Chronic Graft-Versus-Host Disease (cGVHD) Exacerbation after Sars-Cov-2 Covid Vaccination

Abstract INTRODUCTION: Allogeneic hematopoietic cell transplant (allo-HCT) exists as a potential cure to a number of different benign and malignant hematologic conditions. About 50% of patient develop cGVHD, the most important long-term complication of allo-HCT with profound effects on immune recovery. This immunocompromised patient population requires careful consideration regarding approach to vaccination. As the SARS-CoV-2 vaccines were developed and made available at an unprecedented rate, we are learning in real-time how specific vulnerable patient populations are affected, particularly as patients with cGVHD were largely excluded from clinical trials for the SARS-CoV-2 mRNA vaccines. Though the immunomodulatory mechanisms of the Pfizer and Moderna vaccines are poorly understood, societies such as ASH and ASTCT recommend that patients with cGVHD receive it. Here, we report our experience in patients with cGVHD who received the mRNA SARS-CoV-2 vaccine. METHODS: We performed this retrospective analysis of all Huntsman Comprehensive Cancer Center patients who underwent allo-HCT between 2013 and 2020. Patients who had a diagnosis of cGVHD requiring systemic therapy and were alive in December 2020, (when the SARS-CoV-2 vaccine became available), were included in the analysis. The clinical data was queried from the bone marrow transplant (BMT) database, and medical records were individually reviewed for documentation of SARS-CoV-2 mRNA vaccination. Patients meeting criteria were screened in clinic for symptoms post-vaccination. We define worsening or flare of disease as an organ upstage of at least 1 by NIH Consensus Criteria scale, in addition to requirement of intervention with a systemic or topical therapy. All patients were consented under a University of Utah IRB-approved protocol for participation in this study. RESULTS: A total of 52 patients at our institution met the inclusion criteria of being alive with cGVHD at the time Covid mRNA vaccinations became available. Of these 52 patients, 65.4% (n=34) had had two doses of SARS-CoV-2 vaccine. Of these 34 patients, 26.5% (n=9) experienced worsening of their cGVHD manifestations after vaccination. All 9 of these patients (100%) received the Pfizer vaccine. Mean time between transplant day 0 and flare date was 1,222 days (95% CI 511-1,933). At the time of flare, 3/9 patients were on systemic treatment for cGVHD, 6/9 patients had been tapered off systemic therapy, and half of them were on topical therapies. Three patients (33.3%) experienced GVHD flare after SARS-CoV-2 vaccine dose #1. The remaining 6 (66.7%) experienced flare after dose #2, with a median time to flare of 1.5 days. Five of the 9 patients (55.6%) required systemic steroid therapy, with 2 patients (22.2%) requiring >30 days of treatment. The most common organs involved were skin and eyes. Six patients (66.7%) had resolution of flare symptoms. One patient (11.1%) subsequently developed Covid pneumonia and had relapse of AML. CONCLUSION: Though reports have emerged highlighting hematologic and other autoimmune disease recrudescence in response to SARS-CoV-2 vaccination, to our knowledge this is the first large case series demonstrating chronic GVHD flare in response to the vaccine. Almost a third of our cGVHD patients experienced disease flare shortly after vaccination, which raises questions of the degree and mechanism of such heightened immunogenicity in an mRNA vaccine. Consistent with prior studies, most of our patients (66.7%) experienced disease flare after receiving the 2 nd mRNA vaccine dose, Although correlation with vaccine administration does not necessary prove causation of GVHD flare, in counseling patients, the possibility of a severe flare should be weighed against risk of Covid infection. Figure 1 Figure 1. Disclosures Lee: Jazz,: Consultancy; Fresensius Kabi: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; CareDx: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding.

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Mutations Highly Specific for Secondary AML Are Associated with Poor Outcomes in Patients with NPM1-Mutated ELN Favorable Risk AML

Blood ◽

10.1182/blood-2021-150759 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 686-686

Author(s):

Onyee Chan ◽

Najla Al Ali ◽

Hammad Tashkandi ◽

Austin Ellis ◽

Somedeb Ball ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Prognostic Significance ◽

Cancer Center ◽

Cell Transplant ◽

Intermediate Risk ◽

Advisory Committees ◽

Secondary Aml ◽

The Impact

Abstract Background: NPM1 is commonly mutated in acute myeloid leukemia (AML) and represents a distinct entity under the WHO 2016 classification. It is one of the few mutations that can potentially support favorable risk by European LeukemiaNet (ELN) 2017 criteria. Mutations that are highly specific for secondary AML including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 (sMut) (Lindsley et al.) have been shown to confer poor prognosis. The impact of these mutations on NPM1-mutated AML warrants further investigation. Objective: In this study, we explore the outcomes in patients with NPM1-mutated AML. Methods: This was a retrospective study of NPM1-mutated AML patients who were diagnosed and treated at the Moffitt Cancer Center from 2013 to March 2021. Inclusion was restricted to NPM1-mutated patients with mutation analysis (NGS) performed at diagnosis (n=159). Kaplan-Meier, univariate, and multivariate analyses were performed. Results: Among 159 patients (78M/81F, median age 63 years at diagnosis), 80.5% had de novo AML. By ELN 2017 criteria, 63.5% (101/159) had favorable risk, 27.7% (44/159) had intermediate risk, and 8.2% (13/159) had adverse risk disease. Almost 90% had intermediate risk cytogenetics at the time of diagnosis. Common co-mutations included DNMT3A (47.2%), FLT3-ITD (35.8%), TET2 (26.4%), IDH1 (17.6%), FLT3-TKD (15.1%), and IDH2 (13.8%). sMut comprised 19.5% (31/159) of patients and 20.8% (21/101) of those with ELN favorable risk. In patients with treatment response data, those with sMut never achieved CR/CRi in 35.7% (10/28) compared to 17.2% (22/128) of patients without sMut (p=0.038). The overall survival (OS) was 43.7 months with a median follow up of 35.5 months. Patients with sMut had worse OS compared to those without sMut (14.7 months vs 57.6 months, p=0.011). Among patients with favorable risk disease, OS was 11.6 months compared to not reached for those with sMut and without sMut, respectively (p<0.0001). Univariate analysis showed sMut and allogeneic hematopoietic cell transplant (HCT) significantly impacted OS (sMut: HR 3.48, 95% CI: 1.80-6.72, p<0.001; HCT: HR 0.17, 95% CI: 0.07-0.44, p<0.001). Multivariate regression using covariates including age, AML type, sMut, and HCT confirmed their prognostic significance on survival (sMut: HR 2.40, 95% CI: 1.17-4.93, p=0.017; HCT: HR 0.26, 95% CI: 0.08-0.56, p=0.002). Conclusions: Our findings suggest NPM1-mutated AML patients with sMut have significantly worse prognosis despite being classified primarily as favorable risk by ELN 2017 at diagnosis. This may have treatment implications altering the need for and/or timing of HCT. These findings should be assessed prospectively and validated in independent datasets. Figure 1 Figure 1. Disclosures Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy. Talati: AbbVie: Honoraria; Pfizer: Honoraria; Astellas: Speakers Bureau; BMS: Honoraria; Jazz: Speakers Bureau. Kuykendall: Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Research Funding; Celgene/BMS: Honoraria; Abbvie: Honoraria; Blueprint: Honoraria; Pharmaessentia: Honoraria. Padron: Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Kite: 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, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; AbbVie: Consultancy; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Agios: Consultancy; Astellas: Consultancy.

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Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽

10.1182/blood-2021-150948 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2856-2856

Author(s):

Sumithira Vasu ◽

Meghan Kromer ◽

Qiuhong Zhao ◽

Hannah Choe ◽

Karilyn Larkin ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Transplant ◽

Advisory Committees ◽

High Incidence ◽

Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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Long-Term Follow-up of Follicular Lymphoma (FL) Patients (pts) Demonstrating Undetectable Minimal Residual Disease (MRD) Using a Next-Generation Based DNA Assay: Support for FL As a Curable Disease

Blood ◽

10.1182/blood-2019-127262 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2813-2813

Author(s):

Maryam Sarraf Yazdy ◽

Umair Jarral ◽

Chao Yin ◽

Frank Kuhr ◽

Allison P. Jacob ◽

...

Keyword(s):

Next Generation Sequencing ◽

Board Of Directors ◽

Research Funding ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Allogeneic Bone ◽

Next Generation ◽

Advisory Committees ◽

Generation Sequencing

BACKGROUND FL is the most common indolent non-Hodgkin lymphoma (NHL). While very responsive to therapy, it has been considered incurable. Nonetheless, pts remaining in remission >24 months appear to have a survival comparable to an age-matched population without NHL (Casulo et al, J Clin Oncol, 33:2516, 2015), and some are free of disease for many years and die from unrelated events. METHODS Adult pts were accrued from the Lombardi Comprehensive Cancer Center Lymphoma clinic. Pts were required to have histologically confirmed FL or transformed FL that was previously treated resulting in a complete remission, and were required to be free of progression at any time > 24 months following completion of treatment without intervening therapy. Original diagnostic samples were retrieved and subjected to clonality assessment using Adaptive's next generation sequencing (NGS) MRD assay , a research version of clonoSEQ®; (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci as well as translocations in Bcl1/2 IgH. Lymph node biopsy from time of original diagnosis was assessed to identify trackable clonotypes, which were found in 37/43 patients. Peripheral blood was assayed upon entry onto the study and every 6 months thereafter by the NGS-MRD assay to monitor MRD. Samples are being collected every 6 months during follow-up, and the results are being correlated with clinical outcome. RESULTS Of the 60 eligible pts who signed consent 41% were females, with a median age at diagnosis of 56 yrs (21-75) and median age at treatment of 56 years (21-75). Twenty six had received one prior line of treatment (LOT), 4 had 2, 6 had 3, and 1 had 5. The most common immediately prior line of therapy included bendamustine and rituximab (BR, n=16); rituximab, cyclophosphamide, adriamycin, vincristine, prednisone (RCHOP, n=6); double-monoclonal antibody containing regimens(rituximab-galiximab; rituximab-epratuzumab (n=3)), radioimmunotherapy (n=3), and allogeneic bone marrow transplant (n=2). The media follow-up since the start and completion of most recent therapy was 62 months (range 25-183 and 32-193, respectively). Of the 60 pts for whom original biopsy slides were obtainable, the quality was inadequate to amplify the DNA in 18. In another 5 pts, the sample was polyclonal and a dominant rearrangement could not be identified. In 32 of the 37 pts (86.5%), samples were negative at enrollment to this study at a level of detection of 10-5. By prior LOT, samples were negative in 25 of 26 following 1st line; 1 of 4 following 2nd line; 5 of 6 following 3rd line; and in the one pt after 5th line. In all but 1 pt, the assay has remained negative on subsequent determinations as shown in the spider plot (Fig 1). The 5 positive patients had been followed for a median of 85 (56-118) months. Additional follow-up is underway to determine if positive pts will eventually relapse. CONCLUSIONS These data are the first to demonstrate that a high proportion of FL pts in a prolonged clinical remission have undetectable DNA by sensitive next generation sequencing, without evidence of clinical progression, and are potentially cured of their disease. Figure 1 Disclosures Yazdy: Bayer: Honoraria, Speakers Bureau; Genentech: Research Funding; Abbvie: Consultancy; Octapharma: Consultancy. Kuhr:Adaptive Biotechnologies: Employment, Other: shareholder. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Cheson:Epizyme: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding.

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First Reported Case Series of Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD)

Blood ◽

10.1182/blood-2021-148071 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4885-4885

Author(s):

Thomas A Gagliardi ◽

Jordan Milner ◽

Cassey Paula ◽

Mehmet Ozkayank ◽

Oya Levendoglu-Tugal ◽

...

Keyword(s):

Board Of Directors ◽

Lung Biopsy ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Case Series ◽

Advisory Committees ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Grade 3

Abstract Background: Graft-versus-Host Disease (GVHD) is a complication that occurs in 30-70% of hematologic malignancy patients post-hematopoietic stem cell transplant (HCT) (Flowers, February 2021). Steroid refractory GVHD has led to studies approving ruxolitinib and ibrutinib as the first FDA approved therapies for steroid refractory GVHD. Ruxolitinib is approved to treat acute GVHD (aGVHD) and inhibits Janus associated kinase (JAK). Ibrutinib is approved to treat chronic GVHD (cGVHD) and functions by inhibiting Bruton's tyrosine kinase (BTK). Here we describe 2 cases of patients who received both drugs for their GVHD. Patient #1 was a 4-year-old female who had a diagnosis of NK cell dysfunction. The patient underwent a conditioning regimen with melphalan 140 mg/m2, fludarabine 30 mg/m2 X5, and alemtuzumab for 5 days. The allogeneic HCT was performed with cells from a 9/10 NMDP donor and received a CD34+ enrichment with T cell addback of 2.1 x10^5 CD3/kg. Tacrolimus was given for GVHD prophylaxis. The patient developed aGVHD stage 2, grade 3 of the gut on day +148. Patient received steroids, extracorporeal photopheresis (ECP), and cellcept, and the GVHD resolved. The patient then developed skin GVHD on day +189 (stage 1, grade 3) that resolved. Approximately 15 months post-transplant there was concern the patient was developing cGVHD of the skin and gut (chronic though stable diarrhea), and therefore ibrutinib was initiated day +490 at 140 mg daily. The cGVHD persisted despite ibrutinib, ECP, tacrolimus, and sirolimus. Ruxolitinib was then initiated 2.5 mg bid on day +883. Patient demonstrated stable to slightly improved GVHD and tapered ibrutinib to 110 mg between days +951 and +980. The patient remained on ruxolitnib and ibrutinib as of day +1172. Patient #2 was a 1-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother, receiving a CD34+ enrichment with T cell addback of 2x10^5 CD3/kg. The conditioning regimen was busulfan 2 mg/kg, fludarabine 30 mg/m2, cyclophosphamide 50 mg/kg, and thymoglobulin 2 mg/kg with tacrolimus as GVHD prophylaxis. Patient was experiencing fevers, dyspnea and CT was concerning for an infiltrative process. Broad spectrum antibiotics did not improve symptoms. A lung biopsy was performed and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed on day +217 (pathology confirmed GVHD). The pathology report was reviewed at an outside institution, raising the question of thrombotic microangiopathy (TMA) in context of hemolysis markers (high LDH and low platelets). Patient was placed on Fluticasone, Azithromycin, and Montelukast (FAM). Due to persisting BOOP confirmed on lung biopsy on day +407, the patient started ibrutinib 140 mg daily on day +411 and was started on ruxolitinib 2.5 mg bid on day +412. ECP commenced on day +414. Within 1 month, symptoms improved. Lung CT imaging appeared stable since initiation of these modalities. Patient continued with ruxolitinib, ibrutinib and ECP (twice per week) for GVHD, though the ruxolitinib dose was tapered in half starting day +477. Symptoms have improved. Discussion: To our knowledge this is the first reported case series of concomitant use of ruxolitinib and ibrutinib. A literature search (PubMed and abstracts in society meetings) was conducted that found 1 paper focused on ruxolitinib for cGVHD with 3 patients on concomitant ibrutinib, but without further details (Ferreira et al., June 2021). Our cases represent a proof-of-concept approach to GVHD management and demonstrate the feasibility of administrating both agents. The combination was well-tolerated with no significant adverse events noted. Neither patient had to discontinue due to poor tolerance or interactions. We expect this dual-drug therapy will become more common going forward given FDA approvals for both ruxolitinib and ibrutinib. Recently, ruxolitinib underwent a successful trial for glucocorticoid-refractory cGVHD when compared to best available therapies, including ibrutinib, though the drugs were not tested in combination (Zeiser et al., July 2021). These findings may open the door for further concomitant use, especially if ruxolitinib is approved by the FDA for cGVHD. We propose further investigation into dual therapy of these drugs in cGVHD either compared to steroids or as a second line option. Disclosures Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Ruxolitinib is being used here for chronic GVHD, while it is FDA approved for acute GVHD.

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Haplo-Cord Transplantation Vs Unrelated Donor Stem Cell Transplantation in Patients with AML/MDS Older Than 50

Blood ◽

10.1182/blood.v124.21.1235.1235 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1235-1235 ◽

Cited By ~ 3

Author(s):

Joanna Rhodes ◽

Koen van Besien ◽

Hongtao Liu ◽

Usama Gergis ◽

Stephanie B. Tsai ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Cell Transplant ◽

Advisory Committees ◽

Post Transplant

Abstract Haplo-cord Transplantation Vs Unrelated Donor Stem Cell Transplantation In Patients with AML/MDS older than 50 Between 2007 and 2013, 109 patients with AML/MDS who were 50 years and older and had no HLA- matched related donor underwent allogeneic hematopoietic stem cell transplant. 64 had an HLA identical unrelated donor and received fludarabine/melphalan/alemtuzumab conditioning and post transplant tacrolimus for graft vs host disease (GVHD) prophylaxis. 45 underwent haplo-cord (HC) SCT with fludarabine/melphalan/ thymoglobulin; post-transplant tacrolimus and MMF. We compared patient characteristics and transplant outcomes between both groups. (Table 1) Age distribution and ASBMT risk category were similar. There were more patient's with AML in the HC group. (P=0.01) Time to neutrophil recovery, treatment related mortality (TRM), relapse rate, progression free survival (PFS) and overall survival (OS) were nearly identical between the two groups. Time to platelet recovery was on average 5 days longer after HC (p=0.05) The incidences of acute and chronic GVHD were very low in both groups, in part due to the use of in-vivo T cell depletion. HC transplant with reduced intensity conditioning is a curative treatment for older patients with AML/MDS who lack HLA identical unrelated donors. Despite inclusion of many patients with high risk features, nearly two thirds were estimated to be alive one year after transplant and very few had chronic GVHD. Haplo-cord grafts are more readily available, a potential advantage over MUD grafts in situations where transplant is needed urgently. TableMatched Unrelated DonorHaplo Cord PN6445Age (range)62 (50-73)62 (50-74)AML/MDS45/2041/5 0.01ASBMTLow/Int /High21/6/3015/10/200.7KPS 9090Time to ANC >50010110.1Time to Plt >2018230.05PFS@ 1 Y (95% CI)46 (34-58)41 (26-56)0.6OS@ 1 Y (95% CI)57 (44-70)64 (49-79)0.8Cum Inc TRM @100 d (95% CI)9 (2-16)9 (0-18)0.2Cum Inc TRM @ 1 Y(95% CI)25 (14-36)29 (15-44)0.2Cum Inc Relapse @ 1Y (95% CI)30 (18-42)26 (12-40)0.5Cum Inc AGVHD @ 100 D (95% CI)25 (14-36)29 (13-43)0.7Cum Inc CGVHD @ 1 Y (95% CI)6 (0-12)7 (0-15)0.9 Disclosures van Besien: Miltenyi: Research Funding. Mark:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Artz:Miltenyi: Research Funding.

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Safety and Efficacy of Liposomal Cytarabine/Daunorubicin (CPX-351) in Younger Patients < 60 Years Old with Secondary Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-113002 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2677-2677 ◽

Cited By ~ 1

Author(s):

Amanda Przespolewski ◽

Chetasi Talati ◽

Pankit Vachhani ◽

Srinivasa Reddy Sanikommu ◽

Swapna Thota ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Phase 3 ◽

Advisory Committees ◽

Secondary Acute Myeloid Leukemia

Abstract Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) have poor long-term outcomes following standard induction chemotherapy with 7+3. Last year, a liposomal cytarabine and daunorubicin formulation (CPX-351) was FDA approved for upfront treatment of s-AML based on a pivotal phase 3 trial demonstrating improved overall survival in pts aged 60-75 years old (Lancet J et al; JCO 2018). Although CPX-351 treatment is indicated in all adults with s-AML, it is unclear whether CPX-351 is safe and effective in younger pts < 60 years. We sought to address this unanswered question by retrospective review of clinical experience since FDA approval at 4 large academic centers. Methods: Medical records were retrospectively reviewed at Roswell Park Comprehensive Cancer Center, Moffitt Cancer Center, University of Alabama Comprehensive Cancer Center, and Levine Cancer Institute to identify pts aged 18-59 years old with untreated s-AML defined as antecedent MDS or CMML, prior cytotoxic therapy, or AML with WHO defined myelodysplasia related changes (AML-MRC) treated with CPX-351 as induction therapy. Demographics, disease-specific variables, as well as overall outcomes were collected in accordance with the institutional review board approved protocol. Responses were defined according to the 2003 International Working Group (IWG) criteria. Demographics, baseline clinical characteristics, treatment response, and adverse events were analyzed using descriptive statistics. Overall survival was estimated utilizing Kaplan-Meier (KM) analysis. Results: Twenty-one pts with confirmed s-AML received CPX-351 therapy. Mean age was 54 years (range 42 - 59), 13 were male (62%). The majority (62%, N=13) had AML-MRC, 4 (19%) had treatment-related AML (t-AML) and 4 (19%) had MDS-MRC. Four of 5 pts had received prior hypomethylating therapy. Fourteen pts had a complex karyotype (67%), and 4 patients were found to have a normal karyotype (12%). The most common molecular event was TP53 mutation seen in 9 pts (43%), followed by FLT3-ITD identified in 3 pts (14%). At the time of analysis, response assessments were available for 16 pts. Overall response rate (CR/CRi/PR) was 25% with 1 CR (6.25%, 1/16), 1 CRi (6.25%, 1/16), and 2 PR (13%, 2/16). The remaining pts (12/16, 75%) were non-responders (Table 1). One pt has received an allogenic stem cell transplant. The most common adverse event was infection (81%, 17/21) with 3 clinically significant bleeding events. Thirty-day mortality was 14.3%, with 60-day mortality of 19.1%. Overall survival in all evaluable pts (N=21) was 7.1 months (range 0.5 - 7.4 months) (Figure 1), with mean follow up of 14.8 weeks. Conclusions: This multi-institutional retrospective analysis suggests that CPX-351 results in lower response rates (CR/CRi 12.5%) and shorter overall survival (7.1 mos) than reported in the recently published phase 3 trial data in pts aged 60-75 years old (Table 1). Potential explanations for this discrepancy include short follow up, small sample size, the retrospective design of this study, and the significant proportions of pts with complex karyotype and TP53 mutations. Historically, patients < 65 years old with s-AML have had a reported overall survival of approximately 7 months. Further investigation of this regimen in younger pts with s-AML as compared with 7+3 and other approaches is warranted. Disclosures Thota: Incyte: Speakers Bureau. Baron:Pfizer Pharmaceuticals: Other: Previously served as a consult on the Advisory Boards (May 2017).. Griffiths:Alexion Inc.: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding. Sweet:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria; Incyte: Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Speakers Bureau. Wang:Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Feasibility and Activity Of Bortezomib-Based Therapy In Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Carfilzomib

Blood ◽

10.1182/blood.v122.21.1994.1994 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1994-1994

Author(s):

Arti Alagappan ◽

Rupin A Shah ◽

Sheeba K. Thomas ◽

Donna M. Weber ◽

Michael Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Single Agent ◽

Cancer Center ◽

Cell Transplant ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Overall Response

Abstract Introduction Carfilzomib (Car) is a proteasome inhibitor (PI) that was recently approved for the treatment of relapsed or refractory multiple myeloma. It is indicated for patients (pts) who previously received the proteasome inhibitor bortezomib (Bz) and an immunomodulatory drug (thalidomide or lenalidomide (len)) and had disease refractory to the last line of therapy. With the increasing number of therapeutic options, the optimal sequencing strategy of PIs to maximize clinical benefit and patient outcomes is unclear. The objective of our study was to therefore evaluate the activity of Bz after Car exposure. Methods Pts who enrolled and received Carfilzomib-based therapy on clinical trials at The University of Texas M. D. Anderson Cancer Center were screened for subsequent Bz therapy. Carfilzomib was administered as a single agent, or with len/dexamethasone (dex). We evaluated the overall response and tolerability of Bz pre- and post-Car, and to Car-based therapy. Results 16 pts were identified with a mean age of 67 (range 48-85), including 11 women and 5 men. ISS stage was I in 10 pts, stage II in 1, and stage III in 5. Median lines of therapy prior to Car were 3 (1-9), and 11 pts had prior stem cell transplant. Prior to Car-based therapy, 5 pts were Bz naïve, 7 were Bz sensitive, and 4 were Bz intolerant. Among the 16 patients treated with Car as a single agent, or Car in combination with dex (n=1), len/dex (n=12), panobinostat (n=2) and pomalidomide/dex (n=1) the overall response rate (ORR) to Car-based therapy on protocol (≥MR) was 75% (12/16). Among the 16 pts who subsequently received Bz after Car, 4 patients remained sensitive to Car (2/4 were Bz naïve), 5 were intolerant to Car, and 7 were Car refractory (3/7 were Bz naïve). Patients received Bz in combination with various other therapeutics, including cyclophosphamide/dex (n=5), melphalan/dex (n=2), modified-CVAD (n=3), len/dex (n=5), pegylated doxorubicin/dex (n=7) and bendamustine (n=3). The ORR to Bz-based therapy after Car was 81% (13/16). Among the 7 patients who were refractory to Car, 5/7 patients had ≥MR to Bz based therapy, while 2 patients were Bz intolerant due to rash and neutropenia. Among the 13 pts who responded to Bz after Car, 10 patients had received prior Bz. 3/5 pts who were Bz naïve had ≥MR. 4/4 patients who were intolerant to prior Bz had ≥MR, and 6/7 Bz sensitive patients had ≥MR. Discussion Bortezomib-based therapy is feasible after carfilzomib exposure in patients including those who were previously intolerant to bortezomib. The ORR(≥MR) in this patient population to Bz-based therapy was 81%. Disclosures: Thomas: Millenium: Research Funding; Novartis Pharmaceuticals: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Shah:Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

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Comparison of Fixed Dose, Reduced-Intensity Conditioning with Busulfan and Fludarabine to Reduced PK-Guided Busulfan AUC Conditioning in Patients Undergoing Hematopoietic Stem Cell Transplant for AML/MDS

Blood ◽

10.1182/blood-2019-123657 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5715-5715

Author(s):

Brendan Rasor ◽

Tyler Dickerson ◽

Qiuhong Zhao ◽

Jonathan E Brammer ◽

Karilyn Larkin ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Gvhd ◽

Advisory Board ◽

Hazard Ratio ◽

Cell Transplant ◽

Research Support ◽

Advisory Committees ◽

Significant Difference

Background: Consolidation therapy with allogeneic hematopoietic stem cell transplant (HSCT) is recommended to prevent relapse and improve survival in patients with intermediate and poor risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Due to toxicity, older patients with comorbidities were historically not candidates for HSCT. The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to proceed to HSCT by reducing toxicities associated with myeloablative conditioning (MAC).The cornerstone of reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). This can be achieved by the use of patient-specific pharmacokinetic targets. Previous studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day x 4 days in a subset of patients to balance reduced toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. Methods: To compare the two regimens, a retrospective, IRB-approved cohort study was conducted. The inclusion criteria were as follows: age 18-89 years, HSCT for a diagnosis of AML or MDS, and fludarabine + busulfan conditioning regimen ± antithymocyte globulin. In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to neutrophil recovery; time to platelet recovery; incidence of acute and chronic graft vs host disease (GVHD); sinusoidal obstructive syndrome; febrile neutropenia; graft failure; and grade 3-5 mucositis, acute kidney injury, or hepatic dysfunction. The log-rank test was used to compare RFS and OS, and Cox proportional hazard regression model was used to estimate the hazard ratio. Gray's test was used for competing risks analysis of relapse, acute GVHD, and chronic GVHD. Fine and Gray regression models were used to estimate the hazard ratio. Results: Seventy-four patients who received conditioning from 2015-2018 with either AUC 4,000 or RIC were identified. Disease type was similar between groups with 61.8% AML in the AUC 4,000 group and 52.5% in the RIC group. There were no significant differences in disease risk status. In the AUC 4,000 group, 17.6% had either AML with myelodysplastic changes or therapy-related AML/MDS, compared to 17.5% in the RIC group. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different, at 66.9% with AUC 4,000 compared to 57.5% with RIC (p=0.37) (A). Eighteen-month overall survival was also not significantly different with 66.9% alive in the AUC 4,000 group and 60% in the RIC group (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not significantly different (p=0.82, p=0.18, respectively) (C,D). There was, however, a statistically significant difference in the cumulative incidence of relapse over 18 months in favor of the AUC 4,000 regimen (hazard ratio 4.08, 95% confidence interval 1.15-14.5) (E). Grade 2-4 mucositis was more common in the AUC 4,000 group (85.3% vs 30%, p<0.01), but there were no significant differences in transaminitis, kidney injury, neutropenic fever, sinusoidal obstructive syndrome, or graft failure. Discussion: Though no significant difference existed in disease risk between the groups, choice of regimen was driven by physician judgement, perceived fitness, and ability to tolerate potential adverse effects. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower cumulative incidence of relapse. Adverse effects other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed. Figure Disclosures Brammer: Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. William:Guidepoint Global: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: 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; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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