FLT3 Inhibitor Therapy for Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Impact On Survival According to FLT3 Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1026-1026 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Borthakur Gautam ◽  
...  
Keyword(s):  
Research Funding ◽  
Initial Therapy ◽  
Inhibitor Therapy ◽  
Clinical Activity ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Impact On Survival

Abstract Abstract 1026 Poster Board I-48 Background: FLT3 mutations (ITD or D835 point mutation) are frequently observed in patients (pts) with AML and they confer an adverse prognosis, particularly among pts with diploid karyotype. This has made FLT3 an important target for drug development in AML. Several FLT3 inhibitors are currently being developed (eg, sorafenib, PKC-412, AC-220, CEP-701, IMC EB10, sunitinib). Results from early trials with many of these agents suggest they have clinical activity in the treatment of MDS and AML, although most responses are represented by a marked decrease in blast counts, with few complete remissions(CR). Whether these responses ultimately improve long-term outcome of pts, and whether they may be particularly beneficial for pts with FLT3 mutations compared to those with FLT3 wild-type (WT) is being investigated. Aims: To ascertain outcomes of patients given treatment with FLT3 inhibitors, alone or in combination with other therapies, and to compare outcomes in those patients with FLT3 mutations (ITD or D835) versus those with FLT3-WT. Methods: We reviewed the records of patients with MDS and AML who were enrolled on clinical trials with FLT3 inhibitors at our institution. We compared patient outcomes in those who received a FLT3 inhibitor in both FLT3 positive and FLT3 negative patients. Pts were classified as receiving FLT3 inhibitors 1) as part of their initial therapy, 2) as first salvage, or 3) as second salvage or beyond. Results: A total of 128 pts were included: 51 (40%) with FLT3-WT, 56 (44%) with FLT3-ITD, 11 (9%) with D835, and 10 (8%) had both FLT3-ITD and D835. The overall median age was 62 yrs (range, 17-88); by FLT3 status, median age was 70 yrs (35-88) for FLT3-WT pts and 58 yrs (17-81) for FLT3 mutated. Sixty-four pts (50%) were female. Twenty-three (18%) pts received FLT3 inhibitors as part of their induction therapy (18 FLT3-WT, 5 FLT3 mutated; median age 74 yrs); 22 (17%) as first salvage (4 FLT3-WT, 18 mutated; median age 67 yrs); and 83 (65%) as second or later salvage (29 FLT3-WT, 54 mutated; median age 59 yrs). Nine pts overall, all of whom were FLT3 mutated, achieved either CR (n=6) or CRp (n=3) with FLT3 inhibitors. Eight of the nine CR/CRp have been lost with a median CR duration of 8 months (mo) (3-12+). After a median follow-up of 3.5 mo, 115 (90%) pts have died, including 47 (92%) FLT3-WT, and 68 (88%) FLT3 mutated. The median survival is 3.8 mo for the total population. Survival by mutation status and timing of FLT3 inhibitor therapy is presented in table 1. Conclusions: Despite the inferior outcome expected for pts with FLT3 mutations, and the low rate of CR/CRp with FLT3 inhibitors, these results suggest that therapy with FLT3 inhibitors has the potential to improve the outcome of pts with FLT3 mutations. Additional studies incorporating these agents in AML therapy are warranted. Disclosures: Off Label Use: Sorafenib has not been FDA approved for use in MDS and AML. Kantarjian:Novartis: Research Funding. Cortes:Ambit: Research Funding; Novartis: Research Funding; ImClone: Research Funding.

Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3784-3784 ◽  
Author(s):  
Kiran Naqvi ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Research Funding ◽  
Transcript Level ◽  
Initial Therapy ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Molecular Responses ◽  
Transcript Levels ◽  
Frontline Therapy

Abstract Abstract 3784 Background: TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim: To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods: We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results: Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies. Conclusion: New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

Disease Patterns for Patients (pts) with Chronic Myeloid Leukemia (CML) That Have BCR-ABL Transcript Levels > 10% At 3 Month of Therapy with Tyrosine Kinase Inhibitors (TKIs)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3757-3757
Author(s):  
Aziz Nazha ◽  
Hagop M. Kantarjian ◽  
Preetesh Jain ◽  
Elias J. Jabbour ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Research Funding ◽  
Strong Predictor ◽  
Chronic Phase ◽  
Transcript Level ◽  
Initial Therapy ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival

Abstract Abstract 3757 Background: Response to TKIs in CML at 3 month is a strong predictor for long term outcome in CML patients treated with TKIs. Pts who do not achieve a BCR-ABL transcript level < 10% or a MCyR at 3 months have lower event-free survival (EFS) and perhaps overall survival (OS). However, pts have rarely changed therapy based on response at this early time points. The purpose of this analysis is to understand the patterns of disease progression and management in this group of patients. Patients and Methods: A total of 489 newly diagnosed CML pts that received initial treatment with TKIs: imatinib 400 mg daily (83) imatinib 800 mg daily (199), and second generation TKIs (2GTKIs) (207) in consecutive or parallel trials between 7/2000 and 6/2011 were included in this analysis. Cytogentic and molecular responses were evaluated every 3 month for the first year and then every 6 month. Event was defined as transformation to accelerated phase (AP) or blast phase (BP), loss of complete hematologic response (CHR), or loss of MCyR. Results: Among the 489 treated pts, 58 (12%) did not achieve a MCyR or BCR-ABL transcript level < 10 % at 3 months (26 pts (31%) received IM400, 19 (10%) IM800, and 13 (6%) 2GTKIs. Eleven of these pts (19%) had high sokal score at diagnosis (1 pt treated with imatinib 400, 7 with imatinib 800, 3 with 2GTKIs). By 6 months, 52/58 pts (90%) continued on their original therapy: 39 (67%) at the same dose and 19 (33%) with a decreased dose because of adverse events. No pt had a dose increase. Six pts had discontinued therapy by 6 month: 4 due to intolerance, 1 loss of CHR and 1 for progression to BP. At 6 month, 27 pts (47%) achieved MCyR or BCR-ABL transcript level < 10 %. At 12 months, 47 pts (81%) were still receiving their initial therapy, 11 pts (19%) had discontinued their initial TKI: 6 due to intolerance, 1 loss of CHR, 2 for progression to BP, and 2 for resistant disease. After a median follow up of 95 months, 17 pts (29%) continue to receive their initial therapy and their current disease status are: complete cytogenetic response (CCyR) in 14 (82%), 2 (12%) lost their CCyR, and 1(6%) pt who never achieve any cytogenetic or molecular response and remains in chronic phase on the same dose of imatinib for over 8 years. Among these 17 pts, 11 (65%) have MMR, 2 (12%) with MR4.5, and 4 (24%) have lost MMR (2 of them with loss of CCyR). The 5 years OS, EFS and transformation-free survival (TFS) for the patients who did not achieve any response at 3 month was 88%, 77%, and 94%, respectively. The OS, EFS, and TFS for the patients who subsequently achieved a response (MCyR or BCR-ABL transcript level < 10 %) at 6 month was 100%, 66%, and 95%, respectively vs those who continued to have no response 79%, 95%, and 100%, respectively (P = 0.17, 0.07, 0.99, respectively). Conclusions: Although BCR-ABL transcript level at 3 month may predict long-term outcome of pts with CML treated with TKIs, this represents a static, one-time measure. Assessing the response at 6 months of pts with poor response at 3 months may provide a better predictor of long term outcome. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

scholarly journals Streamline - Study of Relapse or Refractory (R/R) FLT3-Mutated Acute Myeloid Leukemia (AML) Using Electronic Medical Records (EMR): First Analysis from a Multicenter, Retrospective Cohort Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5082-5082
Author(s):  
Amer M. Zeidan ◽  
Adrienne Gilligan ◽  
Santosh Gautam ◽  
Nan Hu ◽  
David L. Grinblatt ◽  
...  
Keyword(s):  
Cohort Study ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Advisory Committees ◽  
Mutational Status ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Testing Patterns

INTRODUCTION: In AML, the ability to target disease-related mutations is an important therapeutic innovation. FMS-like tyrosine kinase 3 (FLT3) mutations (FLT3mut+) are common in AML and confer a negative impact on prognosis. Since FLT3 mutational status can change over the course of the disease and FLT3-targeting therapies may benefit FLT3mut+ patients (pts), FLT3 mutational testing is recommended for R/R AML pts, even if testing was performed at initial diagnosis. As the landscape of FLT3mut+ R/R AML evolves, it is important to understand how the utilization/sequencing of therapies and application of FLT3 mutational testing impacts pts in real-world settings. The objective of this analysis was to examine real-world data from a large, multicenter, collaborative EMR database to learn more about treatment and FLT3 testing patterns in pts with FLT3mut+ R/R AML. METHODS: This retrospective, longitudinal, observational cohort study was designed to describe treatment FLT3 testing patterns in adult (≥18 years) pts in the USA with FLT3mut+ R/R AML. For this analysis, initial diagnosis of R/R AML must have occurred between January 1, 2015 and November 30, 2018. This study focuses on data collected prior to the date of approval of gilteritinib for treatment of FLT3mut+ R/R AML (November 28, 2018). Patients were identified by confirmation of diagnosis of AML, followed by confirmation of FLT3mut+ disease, and then ≥1 R/R event. Data were derived from a consolidated EMR database, which combined data from CancerLinQ and Vector Oncology. Data were extracted through an SQL query and abstracted by clinical research nurses. Descriptive statistics were used to examine potential differences among subsets of pts. RESULTS: In the initial phase, data from 99 pts (52.5% male; n=52) with FLT3mut+ R/R AML were evaluated. The majority of pts were Caucasian (72.7%; n=72) with a median age of 62 years (range: 20-86) at first R/R episode. At the first R/R event, treatment regimens were diverse; a total of 89/99 (89.9%) pts underwent 44 different anticancer therapies and only 10.1% (n=10/99) of pts received best supportive care (BSC). At first R/R, the most common anticancer treatments were cytarabine + fludarabine + idarubicin (29.4%; n=10/34) for pts undergoing high-intensity chemotherapy (HIC) and decitabine (45.4%; n=5/11) for pts undergoing low-intensity chemotherapy (LIC). The percentage of pts receiving FLT3 inhibitors, either as single agent or in combination with chemotherapy, was 33.3% (n=33/99) of the total population (Table). Among pts aged <60 years, 47.7% (n=21/44) were treated with HIC-most commonly with cytarabine + fludarabine + idarubicin (33.3%; n=7/21). Only 4.5% (n=2/44) of pts received LIC and 9.1% (n=4/44) received BSC. In the pts aged ≥60 years, 10.9% (n=6/55) received BSC. A higher proportion of pts aged ≥60 years received HIC +/- FLT3 inhibitors (38.2%; n=21/55) compared with LIC +/- FLT3 inhibitors (25.5%; n=14/55). The most common treatments included cytarabine-usually in combination with fludarabine and/or idarubicin (84.6%, n=11/13)-for HIC, and azacitidine (alone or in combination; 55.6%, n=5/9) for LIC. Approximately 38.2% (n=21/55) of pts aged ≥60 years received a FLT3 inhibitor (alone or in combination with chemotherapy), with midostaurin being the most frequently prescribed (47.6%; n=10/21), followed by sorafenib (38.1%, n=8/21). Although most pts (83.8%; n=83/99) were tested for FLT3 mutations at initial AML diagnosis, the majority of pts were not retested; retest at first R/R was performed in 29.0% (n=9/31) of pts. At first R/R, 22.2% (n=2/9) of pts had a change in FLT3 mutational status (Figure). No significant differences were observed in FLT3 retesting among pts <60 years vs ≥60 years (P=0.456). CONCLUSIONS: During the study period, there was substantial heterogeneity regarding the management of FLT3mut+ R/R AML. A total of 89 pts received 44 different anticancer therapies and approximately one-third of pts received a FLT3 inhibitor (alone or in combination) at first R/R. However, during the study period, approved agents for treatment of FLT3mut+ R/R AML were not available. Despite NCCN guidelines, at first R/R, FLT3 retesting was not often performed. With recent approval of FLT3-targeted therapies, it is important to measure rates of retesting in the R/R setting to better understand how elements of pt care, such as monitoring changes in FLT3 mutational status, may impact pt outcomes. Disclosures Zeidan: Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Medimmune/AstraZeneca: Research Funding; ADC Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding. Gilligan:Astellas: Other: Project. Gautam:Astellas: Other: Project. Hu:Astellas: Other: Project. Grinblatt:Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pandya:Astellas Pharmaceuticals: Employment.

scholarly journals FGF2 from Bone Marrow Stroma Protects Acute Myeloid Leukemia Cells from the FLT3 Inhibitor Quizartinib and Facilitates Acquisition of Resistance Mutations

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1080-1080
Author(s):  
Elie Traer ◽  
Nathalie Javidi-Sharifi ◽  
Jacqueline Martinez ◽  
Isabel English ◽  
Jennifer Dunlap ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Domain ◽  
Resistance Mutations ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Fgf2 Expression ◽  
Equity Ownership ◽  
Cells Cultured

Abstract Background: Acute myeloid leukemia (AML) patients with internal tandem duplication of FLT3 (FLT3-ITD AML) routinely develop resistance to FLT3 inhibitor monotherapy. Resistance to inhibitors such as quizartinib can develop through mutation of the FLT3 kinase domain, but not all resistant patients have mutations indicating that additional mechanisms of resistance are important. Although quizartinib induces a rapid reduction of circulating leukemia blasts, residual blasts in the marrow persist, suggesting that the microenvironment protects blasts from quizartinib and may serve as a reservoir for development of resistance. Results: Using a screen of molecules from the microenvironment, we found that FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) were the two most protective proteins of FLT3-ITD MOLM14 cells when treated with 10 nM quizartinib in vitro. FL protection has been previously described by Mark Levis' group, so we focused on the mechanism of FGF2 protection. FGF2 bound FGFR1, activating the MAPK pathway to mediate resistance. FGF2-mediated resistance could be overcome by concomitant inhibition of the FGFR receptor using the inhibitor PD173074 or by siRNA knock-down of FGFR1. FGFR1 is highly expressed in primary AML cells, and exogenous FGF2 protected primary FLT3-ITD AML cells from quizartinib ex vivo in a dose-dependent fashion (p=0.0007 at 100 ng/ml). MOLM-14 cells were cultured continuously with quizartinib in media alone, or media supplemented with 10 ng/ml FGF2 or FL to mimic the effects of the microenvironment. MOLM14 cells supplemented with FL or FGF2 resumed growth after 6-8 weeks, significantly faster than cells cultured in media alone, of which only 2/4 developed resistance after 12 weeks. To test the dependence of resistance cultures on exogenous ligand, we removed ligand from the FGF2- and FL-dependent cultures after 4 months and continued quizartinib treatment. After a temporary pause in growth, the cells regained exponential growth within 1 month. We assayed FLT3 resistance mutations by Sanger sequencing during this time, and again at 8 months with a targeted next-generation sequencing panel of commonly mutated genes in AML. Deep sequencing revealed multiple FLT3 mutations along with recurrent mutations of KRAS and NRAS, indicating the importance of the FLT3 and MAPK signaling pathway in resistance (Figure 1). Multiple FLT3 mutations were identified strongly suggesting that FLT3 mutations were not pre-existing but developed during culture with quizartinib (Figure 1). In contrast, the frequency of the KRAS G13D mutation suggested this mutation was present at a low frequency in MOLM14 cells. FGF2 expression was evaluated by immunohistochemistry in serial bone marrow core biopsies from 10 FLT3-ITD AML patients on the phase II quizartinib trial. Stromal FGF2 expression increased significantly with quizartinib therapy (p<0.01) and remained elevated until patients acquired FLT3 resistance mutations or other intrinsic mechanisms of resistance. Once stromal FGF2 became redundant for survival, expression decreased again. FGF2 protected cells in a paracrine fashion since FGF2 immunofluorescence did not overlap with CD45 (hematopoietic marker) in core biopsies of quizartinib-treated patients. To test the effect of combined FLT3 and FGFR inhibition in a more complex in vitro model of the microenvironment, MOLM14 cells were co-cultured in transwells over HS-5 (FGF2 high expression) or HS-27 stromal cell lines (FGF2 low). HS-5 stromal cells were highly protective of MOLM14 cells treated with quizartinib alone, but this protection was attenuated by combined FGFR and FLT3 inhibition (p<0.01). In contrast, protection of MOLM14 cells in HS-27 co-culture was minimal, and unaffected by combined FLT3 and FGFR inhibition. Conclusions: Our data supports a two-step model of resistance to quizartinib with initial resistance mediated by microenvironmental proteins such as FGF2 and/or FL, followed by kinase domain mutation of FLT3 and/or activating mutations of the RAS pathway. Early resistance mediated by FGF2-expressing stroma can be overcome by concomitant inhibition of FLT3 and FGFR suggesting that pre-emptively targeting extrinsic resistance pathways, in combination with newer FLT3 inhibitors that have activity against kinase domain mutations, will improve the durability of response to FLT3 inhibitors. Figure 1. MOLM14 cells cultured in A) media, B) FGF2 or C) FL. Figure 1. MOLM14 cells cultured in A) media, B) FGF2 or C) FL. Disclosures Agarwal: CTI BioPharma Corp: Research Funding. Kovacsovics:Seattle Genetics: Research Funding. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy.

scholarly journals Measurable Residual Disease Status and FLT3 Inhibitor Therapy in Patients with FLT3-ITD Mutated AML Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1306-1306
Author(s):  
Emily C. Liang ◽  
Connie Chen ◽  
Rong Lu ◽  
Gabriel N. Mannis ◽  
Lori Muffly
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Inhibitor Therapy ◽  
Clinical Relapse ◽  
Free Survival ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Measurable Residual Disease

Abstract BACKGROUND: Measurable residual disease (MRD) is associated with increased risk of relapse and death in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). Recently, next-generation sequencing (NGS) has emerged as a sensitive and specific method to detect MRD from both bone marrow and peripheral blood. NGS methods are particularly useful for detecting internal tandem duplication mutations of the FMS-like tyrosine kinase 3 gene (FLT3-ITD), which define a subgroup of AML patients who may be at higher risk for relapse and who often undergo consolidative allogeneic HCT. The SORMAIN trial recently reported a highly significant relapse-free survival benefit for the first generation FLT3 inhibitor sorafenib as post-HCT maintenance, particularly among patients with detectable MRD following HCT. In 2019 our program initiated prospective FLT3-ITD monitoring by NGS using a commercially available assay (Invivoscribe, Inc., San Diego, CA) of the peripheral blood or bone marrow throughout the first three months following HCT for all patients with FLT3-ITD mutated AML undergoing HCT. We encouraged but did not mandate FLT3 inhibitor use, regardless of MRD status. In this study, we describe the clinical impact of sensitive FLT3 MRD testing early after HCT, maintenance FLT3 inhibitor use in a non-clinical trial setting, and the ability of early post-HCT FLT3 inhibitor therapy to modify transplant outcomes. RESULTS: Thirty-six adults with FLT3-ITD mutated AML underwent HCT at Stanford University between April 2019 and August 2020 and were included in this observational study (Table 1). These patients were not enrolled in clinical trials evaluating FLT3 inhibitor therapy after HCT. Twenty-nine (81%) received pre-HCT FLT3 inhibitors, and 78% were in first complete remission (CR1) at HCT. Median follow up after HCT was 14.0 months (range 4.6-25.7). Two patients were excluded from subsequent analyses due to early graft failure and receipt of azacitadine/enasidenib maintenance, respectively. Of the evaluable cohort, 9 (26%) experienced clinical relapse at a median of 4.2 months after HCT (range 1.8-6.1), and 10 (29%) died, 5 from transplant-related mortality and 5 from AML (Figure 1A and B). Of the 34 patients evaluable for post-HCT MRD analysis, 10 (29%) had detectable MRD within the first three months while 24 (71%) remained MRD-negative (Figure 2A and B). Although there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD (p = 0.13, Figure 3A), OS was not significantly impacted by MRD (p = 0.35, Figure 3B). Among the four patients with early post-HCT MRD negativity who ultimately relapsed, only one was FLT3-negative at time of relapse. Twenty-four patients (71%) received FLT3 inhibitor maintenance, initiated a median of 2.8 months after transplant (range 0.7-17.1), and the median duration was 10.6 months (range 1.7-23.7). The most common FLT3 inhibitor used was gilteritinib (n = 15), followed by midostaurin (n = 9), and sorafenib (n = 5). Among the 10 patients (29%) who did not receive post-transplant maintenance, reasons included graft-versus-host disease (GVHD) (n = 4), clinician decision (n = 3), cytopenias (n = 2), and thrombotic microangiopathy (n = 1). The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS (Figure 3C and D). Interestingly, the use of early FLT3 inhibitors post-HCT augmented PFS and OS in both MRD-negative and MRD-positive patients (Figure 3E and F), and effectively prevented clinical relapse in four patients with post-HCT MRD positivity (Figure 2A). CONCLUSION: In this cohort study, we evaluated the clinical utility of sensitive post-transplant MRD monitoring and maintenance FLT3 inhibitors on transplant outcomes. We demonstrate that clinical relapse can be prevented even in patients with post-HCT MRD through the incorporation of early FLT3 inhibitors. This finding is in keeping with the results from the SORMAIN trial. We also found that real-time sensitive MRD results allowed clinicians to begin early initiation of FLT3 inhibitor therapy, which positively affected outcomes. Figure 1 Figure 1. Disclosures Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Muffly: Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy.

Monocytic Maturation Induced by FLT3 Inhibitor Therapy of Acute Myeloid Leukemia: Morphologic and Immunophenotypic Characteristics

2019 ◽  
Vol 51 (5) ◽  
pp. 478-483
Author(s):  
Cade D Arries ◽  
Sophia L Yohe
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Population ◽  
Myeloid Leukemia ◽  
Inhibitor Therapy ◽  
Molecular Abnormalities ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Abstract Background FMS-like tyrosine kinase-3 (FLT3-ITD) mutations are some of the most common mutations in acute myeloid leukemia (AML), and patient outcomes have improved since the advent of tyrosine kinase inhibitors. First, granulocytic differentiation was described in FLT3-positive AML treated with FLT3 inhibitors, and more recently, monocytic differentiation was reported. Methods Two patients with myelomonocytic cells in their bone marrow were identified during routine follow-up after AML treatment that included FLT3 inhibitors. The bone marrow study was done as standard of care. Results Both patients had FLT3-ITD+ AML and showed an atypical maturing monocytic cell population and a decrease in the leukemic blast cell population after FLT3 inhibitor therapy. Concurrent genetic testing revealed persistent genetic abnormalities. Conclusions These cases illustrate monocytic maturation in FLT3+ AML after FLT3 inhibitor treatment. It is critical for pathologists and clinicians to be aware of the differentiation phenomenon, as these patients have persistent molecular abnormalities despite response to treatment and normalization of blast counts.

Changes in Serum Free Light Chain Rather Than Intact Monoclonal Immunoglobulin Levels Predict Outcome with Therapy in Patients with Light Chain Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 747-747
Author(s):  
Shaji Kumar ◽  
Morie A Gertz ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Light Chain ◽  
Research Funding ◽  
Amyloid Fibrils ◽  
Multivariable Analysis ◽  
Free Light Chain ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Monoclonal Protein ◽  
Hematological Response

Abstract Abstract 747 Background: Light chain amyloidosis is a monoclonal plasma cell proliferative disorder characterized by multiorgan deposition of monoclonal light chain derived amyloid fibrils. The diffuse organ infiltration by the amyloid fibrils leads to various AL related clinical features. Therapy of AL has been primarily aimed at elimination or control of the monoclonal plasma cells, thus decreasing the light chain available for amyloid formation. Assessment of response to therapy has been grouped into hematological response demonstrating elimination or reduction of the monoclonal population and organ response demonstrating actual improvement in its structure or function. Given the potentially long delay in observing organ improvement, hematological response has been the surrogate short term marker for long term outcome given the relatively rapid decline seen in the monoclonal protein with effective therapy, as well as studies showing improved long term outcome with a hematological response, especially complete response. However, conventional hematological response criteria give priority to the intact monoclonal protein rather than the light chain, which is the amyloidogenic protein. We hypothesized that a light chain response will correlate better with outcome than changes in the intact monoclonal protein levels. Methods: We identified 348 patients who had undergone stem cell transplant (SCT) for AL from among a large group of patients undergoing different treatments for AL, and in whom serial tests results were available. We identified the lowest value attained following SCT for various hematological response parameters (intact serum M-protein [MP], the difference between involved and uninvolved serum free light chain [FLC-diff], and urine M-protein [UP]) before an alternate therapy was instituted. We first estimated the best cutoff for the degree of change in each parameter that predicted 5-year survival from SCT. Cox proportional hazards model was used for multivariable analysis of factors influencing overall survival (OS). Results: We first examined the relative contribution of the MP and the FLC-diff on the overall survival following transplant. The best cutoff for reduction in FLC-diff to predict OS at 5 years from SCT was 88% if all patients were considered and 90% if only those with a baseline FLC diff > 7.5 mg/dL were considered. The best cutoff for MP reduction was 40% for 5 year survival for all patients and 67% for those with a baseline MP > 1.0 gm/dL. We then looked at the impact of FLC reduction and MP reduction in a multivariable analysis using OS as endpoint. For all patients, FLC reduction, but not MP reduction significantly impacted outcome, and results were similar when considering patients with MP>1.0 gm/dl and FLC-diff > 7.5 mg/dl at baseline. Among those with a baseline FLC-diff >7.5 mg/dL (n=125), the overall survival was 35 mos from SCT for those with less than 90% decrease in FLC-diff (45 pts) compared to not reached for those with at least 90% decrease (80 pts); P < 0.001 (Figure). Conclusions: The current study supports the notion that reductions in the free light chain parameters represent a more useful measure of hematological response that translates into better overall survival and possible better chance at organ improvement. A reduction in the FLC difference of 90% appears to correlate best with prolonged survival. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:celgene: Research Funding.

Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 72-72 ◽  
Author(s):  
Vivek L. Patel ◽  
Matthieu Mahévas ◽  
Roberto Stasi ◽  
Susanna Cunningham-Rundles ◽  
Bertrand Godeau ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Initial Response ◽  
Response Rates ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

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