Prompt CR Plus Consolidation Therapy Yields Improve Survival after Allogeneic Transplantation for AML Patients Receiving Myeloablative, but Not Reduced-Intensity Conditioning: A CIBMTR Analysis

Abstract Leukemia relapse and treatment related mortality (TRM) remain major obstacles for successful allogeneic hematopoietic cell transplantation (allo-HCT). The number of induction cycles using intensive chemotherapy at AML diagnosis to achieve complete remission (CR) and the number of consolidation cycles and disease status at the time of allo-HCT for patients with acute myeloid leukemia (AML) may each affect TRM and relapse rates. We investigated the impact of the number of induction/consolidation cycles and disease status on the success of allo-HCT in 3113 AML patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2019). They received allo-HCT in first CR or with persistent leukemia (primary induction failure-PIF) receiving myeloablative (MA) or reduced-intensity (RIC) conditioning. 1473 AML patients (median age, 47 years) in CR received MAC; 862 (58%) achieved CR after 1 cycle of intensive induction chemotherapy and 74% of these had no evidence of measurable residual disease (MRD). 454 (31%) patients required 2 cycles to CR (72 % MRD negative) and 157 (11%) patients (69% MRD negative) after ≥ 3 cycles. The overall survival (OS), relapse and TRM by induction cycle number is shown in Table 1. Multivariate analysis demonstrated that CR after 1 cycle led to higher OS vs. 2 cycles (HR 1.32 95%CI 1.11-1.56, p< 0.01) or ≥ 3 cycles (HR 1.47 95%CI 1.16-1.87, p< 0.01), while OS after 2 cycles or ≥ 3 cycles were similar (HR 1.2 95%CI 0.87-1.4, p=0.38). Higher TRM was observed in patients receiving 2 or ≥ 3 cycles vs. only 1 induction cycles (HR 1.34 95%CI 1.05-1.72, p< 0.02). Relapse risk was greater in those needing ≥ 3 cycles to achieve CR. Consolidation therapy after CR was associated with improved OS vs. no consolidation therapy (HR 1.57 95%CI 1.24-1.99, p< 0.01). The need for ≥2 induction cycles plus consolidation therapy was associated with higher TRM (HR 1.34 95%CI 1.05-1.72, p< 0.02). 1162 AML patients (median age, 63 years) in CR received allo-HCT after RIC; 714 (61%) achieved CR after 1 cycle of induction chemotherapy (72% MRD negative); 310 (27%) patients after 2 cycles (67% MRD negative) and 138 (12%) patients (58% MRD negative) after ≥ 3 cycles (Table 1). Multivariate analysis demonstrated that the number of induction cycles did not affect the OS or TRM. Relapse risk was greater in patients requiring ≥2 cycles to achieve CR. The use of consolidation therapy did not affect OS or TRM. MRD status at the time of allo-HCT did not have a significant impact on OS, TRM and relapse rates after either MA or RIC conditioning. 478 AML patients received allo-HCT after PIF (328 patients with MAC [median age, 51 years], 150 patients RIC [median age, 61 years], Table 1). After MAC, OS and relapse were significantly worse in PIF patients compared to any CR patients (p<0.01). After RIC, relapse was significantly more frequent in PIF patients vs. CR patients after 1 or more induction cycles (p<0.01). TRM was similar for PIF vs CR patients after MAC or RIC allo-HCT. These data demonstrate that among patients eligible for allo-HCT, the need for only one induction cycle to achieve CR, particularly when combined with consolidation therapy is associated with better outcomes after MA conditioning. Achieving CR prior to allo-HCT needing one or more induction cycles is associated with lower relapse rates and improved OS compared to patients with PIF that receive allo-HCT. Figure 1 Figure 1. Disclosures de Lima: BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hourigan: Govt. COI: Other. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Saber: Govt. COI: Other. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

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Outcome of Patients with Myelofibrosis after Ruxolitinib Failure: Role of Disease Status and Treatment Strategies in 214 Patients

Blood ◽

10.1182/blood-2018-99-116289 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4277-4277 ◽

Cited By ~ 5

Author(s):

Francesca Palandri ◽

Elena Maria Elli ◽

Nicola Polverelli ◽

Massimiliano Bonifacio ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Strategies ◽

Chronic Phase ◽

Disease Status ◽

Advisory Board ◽

Advisory Committees ◽

Transfusion Dependency ◽

Investigational Agents

Abstract Introduction . Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time. Aims . To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test). Results . After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%). The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%). After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received >2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4). A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7). Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p<0.001), transfusion dependency (p<0.001) and driver mutation status (with triple-negative pts having the worst survival compared to JAK2V617F and CALR-mutated pts, p=0.01). During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p<0.001). In pts who discontinued RUX in chronic phase, the use of second generation TKIs and other investigational agents tended to prolong survival compared to the administration of conventional medical treatments (i.e. HU, danazole, ESA) (Figure 1b, p=0.07) Discussion . After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Reduced-Intensity Induction with Dasatinib Vs. Hypercvad + 2nd Generation TKIs with MRD-Guided Follow-up Therapy Leads to Comparable Rates of MRD-Negative Remission While Reducing Transfusions and Neutropenia in Ph+ ALL

Blood ◽

10.1182/blood-2020-141264 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-44

Author(s):

Jonathan Webster ◽

Hua-Ling Tsai ◽

Eric Gehrie ◽

Tania Jain ◽

Christopher S. Hourigan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Initiation ◽

Advisory Board ◽

High Dose ◽

Allogeneic Bone ◽

Advisory Committees ◽

2Nd Generation ◽

Reduced Intensity

Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age >60 (33.3% vs. 29.2%, p>0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen <150) prior to treatment initiation (4.8% vs. 8.3%, p>0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p>0.99). Table 1 compares the time to ANC recovery >500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

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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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Outcomes of Allogeneic Stem Cell Transplantation for AML and MDS Based on Pre-Transplant MRD Status By Next-Generation Sequencing

Blood ◽

10.1182/blood-2018-99-117410 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2134-2134

Author(s):

Benjamin M Manning ◽

Robyn T Sussman ◽

Safoora Deihimi ◽

Noelle V. Frey ◽

Elizabeth O. Hexner ◽

...

Keyword(s):

Next Generation Sequencing ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Myelogenous Leukemia ◽

Next Generation ◽

Advisory Committees ◽

Post Transplant ◽

Generation Sequencing ◽

Relapse Rates

Abstract Background After induction therapy for acute myelogenous leukemia (AML), the presence of minimal residual disease (MRD) by targeted next-generation sequencing (NGS) during complete remission (CR) predicts relapse and survival, particularly after exclusion of pre-leukemic mutations. MRD assessment is not routinely performed for AML prior to transplant, partly because consensus regarding assay methodology, appropriate timing, interpretation of results, and therapeutic value prior to SCT is lacking. We therefore sought to describe the rates of mutational clearance and correlate these with relapse rates post-transplant. Methods We conducted a retrospective review of sequential AML or myelodysplastic syndrome (MDS) patients undergoing allogeneic hematopoietic cell transplant (alloHCT) at our institution between 2014 and 2017. There were 119 patients with AML/MDS who were treated with either myeloablative or reduced intensity conditioning regimens. Of the 119 patients transplanted, 60 had both pre- and post-treatment NGS results and were included in the analysis. 56 patients had somatic mutations on initial NGS and were therefore eligible for mutational clearance analysis. Twelve patients were in active disease and excluded from further analyses. The remaining patients (n=44) represent the core dataset. Blood and/or marrow specimens were analyzed via a clinical NGS panel targeting 68 leukemia-associated genes. Median coverage (across 88 samples) was 2817 reads. Mutations were considered persistent if present at variant allele frequencies (VAF) ≥ 1% for single nucleotide variants (SNV) or ≥ 2 copies for insertions and deletions (indels). Validated laboratory reporting practice at our institution reports VAF > 4% for SNVs and ≥ 1% for indels with a minimum of 250 total reads. We therefore defined three levels of mutational clearance on the basis of the VAF of residual mutations: VAF for SNV <1% (and/or indels ≤1 copy), between 1-4% (and/or indels <1% and ≥ 2 copies), and >4% (and/or indels > 1%). Patients with ≥ 1 mutation meeting these thresholds were designated NGS(-), NGS-low and NGS(+), respectively. The median follow-up was 332 days. Results On review of NGS data, 120 mutations were present in initial sequencing, with 64 mutations persistent in pre-transplant samples from 26 patients. The most commonly mutated genes from initial samples were FLT3 (18), ASXL1 (11), TET2 (10), NPM1 (9), RUNX1 (8), SRSF2 (8), and DNMT3A (7) (Figure 1A). Mutational clearance varied widely, with the putative pre-leukemic genes DNMT3A, TET2, and ASXL1 (DTA) demonstrating low rates of mutational clearance (Figure 1A). Mutations persisting below the validated reporting threshold were present in 20 patients, including 10 patients otherwise negative by NGS. There were 16 patients categorized as NGS(+), 10 NGS-low, and 18 NGS(-), with relapse rates of 31%, 22%, and 30%, respectively. No difference in relapse risk was observed between NGS(-) and NGS-low subgroups (p = 0.72), and no RFS benefit was observed for patients without persistent mutations > 4% relative to the NGS(+) subgroup (p = 0.56, Figure 1B). Recent work has shown a survival benefit in AML patients in CR without persistent mutations that is enhanced when DTA genes were excluded from the analysis (Jongen-Lavrencic, NEJM 2018). In our cohort, after exclusion of DTA mutations, 6 patients were reclassified by mutational clearance status, and 2 were excluded from the analysis as they had only DTA mutations in pre-treatment samples. Similar to the more comprehensive cohort, no RFS benefit based on NGS status was observed in the post-transplant period (p = 0.42, Figure 1C). Conclusions There were similar outcomes regardless of molecular MRD findings by NGS for patients with advanced myeloid malignancies who were in morphologic CR prior to alloHCT. These results contrast with those in the published literature that address a more uniform patient population of clinical trial participants, not all of whom went on to transplant. Further detailed analyses from larger more homogeneous populations will be useful to determine the prognostic significance of MRD by NGS prior to allogeneic HCT. Figure 1 Figure 1. Disclosures Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Daiichi Sankyo: Consultancy. Stadtmauer:Takeda: Consultancy; Celgene: Consultancy; AbbVie, Inc: Research Funding; Amgen: Consultancy; Janssen: Consultancy. Porter:Genentech: Other: Spouse employment; Kite Pharma: Other: Advisory board; Novartis: Other: Advisory board, Patents & Royalties, Research Funding. Gill:Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership; Novartis: Research Funding.

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Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplant (ASCT) for Patients with POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin Changes): A CIBMTR Analysis

Blood ◽

10.1182/blood-2021-151325 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 120-120

Author(s):

Ankit Kansagra ◽

Angela Dispenzieri ◽

Raphael Fraser ◽

Noel Estrada-Merly ◽

Shaji Kumar ◽

...

Keyword(s):

Multivariate Analysis ◽

Rare Disease ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Poems Syndrome ◽

Plasma Cell Dyscrasia ◽

Cell Transplant ◽

Advisory Committees

Abstract Introduction POEMS syndrome is a rare disease associated with a plasma cell dyscrasia with limited information regarding the role of ASCT. Small single institution series have demonstrated deep and durable responses after ASCT along with neurological improvement. Despite these benefits, ASCT is thought to have higher treatment related morbidity and mortality, limiting its use. We describe the outcomes from an international multicenter database of patients with POEMS syndrome undergoing ASCT. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database to evaluate the outcomes of patients undergoing ASCT for POEMS syndrome. Standard descriptive methods were used to report patient characteristics. Univariate and multivariate analysis were performed to identify predicators for non-relapse mortality (NRM), relapse, progression-free and overall survival (PFS, OS). NRM was compared between POEMS and multiple myeloma (MM) patients who underwent ASCT during the same time period. Results Between 2008-2018, 331 pts with POEMS syndrome who underwent ASCT were identified. The median age was 51 years, with 66% males. Racial distribution was 65% Caucasians, 19% African American, 5% other, and 10% missing. Pre-transplant characteristics included 70% patients had Karnofsky score <90, and 50% had HCT-CI ≥ 3, reflecting underlying disease severity and symptoms. The most common comorbidity was pulmonary (52%). Only 14% of patients were in very good partial response or better at the time of ASCT and 72 (22%) patients underwent ASCT without prior treatment. The median time from diagnosis to ASCT was 7 months and 74% underwent ASCT within 12 months of diagnosis. The most common mobilization strategy was GCSF +/- plerixafor in 50% of pts and 87% of pts received conditioning with 200mg/m2 of Melphalan. The median follow up was 48 (range 3-137) months. At day 100, NRM was 0.9 % (95% CI: 0.2-2.2%). At 4 years, NRM was 4.9% (95% CI: 2.6-7.9%), relapse 15.4% (95% CI 11.3-20.1%), PFS 79.7% (95% CI 74.5-84.3%) and OS 92% (95% CI 89.2-95.6%). Subsequent neoplasms were seen in 16 (5%) with 4 myeloid malignancy and 12 solid tumors. On multivariate analysis, age ≥ 60 years was associated with greater hazards of mortality, HR 2.6 (95% CI 1.2-5.6), p 0.01. The figure shows the comparable NRM between POEMS and MM (p 0.31). Conclusions: We report outcomes of the largest ASCT series of POEMS patients. Despite a high HCT-CI and low functional status among patients with POEMS syndrome, no difference in NRM was seen when compared to MM. Post-transplant outcomes were excellent and support single center data on the role of ASCT in this rare disease. Figure 1 Figure 1. Disclosures Kansagra: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Alnylam: Research Funding; Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Takeda: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; BMS: Consultancy, Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Janssen: Research Funding; Biolline: Research Funding; Oncopeptides: Other: Advisory Board; Angiocrine: Research Funding; Amgen: Research Funding. Shah: GSK: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Nektar: Research Funding; Bluebird Bio: Research Funding; Teneobio: Research Funding; CareDx: Consultancy; BMS/Celgene: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; CSL Behring: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Amgen: Consultancy; Kite: Consultancy. D'Souza: Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy.

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Bortezomib, Lenalidomide, and Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Frontline Multiple Myeloma Patients: Updated Results of the IFM 2008 Phase II VRD Intensive Program

Blood ◽

10.1182/blood.v118.21.1872.1872 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1872-1872 ◽

Cited By ~ 10

Author(s):

Murielle Roussel ◽

Nelly Robillard ◽

Philippe Moreau ◽

Lotfi Benboubker ◽

Cyrille Hulin ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Response Rate ◽

Advisory Board ◽

Consolidation Therapy ◽

Advisory Committees ◽

Duration Of Response ◽

Grade 3

Abstract Abstract 1872 Background: Introduction of new drugs in the intensive pathway have markedly increased survival rates for MM patients within the last 10 years. Efforts to further improve response and survival are still needed, mainly by increasing the depth of tumor reduction and the duration of response. Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) combination demonstrated substantial activity in frontline MM (Richardson P et al., Blood 2010); the IFM reported primary results of the VRD regimen as induction and consolidation therapy in the transplant setting (Roussel M et al. ASH 2010). We currently present updated data of the IFM 2008 trial. Methods: This phase II study was conducted at 10 transplant centers in France, with enrollment between Sept. 7 and Dec. 15, 2009. Pts with symptomatic upfront MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (D1, 4, 8, 11), Len 25 mg/day (D1–14), and Dex 40 mg/day once a week (D1, 8 and 15). Stem cell collection (STC) was planned after high dose cyclophosphamide (3g/m2). All pts then proceeded to melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts received two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 15 mg/day. All pts received, unless contraindicated, anticoagulation for prevention of deep-vein thrombosis (DVT), and anti-viral therapy. Pts with grade ≥2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved after consolidation. The secondary endpoints were: response rate after 3 cycles of VRD as induction, after ASCT and after maintenance; safety profile of the program; feasibility and quality of STC; duration of response, PFS, and OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells for minimal residual disease (MRD) was performed before and after ASCT, after consolidation and after maintenance. Adverse events (AEs) were graded using the CTC for Adverse Events (AE) v4. Patients: Thirty-one pts were enrolled. Baseline characteristics were: median age= 58 (range 33–65); women= 55%; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 17p del in 18% and t(4;14) translocation in 11% among 27 assessable pts. Results: All pts but 7 remain on study program at data cut-off (01/08/11). One pt discontinued treatment due to mobilization failure, 5 pts stopped maintenance because of serious AE (1 extensive DVT unless efficient anticoagulation) or AEs ( 3 grade 3/4 neutropenia and/or thrombocytopenia, 1 grade 3 hypothyroidism) and 1 pt went off study because of progressive disease. Currently, Len maintenance is on going for 6 pts and 4 pts just completed their last cycle. Therefore, 30 pts are evaluable for response after consolidation, and 20 after maintenance. All results are summarized in table 1. In ITT analysis, the overall response rate (ORR) after consolidation is 94%, including 36% VGPR, 48% RC or better (9% CR, 39% sCR). Consolidation therapy with 2 VRD cycles upgraded response in 26% of pts but only 1 pt achieved MRD negative (among 24 assessed). At time of reporting, Len maintenance did not improve response rate but 1 pt get MRD negative. One pt progressed during maintenance phase and 2 pts turned into MRD positive again without evidence of relapse. Considering the safety profile, 18 serious AEs were reported. There was no treatment-related mortality. The most common toxicities during consolidation therapy were: emergent PNY (23%), including 10% grade 1 and 13% grade 2; grade 3/4 neutropenia (17%), and thrombocytopenia (10%). The most common toxicities during Len maintenance were: grade 3/4 neutropenia (43%), and thrombocytopenia (10%); fatigue (13%); erythrodermia (10%); zona (10%). One extensive DVT and one pulmonary embolism were reported. There was no evidence of secondary malignancy. Conclusions: VRD consolidation plus Len maintenance after VRD induction and HDT produce high quality responses with 38% of sCR and is well tolerated in de novo MM pts. Updated efficacy and safety data will be presented at the meeting. Disclosures: Roussel: Janssen: Honoraria; Celgène: Honoraria. Off Label Use: bortezomib, lenalidomide and dexamethasone as induction and consolidation therapy lenalidomide maintenance. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Hulin:Celgene: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Leleu:celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Facon:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Attal:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Post-Marketing Observational Study to Assess the Incidence of Infusion-Related Reactions in Adult Patients with Therapy-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes Who Were Treated with CPX-351

Blood ◽

10.1182/blood-2020-136880 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-19

Author(s):

Meagan A. Jacoby ◽

Laura E. Finn ◽

Ashkan Emadi ◽

Nakhle S. Saba ◽

Bayard L. Powell ◽

...

Keyword(s):

Observational Study ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Phase 3 ◽

Advisory Committees ◽

Pivotal Phase ◽

Post Marketing ◽

Induction Cycle

Introduction: CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, has been approved by the US FDA and EMA for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes. The primary endpoint analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for the approvals evaluated older patients with newly diagnosed high-risk/secondary AML; after a median follow-up of 20.7 months, CPX-351 significantly improved median overall survival (OS) versus conventional 7+3 (9.56 vs 5.95 months; HR = 0.69 [95% CI: 0.52, 0.90]; 1-sidedP= 0.003), with a comparable safety profile and 2 infusion-related reaction events. After 5 years of follow-up, the improved median OS was maintained, with a HR (0.70) consistent with the primary endpoint analysis. Infusion-related reactions are generally common with liposomal drugs; this post-marketing observational study was therefore requested by the FDA to confirm observations from the phase 3 study by assessing the incidence and severity of infusion-related reactions during induction with CPX-351 in adults with AML. Methods: This was an observational, single-arm study (NCT03526926); prior to enrollment, the decision to prescribe CPX-351 was made based on the approved US indications and dosing. Patients who had been previously treated with CPX-351 or any investigational agent were ineligible. Eligible patients aged ≥18 years were to receive induction with CPX-351 at the label dosage of 100 units/m2 (cytarabine 100 mg/m2 and daunorubicin 44 mg/m2) by 90-minute IV infusion on Days 1, 3, and 5; the observation period included only the first 6 days of the first induction cycle, although patients may have received subsequent treatment cycles at their physician's discretion. The incidence and severity of infusion-related reactions were evaluated during and for 90 minutes after the completion of each infusion. Treatment-emergent adverse events (TEAEs) were collected from the start of the first infusion until 1 day after the last infusion of the first induction cycle (Day 6) and graded according to CTCAE v4.03. TEAEs were followed until resolution, stabilization, or permanent sequelae were identified, or the patient was lost to follow-up. Results: In total, 52 patients were enrolled in the study. The median age was 64 years (range: 28, 78), with 67% of patients aged ≥60 years; 56% were male; and 23%, 46%, and 23% of patients had an ECOG performance status of 0, 1, and 2, respectively. A majority of patients had no history of allergies (64%), allergic asthma (98%), or autoimmune disorders (87%). Most patients (94%) received all 3 CPX-351 infusions, with a mean of 2.9 infusions per patient (standard deviation: 0.3). Patients received a median cumulative daunorubicin dose of 247.5 mg (range: 88, 339) and cytarabine dose of 562.5 mg (range: 204, 774). One (2%) patient experienced infusion-related reactions during the study. The patient experienced grade 1 pyrexia on Day 2 (25 hours after the Day 1 infusion) and grade 2 dyspnea on Day 4 (21 hours after the Day 3 infusion). The infusion-related reactions did not lead to dose change, interruption, or discontinuation of treatment. In total, 39 (75%) patients experienced any-grade TEAEs, and 13 (25%) patients experienced grade 3 or 4 TEAEs within the 6-day study period. Serious TEAEs were reported by 6 (12%) patients and included respiratory failure (n = 2 [4%]), pyrexia, lung infection, sepsis, tumor lysis syndrome, cerebrovascular accident, embolism, and dyspnea (n = 1 [2%] each); serious TEAEs resolved after treatment in 2 patients. Three deaths reported during the study were due to serious TEAEs considered unrelated to CPX-351 (sepsis, thromboembolic event, and stroke; n = 1 [2%] each). Conclusions: In this post-marketing observational study in patients with AML, the frequency of infusion-related reactions was low (1 of 52 patients) and the reactions were grade 1-2 in severity. Although this study only collected data on adverse events during and immediately after infusion of the first induction cycle of CPX-351, the TEAEs and serious TEAEs reported were consistent with those seen in AML patients receiving induction chemotherapy. These data support the prior safety profile reported in the pivotal phase 3 study, with no new safety signals identified. Disclosures Jacoby: Jazz Pharmaceuticals:Research Funding;AbbVie:Research Funding.Finn:Jazz Pharmaceuticals:Speakers Bureau;Celgene:Speakers Bureau;Seattle Genetics:Speakers Bureau.Emadi:Jazz Pharmaceuticals:Research Funding;NewLink Genetics:Research Funding;Amgen:Membership on an entity's Board of Directors or advisory committees;KinaRx:Other: co-founder and scientific advisor;Genentech:Membership on an entity's Board of Directors or advisory committees;Servier:Membership on an entity's Board of Directors or advisory committees.Saba:Kyowa Kirin:Other: Advisory Board;Janssen:Other: Advisory Board, Speakers Bureau;AbbVie:Consultancy, Other: Advisory Board, Speakers Bureau;Pharmacyclics:Other: Advisory Board, Speakers Bureau;Kite:Other: Advisory Board.Powell:Pfizer:Research Funding;Novartis:Research Funding;Jazz Pharmaceuticals:Consultancy, Other: Advisor, Research Funding;Rafael Pharmaceuticals:Consultancy, Other: Advisor, Research Funding;Genentech:Research Funding.Seiter:Alexion:Speakers Bureau;AbbVie:Speakers Bureau;Onconova:Research Funding;Forma:Research Funding;Jazz Pharmaceuticals:Honoraria, Research Funding, Speakers Bureau;Sanofi:Honoraria, Speakers Bureau;Incyte:Honoraria, Speakers Bureau;Celgene:Honoraria, Research Funding, Speakers Bureau;Novartis:Honoraria, Research Funding, Speakers Bureau;Sun Pharma:Research Funding;Roche:Research Funding;Amphivena:Research Funding.Garcia:Jazz Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Faderl:Jazz Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.

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A Phase II Study of CPX-351 As a Novel Therapeutic Approach for Patients with Myelodysplastic Syndromes (MDS) after Hypomethylating Agent Failure

Blood ◽

10.1182/blood-2020-139515 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Aziz Nazha ◽

Sudipto Mukherjee ◽

Anjali S Advani ◽

Madeline Waldron ◽

Caitlin Siebenaller ◽

...

Keyword(s):

Overall Survival ◽

Complete Remission ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Steering Committee ◽

Advisory Board ◽

Consolidation Therapy ◽

Advisory Committees

Treatment options are limited for patients (pts) diagnosed with MDS at the time of hypomethylating agent (HMA) failure. One goal is to introduce another line of therapy to reduce tumor burden and enable patients to undergo hematopoietic stem cell transplant (HSCT), which may prolong survival for a subset. CPX-351, has shown better overall response rates and improved overall survival in patients with acute myeloid leukemia with underlying MDS changes compared to 7+3, suggesting that CPX-351 can be used in an MDS patient population. We hypothesized that treating MDS pts, who were failed by HMAs or were intolerant with CPX-351 would overcome HMA resistance. This is a phase II study of single agent CPX-351 administered at the standard FDA approved dose of 44 mg/m2 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) intravenously on days 1, 3, 5 of the induction cycle. If patients achieve complete remission (CR), marrow CR, partial remission or hematologic improvement per 2006 IWG criteria they will be eligible to continue on to consolidation therapy, which consists of CPX-351 at a dose of 15.4 mg/m2 (daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) every 28 days. Pts can receive up to 4 cycles of consolidation therapy in the absence of toxicity. The primary objective of the trial is to evaluate the efficacy of CPX-351 as measured by overall response rate (ORR) by IWG 2006 criteria. Secondary objectives include: ,1) determine the time to response (TTR), 2) evaluate the duration of response (DOR), 3) evaluate the event-free survival and the overall survival probability during trial period. Pts are risk stratified into lower vs higher-risk prior to enrollment using the Post-HMA model (Nazha A, et al. Hematologica 2016). Eligibility includes: pts >18 years with primary or secondary resistance to HMA, ECOG performance status < 2 and adequate organ function. Pts are excluded if they have uncontrolled infection or active malignancy. A total of 18 pts will be enrolled to each arm (lower and higher risk). To date, three pts were enrolled. One with MDS refractory to HMA who achieved complete remission and proceeded with 4 cycles of consolidation. The pt remained in remission 6+ months after the completion of consolidation. Another patient achieved a marrow CR but had a fungal pneumonia and then was taken off the trial (patient choice for going to hospice). The third patient had MDS/MPN, completed induction and achieved stable disease with improvement in platelets and neutrophils. All patients were lower-risk per the stratification model. No unexpected toxicity was observed. In conclusion, preliminarily CPX-351 is effective in MDS patients after HMA failure who are eligible to receive intensive chemotherapy. The treatment was well tolerated and toxicities were similar to what was observed in pivotal CPX-351 trials. The trial is ongoing and the results will be updated in the meeting. Disclosures Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Mukherjee:Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Carraway:Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC). Gerds:AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Apexx Oncology: Consultancy; Pfizer: Research Funding. Patel:Alexion: Other: educational speaker. Sekeres:Takeda/Millenium: Consultancy; Pfizer: Consultancy; BMS: Consultancy. OffLabel Disclosure: CPX-351 in MDS

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Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

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