scholarly journals Retrospective Analysis of the Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Included in a Patient Named Program of Gemtuzumab Ozogamicin

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 876-876
Author(s):  
Juliette Lambert ◽  
Pierre Peterlin ◽  
Cecile Pautas ◽  
Emmanuel Raffoux ◽  
Denis Caillot ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Gemtuzumab Ozogamicin ◽  
First Relapse ◽  
De Novo Aml ◽  
Grade 3 ◽  
Refractory Aml

Abstract Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age <50 years, de novo AML and relapse status. Among the 191 responders, 110 received additional courses of chemotherapy, 69 with GO. Main reason to not receive additional course (with or without GO) was allo-HSCT project. In the whole population, median overall survival (OS) after day 1 of treatment with GO was 11.2 months. In the population of responders, median OS after response was 20.4 months. In multivariate analysis, longer survival was associated with age < 50 years, de novo AML and favorable ELN group. Cumulative incidence of relapse at 24 months after response was 46%. One hundred and forty-seven patients received allo-HSCT, including 122 responders after GO-based regimen and 25 patients in treatment failure. Cumulative incidence of allo-HSCT at 18 months was 48%. Four-year OS was 48% in transplanted patients versus 19% in non-transplanted patients (Figure 1). Regarding safety of GO-based regimen, early deaths occurred within <30 days after the first dose of GO in 14 patients, and within <60 days in 35 patients. Myelosuppression was observed in all patients. Mean duration of thrombocytopenia <100 G/L was 35 days in responders. Bleeding grade 3 or more was observed in 22 patients (7%). Infection grade 3 or more was observed in 112 patients (30%). Sinusoidal obstruction syndrome (SOS) after GO treatment was reported in 6 patients, resolving in 4 of them. Four cases of fatal SOS were reported after allo-HSCT. Toxic deaths, i.e., not related to worsening leukemia, were reported in 20 patients after the first course of chemotherapy, 3 after additional courses and 33 after allo-HSCT. Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

Gemtuzumab Ozogamicin In Combination With Vorinostat and Azacitidine In Older Patients With Relapsed Or Refractory Acute Myeloid Leukemia (AML): Final Results From A Phase 1/2 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3936-3936 ◽  
Author(s):  
Roland B. Walter ◽  
Bruno C. Medeiros ◽  
Kelda M. Gardner ◽  
Kaysey F. Orlowski ◽  
Leonel Gallegos ◽  
...  
Keyword(s):  
Research Funding ◽  
Blood Count ◽  
Treatment Initiation ◽  
Phase 1 ◽  
Gemtuzumab Ozogamicin ◽  
Hematologic Toxicity ◽  
First Relapse ◽  
Grade 3 ◽  
Refractory Aml ◽  
Count Recovery

Abstract Background Epigenetic therapeutics such as the histone deacetylase (HDAC) inhibitor, vorinostat, and the DNA methyltransferase (DNMT) I inhibitor, azacitidine, sensitize AML cells in vitro to the CD33-targeting immunoconjugate, gemtuzumab ozogamicin (GO). This observation, together with the improved clinical activity when HDAC inhibitors are used with DNMT inhibitors, prompted a phase 1/2 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1stsalvage therapy. Methods Patients aged ≥50 years were eligible if they had an ECOG performance status of 0-3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation (HCT) were eligible if relapse occurred 6-12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. If there was persistent leukemia on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission was not achieved by the end of cycle 3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle 6. During phase 1, patients were assigned to therapy according to a “3+3” study design; dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). During phase 2, a Simon minimax two-stage design was to monitor whether a response rate of 0.34 was reached, with type I and II errors set at 0.1 and assuming a historical CR rate of 17% in these patients. Results 52 eligible patients, median age 64.8 (range, 50.2-78.9) years, with either primary refractory disease (n=29) or first relapse (n=23; median duration of first CR: 3 months) were enrolled and received a median of 2 (range, 1-4) cycles of therapy. During dose escalation, 1 DLT (death due to sepsis and respiratory failure) occurred at the 4th tested dose level after cycle 1, identifying vorinostat (400 mg/day orally from days 1-9), azacitidine (75 mg/m2/day IV or SC from days 1-7), and GO (3 mg/m2/day IV on days 4 and 8) as the maximum tolerated dose (MTD). A total of 43 patients received therapy at the MTD level. Ten of these achieved CR, while 8 achieved CRi, for a CR/CRi rate of 18/43 (41.9%; exact 95% CI: 27.0-57.9%). Thirteen of the 18 patients that achieved CR/CRi were taken off protocol to receive additional, more intensive consolidative chemotherapy, including HCT (n=12). Of these 18 patients, 5 relapsed after a median of 122 (38-146) days, while 3 died while in remission after a CR duration of 46, 97, and 130 days, and 10 are in ongoing remission after a median of 326 (68- 710) days, respectively. Median overall survival for the 18 patients achieving CR/CRi was significantly longer than for those 21 patients who failed therapy but lived at least 29 days (i.e. did not experience treatment-related mortality) after treatment initiation (224.5 [range 70-798]) vs. 95 [36-900] days, log rank P-value=0.0023). Four patients died within 28 days of treatment initiation. Besides grade 3-4 cytopenias, infectious complications were the most common grade 33 adverse events. Only 1 patient developed possible liver toxicity (abdominal pain/distention and mild ascites) after 4 cycles of therapy, although bilirubin and transaminases were only minimally elevated and doppler studies were unremarkable. Conclusion Our study indicates that GO in combination with vorinostat and azacitidine has encouraging anti-AML activity in older adults with relapsed/refractory AML. Disclosures: Walter: Amgen, Inc: Research Funding; Seattle Genetics, Inc: Consultancy, Research Funding. Off Label Use: Use of vorinostat/azacitidine/gemtuzumab ozogamicin for the treatment of relapsed/refractory AML.

scholarly journals Efficacy, Toxicity and Cost of Venetoclax-Based Combinations for the Treatment of Acute Myeloid Leukemia: Real-World Evidence from a Canadian Academic Center

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1253-1253
Author(s):  
Philippe Bouchard ◽  
Annie Brisebois-Boyer ◽  
Anne Beaudry ◽  
Jean-Francois Berthiaume ◽  
Nadia M. Bambace ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Response Rates ◽  
First Line ◽  
De Novo Aml ◽  
Dose Reductions ◽  
Acute Myeloid

Abstract Introduction: Venetoclax (ven) in combination with azacitidine (aza) or low-dose cytarabine (LDAC) has demonstrated efficacy for the first-line treatment of acute myeloid leukemia (AML) patients who are deemed unfit for intensive induction chemotherapy. The efficacy of ven-based treatment for relapsed or refractory (r/r) AML has not been prospectively evaluated. We have used off-label ven-based combinations to treat r/r AML patients and de novo AML in otherwise fit patients to avoid prolonged hospitalization. The objective of this study was to review the efficacy, toxicity and medication costs associated with ven-based treatments for AML in a Canadian university hospital. Methods: After local IRB approval, we conducted a retrospective chart review of all patients who received ven-based treatments, outside of a clinical trial, for AML at Hopital Maisonneuve-Rosemont. Supportive care included tumor lysis syndrome (TLS) prophylaxis, antiviral, antifungal and antibacterial prophylaxis. Results: 40 patients received 41 ven-based treatments between November 2017 and July 2021. Most patients had r/r AML (n=25, including 17 in first relapse after allogeneic hematopoietic cell transplantation), while 16 patients had de novo AML (10 deemed fit for intensive chemotherapy). Median age was 62 years old. Median duration of ven-based treatment was 4 cycles and median follow-up was 140 days after ven initiation. Ven-aza was used for 33 patients. ven-LDAC was used for the first 7 patients. One patient received ven-gilteritinib. Posaconazole was the main antifungal agent used, with ven dose reduced to 70 mg daily (25 patients). The complete remission (CR) and CR with incomplete hematological recovery (CRi) rate was 46%, higher for de novo vs r/r AML (56% vs 40%). Most patients achieved blast clearance with treatment: CR+CRi+morphologic leukemia-free state (MLFS) rate 63% (75% de novo and 56% r/r). Median overall survival was 258 days (376 days for ven-aza treated patients). All 8 patients (de novo n=5, r/r n=3) with NPM1 or IDH1/2 mutations achieved blast clearance (CR+CRi 87%), while 22 patients with adverse-risk AML as defined by 2017 ELN risk stratification had a lower yet respectable response rate (CR+CRi 36%). Ven-LDAC had no activity in advanced disease, with no response for 6 r/r patients who all had adverse-risk AML, and is no longer used in our institution. The majority of patients were able to receive treatment on an outpatient basis after a brief hospital stay during ven ramp-up. Five patients remained hospitalized for the entire first cycle. Four patients died from infectious causes during the first cycle (2 unfit patients with first line ven-aza, 2 r/r patients with ven-LDAC). Two cases of suspected TLS requiring treatment delays occurred, with no clinical TLS. Venetoclax dose reductions for hematological toxicity were frequently required (51% for all patients, 73% of patients that achieved a response to ven). The average medication cost per cycle of ven-aza was 4 394 $ CAN and was 6 765 $ CAN per cycle for ven-LDAC. Conclusion: In this retrospective real-life review, ven-based treatment produced response rates in line with published prospective evidence among de novo AML patients, and a very clinically meaningful response rate for r/r AML, where therapeutic options are limited and outcomes with conventional chemotherapy dismal. The presence of NPM1 or IDH1/2 mutations was predictive of high response rates. Dose reductions were often required for cytopenias but non-hematological toxicities were limited. Although associated with significant cost, ven-aza represents a safe and effective treatment option for r/r AML which can successfully be delivered in an ambulatory setting. Figure 1 Figure 1. Disclosures Bouchard: Otsuka: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Bambace: AbbVie: Consultancy; Excelthera: Research Funding; Kiadis: Research Funding. Bernard: Kiadis: Research Funding; Excelthera: Research Funding; BMS: Consultancy; Taiho: Consultancy. Hebert: BMS-Celgene: Research Funding. Bergeron: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Servier: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy. OffLabel Disclosure: Venetoclax to treat relapsed or refractory acute myeloid leukemia

Update of a Phase I/II Trial of 5-Azacytidine Prior to Gemtuzumab Ozogamicin (GO) for Patients with Relapsed Acute Myeloid Leukemia with Correlative Biomarker Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3286-3286 ◽  
Author(s):  
Edward D. Ball ◽  
Bruno C. Medeiros ◽  
Larissa Balaian ◽  
Tracy Roque ◽  
Sue Corringham ◽  
...  
Keyword(s):  
Phase I ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Overall Response Rate ◽  
Average Length ◽  
Gemtuzumab Ozogamicin ◽  
Leukemia Cells ◽  
Grade 3 ◽  
Age Range

Abstract Abstract 3286 Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that is a down-regulator of cell growth when ligated by a monoclonal antibody in a Syk-dependent manner. The response of AML cells to gemtuzumab ozogamicin (GO) also depends on Syk and SHP-1 expression (Leukemia 20:2093, 2006). The hypomethylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, therefore increasing the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. We initiated a phase 1/2 clinical trial examining if treatment with 5-aza prior to GO is safe, efficacious, and whether in vivo responses to GO correlated with Syk expression and induction by 5-aza. Here we update the interim results of this trial (NCI registration number NCT00766116). In Phase I, 14 patients (9 males, 5 females), age range: 39–82 years [median: 66]) were treated with 75mg/m2 5-aza daily and GO in a dose-escalation manner, 4 cohorts total. The first cohort (n=3) received 5-aza for 2 days followed by GO at 3 mg/m2 on days 3 and 17; the second cohort (n=3) received 5-aza for 2 days followed by GO at 6 mg/m2 on days 3 and 17; the third cohort (n=4) received 5-aza for 4 days followed by GO at 6 mg/m2 on days 5 and 19; and the fourth cohort (n=4) at 5-aza for 6 days followed by GO at 6 mg/m2 on days 7 and 21. There were no responses in the first 2 cohorts. One patient in cohort 3 achieved CR, and 2 in cohort 4 achieved CR and CRp. Adverse events (≥ Grade 3) included febrile neutropenia 36%, infection 14%, pancytopenia 7%, dyspnea 7%, and retinopathy 7%. Average length on study (n=14) was 45 days with a mortality rate of 14% (unrelated to treatment). No dose-limiting toxicities were encountered in phase I, therefore the MTD is the dose in cohort 4. The overall response rate in evaluable patients in phase I (n=11) is 27%. Average time to ANC recovery (n=6): 30 days (range 15–42, median 33 days). In Phase II, 10 patients (5 males, 5 females), age range: 29–64 years (median 60) were treated at the MTD: 5-aza for 6 days and GO at 6 mg/m2 on days 7 and 21. 8 patients were in 1st relapse, 1 in 2nd and 1 in 3rd. There were 3 responders (2 CR, 1 CRp) in this phase, all in 1st relapse at baseline. Adverse events (≥ Grade 3) include febrile neutropenia 50%, infection 20%, increased LFTs 10%, thrombocytopenia 10%, dyspnea 10%, wheezing 10%, mucositis 10%, cough 10%, and hypoalbuminemia 10%. The average length on study (n=10) was 40 days with a mortality rate of 10% (not related to study treatment). Average time to ANC recovery in phase II (n=2): 15 days (range 12–17, median 15) with an overall response rate in evaluable patients (n=7) of 43%. The ORR for phase I/II (n=18) is 33%. 21 of the 24 patient sample pairs have been analyzed for Syk and SHP-1 expression (one patient did not have a baseline sample). Prior to therapy, Syk was expressed in 16 of 20 cases. After 5-aza treatment, Syk was re-expressed in all 4 negative cases, and increased over baseline in one case that was previously Syk +. SHP-1 was positive in 17 of the 20 cases and was re-expressed in all 3 negative cases. Leukemia cells from patients who achieved CR were Syk+ in 3 of 5 cases (the 6th hasn't been analyzed). Syk was re-expressed in the two negative cases after 5-aza. SHP-1 was expressed in 4 of 5 cases at baseline, and re-expressed in the one negative case after 5-aza. In vitro we analyzed inhibition of proliferation (for patients 1–6) or colony formation (for patients 7–24) induced by 5-aza and GO. 5-aza alone allowed 62.3+/−3.5 survival of leukemia cells and GO alone allowed survival of 59.5+/−1.7 leukemia cells. However, exposure to both agents resulted in a survival rate of 24.8+/−1.6 (P<0.05, Students t-test). We also compared pre- and post 5-aza samples from the same patients: in all cases 5-aza treatment increased the GO-mediated cytotoxicity from 39.4+/−3.1 to 66.8+/−2.4 ((P<0.05, Students t-test). These data show that in vivo exposure to 5-aza can induce the expression of two biomarkers involved in the response to GO. This ongoing study indicates the combination of 5-aza and GO is well-tolerated, that Syk and SHP-1 are modulated by 5-aza in vivo, and that complete responses have been noted with this combination. Disclosures: Ball: Celgene: Equity Ownership, Research Funding. Off Label Use: Will discuss use of 5-azacytidine (Vidaza) for treatment of relapsed AML in combination with Mylotarg (on label, but only as monotherapy). Medeiros:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding; Alexion: Speakers Bureau.

scholarly journals Venetoclax Combined with Daunorubicin and Cytarabine (DAV) As Induction Therapy in De Novo Young Adult Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2334-2334
Author(s):  
Huafeng Wang ◽  
Liping Mao ◽  
Wanzhuo Xie ◽  
Hongyan Tong ◽  
Min Yang ◽  
...  
Keyword(s):  
Young Adult ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
The Novel ◽  
Poor Risk ◽  
De Novo Aml ◽  
Grade 3

Abstract Background: Anthracycline and cytarabine ("3+7") have been the standard induction therapy for acute myeloid leukemia (AML) for almost 4 decades. Only 60%-70% patients can achieve complete remission (CR) with "3+7" induction treatment in de nove AML. The novel induction regimens with higher CR rate are urgent needed. Venetoclax, a b-cell lymphoma 2 (BCL-2) inhibitor combining with hypomethylation agents (HMA) or low dose cytarabine has showed a high response rate and safe in elder AML patients [Dinardo CD, N Engl J Med. 2020; Dinardo CD, Lancet Oncol 2018; Wei AH, J Clin Oncol 2019]. Recently, venetoclax combined with FLAG-IDA induction achieved 90% CR rate in newly diagnosed adult AML (Dinardo CD, J Clin Oncol. 2021). Whether venetoclax combined with standard 3+7 regimen (daunorubicin + cytarabine) as induction therapy can further improve the CR rate in adult AML patients need to be investigated in a well-designed trial. Objective: To evaluate the efficacy and safety of "3+7" (daunorubicin and cytarabine) combined with venetoclax induction regimen (DAV regimen) in young adult patients with de novo AML. Design, setting and participants: Single-arm, prospective clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (18-60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since December 25, 2020, with final follow-up in July 31,2021. Interventions: Patients were treated with daunorubicin 60mg/m 2 on days 1-3 (d1-3) and cytarabine 100 mg/m 2/d by continuous intravenous infusion daily on d1-7, combined with venetoclax (100mg d4, 200mg d5, 400mg d6-11). Main outcomes and measures: The primary endpoint was the percentage of patients who achieved CR/CR with incomplete count recovery (CRi) after once cycle of DAV regimen. Secondary endpoints included minimal residual disease (MRD), overall survival (OS), event-free survival (EFS) and adverse events. Results: Thirty-two patients were enrolled. Median age was 40 years old (range, 19-59), with poor-risk in 25% (8/32) of patients (European LeukemiaNet 2017 risk). Other characteristics of patients were listed in Table 1. The CR rate were 90.6% (29/32) (Table 1). Seven out eight (87.5%) patients with poor-risk achieved CR. Measurable residual disease-negative composite CR was attained in 65.5% (19 out 29) of total patients achieved CR, and 71.4% (5 out 7) of poor-risk patients achieved CR (Table 1). Common adverse events (&gt;30%) included fatigue, nausea, bleeding, febrile neutropenia, infection, neutropenia, anemia and thrombocytopenia. The main grade ≥ 3 hematologic toxicities during induction were neutropenia (100%), anemia (100%) and thrombocytopenia (100%). The main grade ≥ 3 nonhematologic toxicities during induction were infection (81.3%), bleeding (28.1%) and mucositis (3.1%) (Table 1). No tumor lysis syndrome was observed. After a median follow-up of 118.5 days, no patient relapsed or died, and 24.1% (7/29) received allogeneic hematopoietic stem-cell transplantation in CR1. Conclusions: The novel combination of "3+7" (daunorubicin and cytarabine) with venetoclax (DAV regimen) was effective and well tolerated in young adult patients with de novo AML, with high CR rate and deep remission. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR2000041509. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Incidence and Risk Factors for Central Nervous System Relapse in Adult Patients with Acute Myeloid Leukemia: A Single Center Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4579-4579
Author(s):  
Pau Montesinos ◽  
Guillermo Martin ◽  
Mari-luz Perez-sirvent ◽  
Jaime Sanz ◽  
Ignacio Lorenzo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Intrathecal Chemotherapy ◽  
Adult Patients ◽  
Cns Relapse ◽  
First Relapse ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: There is scarce information concerning incidence and risk factors for central nervous system (CNS) relapse in adult patients with acute myeloid leukemia (AML). In acute lymphoblastic leukemia CNS relapse occurs in up to 30% of patients without prophylactic intrathecal chemotherapy (ITC). This has lead to establish its prophylactic use during induction and post-remission phase. Due to the lack of information about incidence of CNS relapse in adult patients with AML, the usefulness of ITC prophylaxis is not clear. Objectives: Analyze incidence and risk factors for CNS relapse in a large cohort of adult patients with newly diagnosed AML. Material y methods: Between 1976 y 2005, 747 adult patients (median 54 years, range 16–81) were diagnosed of de novo AML in our institution. All of them received induction with intensive chemotherapy. Prophylactic ITC was not administered, and cerebrospinal fluid was analyzed only if CNS infiltration was suspected. We analyzed the incidence and risk factors for CNS relapse in patients who reached a complete remission. To calculate the Kaplan-Meier estimates of event-free survival (EFS) we considered as an event the first relapse in CNS, censoring patients at the moment of death or at first relapse in a site different than CNS. Results: 432 patients (58%) obtained complete remission. Between 1976 and 1989 (period 1) 12 of 136 patients (9%) were submitted to autologous or allogeneic stem-cell transplantation (SCT), whereas 129 of 296 (44%) received SCT between 1990 and 2005 (period 2). Overall, 8 of 432 patients (2%) had a CNS relapse, 3 isolated in CNS and 5 in bone marrow plus CNS. Of them, only 1 presented CNS infiltration at diagnosis. In univariate analysis, CNS relapse was associated with high LDH (3% vs 0%, p=0.06), lisozyme >30 (8% vs 1%, p=0.06), FAB M4–M5 (5% vs 1%, p=0.04) and period 1 (5% vs 0.3%, p<0.01). The median follow-up of the cohort was 85 months. CNS relapses occurred at a median of 10 months after complete remission (range, 3 to 84 months). The EFS at 10 years was 95%, and it was lower in patients with elevated LDH (91% vs 100%, p=0.02), FAB M4–M5 (88% vs 97%, p<0.01), leukocytes >10 ×109/L (92% vs 98%, p=0.07), no SCT (92% vs 100%, p<0.01), and period 1 (80% vs 99%, p<0.01). In multivariate analysis, AML M4–M5 remained as the only independent prognostic factor for EFS (HR 6.4, p=0.01). Only 1 of 8 patients with CNS relapse is alive (AML M3, 11 years after a second complete remission). Median survival after CNS relapse was 168 days (range, 16 to 3821 days). Conclusion: In adults with de novo AML CNS relapse is an infrequent event. Intensification of post-remission therapy, especially with SCT, during the last decades may have contributed to reduce its incidence. Therefore, administration of prophylactic intrathecal chemotherapy should not be recommended, even in patients with high risk of CNS relapse, such as monocytic AML.

A Phase II Study of Twice Daily Cytarabine and Fludarabine and Gentuzumab Ozogamycin (GO) In Patients (pts) with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2188-2188
Author(s):  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Hady Antoine Ghanem ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase Ii Study ◽  
Platelet Recovery ◽  
First Relapse ◽  
De Novo Aml ◽  
To Receive

Abstract Abstract 2188 Background: Treatment options for pts with refractory/relapsed (R/R) AML are limited. High dose cytarabine (A) containing regimens are still considered standard options for pts with AML relapsing after a first complete remission (CR) lasting more than 12 months. The combination of A with fludarabine (F) was found to be superior to A alone in this setting, particularly when administered twice daily (BID). In addition, gemtuzumab ozogamicin (GO) has been shown to be active in combination or as single agent in pts with R/R AML. Therefore, we conducted a phase II study assessing the efficacy and safety of BID FA-GO. Patients and Methods: Pts with R/R AML, de novo AML patients unfit for other medical therapies, intermediate-2 and high-risk MDS, and chronic myeloid leukemia in myeloid blast crisis (CML-BC), with a performance status (PS) of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive F 15 mg/m2 IV q12 hrs day 1 to 5 as well as A at the dose of 0.5 g/m2 IV over 2 hrs q12 hrs day 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1. Treatment course was shortened to 4 days in pts older than 65 years and to 3 days in pts with a PS of 3. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML were allowed to receive concomitant tyrosine kinase inhibitors. Results: Sixty-five evaluable pts were enrolled: 6 (9%) with de novo AML, 5 (8%) with AML in first relapse with a duration of 1st CR (CRD1) of ≥12 months, 21 (32%) with AML with CRD1 <12 months, 24 (37%) with AML in second relapse and beyond, 3 (5%) with MDS, and 6 (9%) with CML-BC. Median age was 60 years (range, 19 to 80); 58 pts (89%) had a PS ≥1. Cytogenetic analyses were abnormal in 63 % including chromosomes 5 and 7 abnormalities in 17%. The overall response (OR) rate was 31% including CR in 17 pts (26%) and CR without platelet recovery (CRp) in 3 (5%). The overall 4-week mortality rate was 8%. The OR rates for pts with de novo AML, relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage (S) were 43%, 60%, 35%, and 19%, respectively. The CR rates were 29%, 60%, 27%, and 19%, respectively. The 4-week mortality rates were 19% for pts with R/R AML beyond the first salvage and 0% for the rest (Table1). With a median follow-up of 8 months (range, 1 to 27), the 16-week event-free survival (EFS), overall survival (OS), and complete remission duration (CRD) rates were 25%, 61%, and 89%, respectively. The median EFS and OS for the responding pts were 27 weeks (4-31 weeks). When compared to historical match cohort pts treated at our institution, BID FA-GO was better, with an ORR rate of 60 % in pts with AML in first relapse with CRD1 ≥12 months compared to an expected rate of 50%, 19% in pts with relapsed AML with CRD1< 12 months compared to 11%, and 35% in pts with AML beyond the first salvage compared to 7% (Table 2). The treatment was well tolerated with only 3% of the pts experiencing grade 3 and 4 toxicities including mainly skin rash. The main toxicities were of gastro-intestinal origin and all were of grade 1 and 2. There was no case of veno-occlusive disease reported. Conclusion: BID FA-GO appears to be active with an ORR of 31% in heavily pre- treated population. This combination appears to be safe as well with a low rate of 4-week-mortality of 5%. Ongoing studies are exploring the role of the new generation of nucleoside analogues in this setting. Disclosures: Cortes: Pfizer: Consultancy, Research Funding.

Fusion Gene Detection Using Whole Transcriptome Analysis in Patients with Chronic Myeloproliferative Neoplasms and Secondary Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4093-4093 ◽  
Author(s):  
Fiorella Schischlik ◽  
Jelena D. Milosevic Feenstra ◽  
Elisa Rumi ◽  
Daniela Pietra ◽  
Bettina Gisslinger ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Chronic Phase ◽  
Loss Of Function ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Whole Transcriptome

Abstract Fusion oncogenes resulting from chromosomal aberrations are common disease drivers in myeloid malignancies. The most prominent example is BCR-ABL1 fusion present in chronic myeloid leukemia, which together with essential thromobocythemia (ET), primary myelofibrosis (PMF) and polycythemia vera (PV) belongs to the classic myeloproliferative neoplasms (MPN). The BCR-ABL1 negative MPNs are driven by somatic mutations in JAK2, MPL and CALR. MPN patients can progress to acute myeloid leukemia (AML) but the transformation process is not well understood. Studies using standard karyotyping and SNP microarrays have shown that disease progression is characterized by an increase in karyotype complexity. We aimed to identify novel fusion oncogenes in patients with BCR-ABL1 negative MPN during chronic phase and disease progression in high-throughput and cost-efficient manner using RNA-seq technology. In addition this approach enabled us to perform RNA-seq variant calling for identification of gene mutations on the same cohort of patients. Whole transcriptome sequencing was performed on 121 patients (112 chronic phase MPN and 9 secondary AML samples) and 23 healthy controls in a 100 base pair paired-end manner. The cohort consisted of 44% PMF, 22% ET, 12% PV and 6% secondary AML patients. The output of three fusion detection tools (Defuse, Tophat-fusion and SOAPfuse) was combined in order to increase sensitivity. Extensive filtering steps were applied in order to enrich for cancer specific fusion events, including filtering for fusions appearing in healthy individuals, filtering for read-throughs and false positives with external databases and manual inspection of sequencing reads. The outcome of analysis for Defuse, Tophat-fusion and SOAPfuse resulted in the total of 52, 54 and 38 candidate fusions, respectively. Candidate fusions were Sanger-sequenced and for Tophat-fusion and Defuse the validation rate was 60%, while for SOAPfuse only 20% could be validated. Approximately 70% of the fusion candidates were not shared among the 3 tools which underlines the importance of selecting the union of all calls from each tool rather than the intersect. We did not observe clustering of breakpoints along the genome. Most fusion candidates could be detected in PMF which corresponds to the disease entity that was most represented in the cohort (44% of patients). No enrichment for fusions was found in 7 triple negative (no JAK2, CALR, MPL mutations) cases. 42% of chromosomal aberrations were translocations, followed by duplication (31%), inversion (14%) and deletion events (11%). Among the intragenic fusions, approximately half had genomic breakpoints less than 1 Mb apart. 70% of validated fusions were out of frame, while 28% were in frame. In the leukemic samples a higher abundance of fusions was found (4/9). Typical fusions for de novo AML were not detected within secondary AML (sAML) samples. We did not detect a recurrent fusion oncogene in our patient cohort. In a PMF patient with JAK2-V617F mutation we identified a BCR-ABL1 fusion, indicating a clonal exchange which was consistent with patient's phenotype. Another PMF patient exhibited an inversion event involving the first exon of CUX1, causing a CUX1 loss of function. Other fusions in chronic MPN patients affected genes involved in histone modifications (SMYD3-AHCTF1, KDM4B-CYHR1). In post-MPN AML patients we identified a somatic in frame-fusion involving INO80D and GPR1 and a fusion truncating the first 3 exons of RUNX2 (XPO5-RUNX2). The high quality of RNA sequencing data, allowed us to set up a variant detection workflow that will be compared with matched samples that have been exome sequenced. Preliminary results could demonstrate that mutations in the JAK2 gene in a cohort of 96 patients were all correctly recalled, emphasizing its sensitivity. Fusion events among patients in chronic phase MPN are rare and the majority of these events imply loss of function of both fusion gene partners. This approach adds valuable information on the true frequency of inactivation of genes such as CUX1 in patients, as small inversions like the one described above would not be detectable by other methods. Detection of a subclone with BCR-ABL1 fusion underlines the strength of the fusion detection workflow for diagnostic purposes. Typical de novo AML fusions were not found in sAML and further suggests that de novo AML and sAML are distinct disease entities on a genetic level. Disclosures Gisslinger: Janssen Cilag: Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2318-2318
Author(s):  
Elizabeth A. Griffiths ◽  
William Brady ◽  
Wei Tan ◽  
Carlos E Vigil ◽  
James E. Thompson ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Single Agent ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Intermediate Dose

Abstract Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML. Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.). Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML. Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months. Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. Disclosures Griffiths: Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

scholarly journals Genome Wide Association Analyses Identify Pleiotropic Variants Associated with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Susceptibility

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1500-1500
Author(s):  
Junke Wang ◽  
Alyssa I. Clay-Gilmour ◽  
Ezgi Karaesmen ◽  
Abbas Rizvi ◽  
Qianqian Zhu ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Case Control ◽  
Pleiotropic Effects ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Increased Risk ◽  
De Novo Aml

Abstract The first two authors and last two authors contributed equally. Genome-wide association studies (GWAS) have identified risk loci for Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoblastic Leukemia (CLL) and Non-Hodgkin Lymphoma, however an Acute Myeloid Leukemia (AML) GWAS has not been published to date. We performed a GWAS to identify AML and Myelodysplastic Syndrome (MDS) risk loci using a nested case-control study design in the DISCOVeRY-BMT cohorts which includes almost 2000 AML and MDS patients as cases and 2813 unrelated donors as controls. Genotyping was performed using the Illumina Human OmniExpress BeadChip and imputed using the Haplotype Reference Consortium, yielding > 8 million high-quality variants for statistical analysis. Logistic regression models with AML (de novo AML with normal cytogenetics, de novo AML with abnormal cytogenetics and therapy-related AML) and MDS cases and European American healthy donor controls adjusted for age and sex were used to test the association of each SNP with disease status. To identify the strongest association signal with disease we conducted a summary statistic SNP-based association analysis (ASSET) using non-overlapping AML and MDS cases implemented in R statistical software. ASSET uses an exhaustive search for SNPs with small but common pleiotropic effects across groups of traits while accounting for the multiple tests required by the subset search, as well as any shared controls between groups. This approach allowed us to further investigate the heterogeneity within AML subtypes and to gain increased power by pooling subtypes that show pleiotropic effects. ASSET genome wide (GW) significance is defined as P<5.0x10-8, however, we present results of each subset analysis. ASSET analyses identified an association of T allele at rs12203592, Interferon Regulatory Factor 4 (IRF4), with increased risk of de novo AML and MDS (Figure 1) (OR=1.37; 95% CI, 1.25-1.51, Pmeta=1.59x10-10). The variant has been reported significant in GWAS of skin pigmentation, hair color, non-melanoma skin cancer, squamous cell carcinoma, actinic keratosis, and childhood ALL; GW case-control studies of neuroblastoma and breast cancer show suggestive association signals (P<5 x 10-6). IRF4 belongs to the IRF family of transcription factors and is a key regulator of differentiation stages in hematopoiesis. The T allele at rs12203592 is associated with significantly increased expression of IRF4 in whole blood and lung tissue and in vitro mouse studies have shown the T allele to be associated with higher levels of IRF4 transcription. rs12203592 is <80bp from an IRF4 transcription start site and in an important position within NF-κB motifs in multiple blood and immune cell lines, supporting the hypothesis that this SNP modulates NF-κB repression of IRF4 expression. Another variant in the IRF4 regulatory region, rs62389423 (A allele), showed a putative association with subsets of de novo AML and MDS (OR=1.36; 95% CI,1.21-1.52, Pmeta=1.2x10-7). Although not in linkage disequilibrium with rs12203592, the A allele has also been previously associated with susceptibility to skin cancer and melanoma in multiple GWAS. Analysis of 596 UKbiobank CLL cases and >300,000 controls, shows the A allele correlates with a 50% increased risk of CLL (95% CI, 1.32-1.73, P= 2.4x10-9).Several other GWAS also show an association between additional IRF4 variants and CLL. Analyses in individual subtypes also revealed an intronic variant, rs10098598, in RAD21 to be associated with de novo AML (OR=2.18; 95% CI, 1.60-2.97; Pmeta=8.9x10-7). RAD21, on8q24, a region known to be associated with multiple cancer types, is involved in DNA double-stranded break repair and in chromatid cohesion in mitotic cells. Loss of function would theoretically lead to chromosomal instability and tumorigenesis. Components of the cohesion complex (including RAD21) are somatically mutated in ~12% of de novo AML and MDS patients, where it is frequently an early event. We provide the first GW evidence of association between a common variant and AML susceptibility. This SNP has been shown to be associated with multiple phenotypes, suggesting that there are pleiotropic effects at work. Our RAD21 finding is consistent with the role of cohesion in leukemogenesis and provides some evidence of its role in de novo AML susceptibility. Replication and further subset analyses with genome-wide data in >2000 AML cases are ongoing. Disclosures Griffiths: Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. McCarthy:Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

scholarly journals BrUOG 345: Fractionated Gemtuzumab Ozogamicin Followed By Non-Engraftment Donor Leukocyte Infusions for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4460-4460
Author(s):  
Adam Zayac ◽  
Pamela C Egan ◽  
Thomas A Ollila ◽  
Adam J Olszewski ◽  
Peter Barth ◽  
...  
Keyword(s):  
Null Hypothesis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Extracellular Vesicle ◽  
Gemtuzumab Ozogamicin ◽  
Primary Objective ◽  
Phase 2 ◽  
Cytokine Release

Background: Allogeneic stem cell transplant (allo-SCT) is a cornerstone in the treatment of Acute Myeloid Leukemia (AML) exerting much of its therapeutic efficacy through the graft-versus-leukemia effect. The administration of immunoregulatory cells via engrafted donor lymphocytes is essential to the eradication of residual malignancy and long-term survival. Many patients, however, either do not have an allo-SCT donor or cannot withstand the toxicity of allo-SCT. Previous studies have shown durable responses in AML patients following donor lymphocyte infusions in the absence of engraftment in both the frontline and relapsed setting (Dey et al, BJH 2005, Colvin et al, BBMT 2009, Ai et al, Blood 2010). In this clinical trial we propose a role for donor leukocyte infusions (DLI) in the absence of engraftment. Without the need for engraftment patients will not need to receive high dose chemotherapy or radiation and the toxicities that accompany these therapies. Instead, allogeneic donor cells are infused into patient with relapsed/refractory (R/R) AML to serve as a potent immune stimulator. Prior to DLI, patients will receive fractionated dosing of gemtuzumab ozogamicin (GO). GO is an anti-CD-33 antibody drug conjugate approved in combination with induction therapy for de novo AML and in R/R disease. Patients who demonstrate a CR or CRi to therapy will go on to have up to 2 additional GO + DLI treatments. Bone marrow and blood samples will be obtained from patients before, during, and after treatment to determine immune effector cells (both donor and patient), cytokine release profiles, and extracellular vesicle components. Study Design and Methods: Our study, BrUOG 345 [NCT03374332], evaluates the combination of fractionated GO with non-engraftment DLI in the treatment of patients with R/R AML. Adults patients 18 years of age and older with histologically confirmed R/R AML who have had recurrence or progression after at least 1 prior standard treatment are eligible. Enrollees must have no active systemic infections and have adequate lung, liver, cardiac, and renal function with an ECOG PS 0-1. Fractionated GO 6-9mg/m2 will be administered on days 1, 4, and 7 followed by infusion of 1-2x108 CD3 cells/kg from a 0-3/6 HLA mismatched related donor cell. Patients that are in CR or CRi can receive up to 2 additional treatments with GO+DLI (Figure 1). The primary objective of the phase 1 portion is to determine the maximum tolerated dose (MTD) of DLI in combination with GO while the primary objective of Phase 2 portion is to assess the response rate after one cycle of fractionated GO followed by non-engraftment DLI in patients with relapsed/refractory AML. The study will initially utilize a 3+3 design in Phase 1 to determine if 1-2x108 CD3 cells/kg can be safely administered with GO. This study will target a response rate of 57% considered to be interesting enough to warrant further study in a randomized setting. With this hypothesis in mind, the phase 2 portion of the study will use Simon's two-stage design. The null hypothesis that the true response rate (CR and CRi) is only 29% will be tested against a one-sided alternative. In the first stage, 9 subjects will be accrued. Patients treated at MTD in the Phase 1 portion of the study will be included in this cohort. If there are 3 or fewer responses in these 9 patients, the study will be stopped for futility. Otherwise, 6 additional subjects will be accrued for a total of 15. The null hypothesis will be rejected if 7 or more responses are observed in 15 patients. This design yields a type I error rate of 0.1 and power of 80% if the true response rate is 57%. A continuous assessment of toxicity will be utilized for the Phase 2 portion of this study. Sequential boundaries will be used to monitor dose-limiting toxicity rate for patients after the initial MTD is determined. Accrual will be halted if excessive numbers of dose-limiting toxicities are seen. The primary outcome of the Phase 2 portion is the CR/CRi rate following GO and non-engraftment DLI. Secondary outcomes will include survival, both progression-free (PFS) and overall (OS) until two years post treatment, and dose limiting toxicities until 16 weeks post-infusion. Additional lab correlative studies will be performed including CD33 expression before, during, and after GO infusion and T-cell activation markers, antigen presenting cell/macrophage amounts, cytokine release profiles, and extracellular vesicle measurements (Figure 1). Disclosures Olszewski: TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Research Funding. Reagan:Pfizer: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

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