE-NC; p=0.77). At a median follow-up duration of 19.4 months (range: 2.7-48.4), similar 1-year OS was achieved in both groups (67.4% in VRE-C and 76.5% in VRE-NC; p=0.11) but 1 year PFS was significantly lower in the VRE-C cohort (55.6% Vs. 69.4%; p=0.038). Higher NRM was achieved in the VRE-C cohorts on days +100 and +365 (11.8% Vs. 7.2% and 25.1% Vs. 14.4%, respectively, p=0.041). (Figure 1) There were no differences in rates of day 100 aGVHD (grades II-IV) (Figure 2) and relapse rates at 12 months between the two groups. Conditioning regimen intensity, donor type, KPS, and primary diagnosis were significantly associated with NRM. When these variables were included in the multivariate model, VRE-C was found to be independently associated with higher NRM (HR=1.82, 95%CI: 1.12-2.93; p=0.015). In conclusion, in our cohort of patients receiving predominantly T/S-based aGVHD prophylaxis, no association was detected between VRE-C and aGVHD incidence. Higher rate of VRE-BSI in the VRE-C group is in accordance with published data, albeit lower rates of VRE-BSI was seen in our cohort. VRE-C contributed to higher NRM at days 100 and 365 post-aHCT and was an independent risk factor for poor HCT outcomes Since VRE-C is a potentially modifiable risk factor, our data supports continued efforts for specific interventional strategies (i.e. antimicrobial stewardship) to reduce drug resistant bacterial colonization, and for clinical research to reverse the impact of VRE-C, such as the use of agents, which may modulate gut microbiome. Disclosures Salhotra: Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Dadwal:AiCuris: Research Funding; Gilead: Research Funding; MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding.

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Final Results of Northern Italy Leukemia Group (NILG) Trial 10/07 Combining Pediatric-Type Therapy with Minimal Residual Disease Study and Risk-Oriented Hematopoietic Cell Transplantation in Adult Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v128.22.176.176 ◽

2016 ◽

Vol 128 (22) ◽

pp. 176-176 ◽

Cited By ~ 13

Author(s):

Renato Bassan ◽

Arianna Masciulli ◽

Tamara Intermesoli ◽

Orietta Spinelli ◽

Manuela Tosi ◽

...

Keyword(s):

Board Of Directors ◽

Minimal Residual Disease ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Residual Disease ◽

Hematopoietic Cell ◽

High Dose ◽

Advisory Committees ◽

Study Results ◽

Minimal Residual

Abstract Introduction. The application of Pediatric-Type Therapy (PTT) programs to adults with ALL can improve outcome significantly despite higher age-related toxicity. Recent series reported survival rates ≥ 50%, but only few combined PTT with Minimal Residual Disease (MRD) study for risk-oriented Hematopoietic Cell Transplantation (HCT) and/or explored the value of specific PTT element such as higher dose, lineage-targeted MTX up to 5 g/m2. Methods. To improve over prior data, NILG protocol 10/07 (Clinical.Trials.gov NCT-00795756) for unselected adult patients aged 18-65 years combined PTT together with MRD study for risk/MRD-based HCT. The 8-course program consisted of a 5-drug complete remission (CR) induction (cycle no. 1; imatinib added if Ph+) followed by 3 modified BFM blocks (no. 2, 4 and 6), 3 lineage-targeted MTX blocks (no. 3, 5 and 7; MTX 5 g/m2 for T-ALL and 2.5 g/m2 for B-ALL [1.5 g/m2 if age > 55 years or Ph+]; no. 3 and 7 with high-dose Ara-C 2 g/m2 x4, no. 5 with L-Asp 10,000 IU/m2 x2) and reinduction (no. 8). CNS prophylaxis was with triple intrathecals or liposomal cytarabine (Haematologica 2015;100:786). MRD was studied molecularly with sensitive probe(s) (sensitivity 10-4 or greater) on marrow samples obtained at end of induction (week 4, w4) and after cycles 3 (w10), 5 (w16), 7 (w22) i.e. after 1st, 2nd and 3rd lineage-targeted MTX block. Patients were risk-stratified at diagnosis and after MRD analysis for the purpose of allocation to HCT or conventional maintenance. The HCT allocation cohort consisted of predefined very high-risk patients (vHR: WBC >100, highly adverse cytogenetics, pre-T/mature T-ALL) regardless of MRD, of HR patients without MRD study (HR: late CR; B-ALL with WBC >30 or pro-B phenotype), and of HR or standard-risk (SR) patients with MRD ≥ 10-4 at w10/16 or positive at w22. Conversely, the maintenance allocation cohort consisted of SR and HR patients with MRD < 10-4 at w10/16 and negative at w22 and of SR patients without MRD study. A family related/unrelated donor search was activated at diagnosis in order to proceed to HCT soon after cycle no. 3 when needed. Results. 205 patients were enrolled, with a median age of 41 years (range 17-67 years, 11% > 60 years). 55% were male, 42 had Ph+ ALL, 119 Ph- B-ALL and 44 T-ALL. Of 163 patients with Ph- ALL, 45% were SR, 13% HR and 42% vHR. CR rate was 98% in Ph+ ALL and T-ALL, and 83% in Ph- B-ALL (88% vs 58% in patients ≤ vs > 60 years, P .0013). The MRD study was successful in 109/142 CR patients with Ph- ALL (77%), contributing to the final risk classification in 63 patients, of whom 41 were MRD responsive (65%) and 22 MRD resistant (35%). Altogether, 55 CR patients constituted the maintenance allocation group (39%) and 87 the HCT allocation group (61%), which included mainly vHR patients (n=61, 43%) selected for HCT independently of MRD study results. According to intention-to-treat, median OS is not reached (53% at 5 years, figure) and median DFS is 4.8 years (48% at 5 years). In Ph- ALL, 5-year OS/DFS are 74%/61% in T-ALL (medians not reached) and 48% each in B-ALL (medians 3.9 and 4.7 years). Median OS is not reached in both HCT and maintenance allocation groups (58% and 73% at 5 years, respectively, P .078), with a median DFS of 4.7 years (48% at 5 years) versus not reached (59% at 5 years) (P .19). Treatment adherence was good with some exceptions in maintenance allocation group (6 HCT, 11%) and a transplant realization of 68% (53 allogeneic; 6 autologous) in HCT allocation group. With HCT, 5-year incidence of nonrelapse mortality was 17%. The MRD analysis proved that DFS of patients achieving an MRD response <10-4 at w4 (n=46/90, 51%) or w10 (n=76/107, 71%) was significantly improved compared to those with MRD ≥ 10-4, with median not reached and 5-year rate 67% versus 4.5 years and 41% (w4 MRD; P .041), and 7.2 years and 64% versus 1 year and 23% (w10 MRD; P .0001). Conclusion. The current PTT and MRD-based risk-oriented strategy was applicable to adults with ALL in a wide age range, with some limitations in patients > 60 years. 5-year OS and DFS of 55% and 52% respectively in Ph- patients aged up to 65 years represent an improvement over prior NILG study (5-year OS and DFS of 36% and 35% respectively). MRD was essential in orientating the HCT choice in SR and HR patients and retained a major prognostic role in all patients. Optimizing the early MRD response with new immunotherapeutics and clarifying the role of HCT in MRD responsive vHR patients are some relevant topics of future research. Figure Figure. Disclosures Ciceri: MolMed SpA: Consultancy. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gallamini:Millenium Takeda: Membership on an entity's Board of Directors or advisory committees.

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Allogeneic Hematopoietic Cell Transplantation for Consolidation of VGPR or CR In Myeloma

Blood ◽

10.1182/blood.v118.21.4581.4581 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4581-4581

Author(s):

Taiga Nishihori ◽

Jose L. Ochoa-Bayona ◽

Joseph Pidala ◽

Kenneth H. Shain ◽

Daniel Sullivan ◽

...

Keyword(s):

Single Dose ◽

Board Of Directors ◽

Cell Transplantation ◽

Induction Therapy ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Advisory Committees ◽

Allogeneic Hct ◽

One Year

Abstract Abstract 4581 Allogeneic hematopoietic cell transplantation (HCT) from HLA-identical siblings has been shown to prolong survival of patients with multiple myeloma in some studies. However, all published clinical trials of up front allogenic transplant for myeloma were conducted before thalidomide, lenalidomide and bortezomib became available; as such, less than 10% of the patients were in complete remission (CR) at time of transplantation. With contemporary therapy incorporating novel agents, more than 50% of patients achieve very good partial response (VGPR) or better (VGPR or CR). We summarize our experience with the safety and efficacy of allogeneic transplantation for patients achieving VGPR or better following induction therapy containing novel agent(s). Thirteen myeloma patients with first VGPR or CR received allogeneic HCT between July 2007 and January 2011. Median age at transplant was 45 years (range, 25 – 59), median time from initial therapy to transplant was 236 days (range, 122 – 410). Six patients (46%) have high-risk cytogenetics/FISH. Five patients received bortezomib plus lenalidomide induction therapy and eight patients received bortezomib-induction. Three patients (23%) underwent autologous HCT with melphalan plus bortezomib conditioning (melphalan 100 mg/m2 for 2 days followed by bortezomib 1.3 mg/m2) subsequent to induction therapies to achieve further cytoreduction prior to allogeneic HCT. Median number of prior therapies was 2 (range, 1–2). Disease status at the time of allogeneic HCT was stringent CR (n=5), CR (n=3), and VGPR (n=5). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=5) and HLA-matched unrelated donors (n=8). Six patients received fludarabine 30 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days followed by a single dose of bortezomib 1.3 mg/m2 (Flu/Mel/Vel). Seven patients received fludarabine 40 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days (Flu/Mel). Graft-versus-host disease (GVHD) prophylaxis constitutes tacrolimus/methotrexate (n=5), tacrolimus/mycophenolate mofetil (n=4), and tacrolimus/sirolimus (n=4). All patients achieved neutrophil engraftment after a median of 17 days (range, 11 – 19), and all patients achieved platelet engraftment after a median of 17 days (range, 12 – 21). All patients established stable donor cell chimerism. Best responses after allogeneic HCT were sCR (n=10), CR (n=2) and VGPR (n=1). The cumulative incidence of grades 2–4 acute GVHD at day 100 was 57% (95% CI 0.30 – 1.00) with Flu/Mel conditioning and 33% (95% CI 0.11 – 1.00) for Flu/Mel/Vel conditioning, respectively (p=0.24). This observation suggests that a single dose of bortezomib 48 hours before HCT may prevent GVHD. One patient died of GVHD complications, 1 had disease progression and 11 remain alive, progression free with a median follow-up of one year (range 4 months to 4 years). The one year progression-free survival estimate is 90% (95%CI 0.71 – 1.00). These initial data indicate that allogenic transplant for myeloma in VGPR or CR is well tolerated. Longer follow-up is required to assess the efficacy of allogeneic HCT in the era of novel agents in preventing progression of the disease. Disclosures: Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina:Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Allergan: Research Funding.

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