Randomized Phase II Trial of Timed-Sequential Therapy (TST) with Flavopiridol (Alvocidib), Ara-C and Mitoxantrone (FLAM) Versus “7+3” for Adults Ages 70 Years and Under with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 47-47 ◽  
Author(s):  
Joshua F. Zeidner ◽  
Jonathan M. Gerber ◽  
Amanda Blackford ◽  
Mark Litzow ◽  
Matthew C. Foster ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Tumor Lysis Syndrome ◽  
Disease Free Survival ◽  
Adult Patients ◽  
Clinical Relapse ◽  
Newly Diagnosed ◽  
Aldh Activity ◽  
Hematopoietic Stem ◽  
Poor Risk

Abstract Abstract 47 Background In adults with newly diagnosed, poor-risk AML we previously demonstrated that induction therapy with Flavopiridol in combination with Ara-C and Mitoxantrone (FLAM,) in a timed-sequential manner, yields complete remission (CR) rates of 67% and median disease-free survival (DFS) of 13.6 months. These data suggest that FLAM might improve outcomes relative to standard “7+3” in newly diagnosed AML with poor-risk features. Thus, we are conducting a phase II randomized trial comparing the CR rates with FLAM vs. 7+3 induction for all newly diagnosed adult patients with AML with intermediate and poor-risk features. We also previously identified a population of CD34+CD38− cells with intermediate aldehyde dehydrogenase (ALDH) activity that appears to represent a leukemic stem cell (LSC) population. We are examining the effects of FLAM vs. 7+3 in eradicating this LSC population and determining if persistence of LSC's predicts for relapse. Objectives The primary objective is to compare the rate of CR after 1 cycle of FLAM vs. 1 cycle of 7+3. The secondary objectives are to compare toxicities, survival rates, and presence or absence of minimal residual disease (MRD) after both induction regimens. Methods All newly diagnosed adult patients aged 18–70 without favorable risk features were randomized in a 2:1 fashion between FLAM and 7+3 at 90 mg/m2 of Daunorubicin. To achieve balanced randomization, patients were stratified by age, secondary AML and leukocyte count. CD34+ cell subsets were analyzed by flow cytometry for CD38 expression and ALDH activity by Aldefluor. The trial is ongoing. Results To date, 62 patients are evaluable for the primary end point. Demographics and results are depicted in table 1. Patient characteristics were similar in both arms, although there were more patients with poor risk features in the FLAM arm than 7+3. Overall grade > 3 toxicity was similar between both arms. However, there were 3 cases of grade > 3 tumor lysis syndrome (TLS) with FLAM, with 1 death, vs. 0 with 7+3. There were also 3 deaths with FLAM before day 60 vs. 0 with 7+3. CR rate with FLAM was 68% (28/41), with 1 cycle of 7+3 was 48% (10/21) (p = 0.17), and with 2 cycles (7+3 + 5+2) was 52% (11/21). CR rates based on specific risk factors are depicted in table 2. There was a trend toward improved CR rates in patients with adverse genetics with FLAM (p = 0.17). Putative AML LSC's were distinguished from normal hematopoietic stem cells based on ALDH activity. The persistence of putative LSC's in patients after therapy was highly predictive of subsequent clinical relapse. Conclusions Based on the current CR rate of 68%, FLAM holds promise as a therapeutic option for patients with newly diagnosed AML with intermediate and poor risk features. In this preliminary analysis, there is a suggestion that FLAM leads to higher CR rates in patients with adverse genetics than 7+3. Additionally, the detection of MRD consisting of a residual putative LSC population strongly portended subsequent relapse, even in patients without evidence of leukemia. Disclosures: Off Label Use: Flavopiridol (Alvocidib) is an anti-leukemia agent.

Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 186-186 ◽  
Author(s):  
Judith E. Karp ◽  
John M. Pagel ◽  
B. Douglas Smith ◽  
Jacqueline M Greer ◽  
D. Michelle Drye ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Disease Free Survival ◽  
Sequential Therapy ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Poor Risk

Abstract Abstract 186 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below. Age # < 50 Secondary AML Adverse Genetics MDS/MPD t-AML Single Complex Flt3 ARM A (n = 36) 59ü(24–78) 3 19 5 6 13 3 Total 24/36 = 67% Total 22/36 = 61% ARM B (n = 34) 58ü(20–73) 5 16 9 8 10 5 Total 25/34 = 74% Total 23/34 = 68% Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures: No relevant conflicts of interest to declare.

Phase II Study of Combination of the HyperCVAD Regimen with Dasatinib in Patients with Philadelphia Chromosome (Ph) or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Myeloid Leukemia (CML-LB).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2814-2814 ◽  
Author(s):  
Farhad Ravandi ◽  
Deborah Thomas ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
Charles Koller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinical Activity ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Platelet Recovery

Abstract Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL and resulted in eradication of minimal residual disease and durable remissions without allogeneic stem cell transplant in some patients (Thomas D, Blood, 2004; Yanada M, JCO, 2006; Wassmann B, Blood, 2006; de Labarthe A, Blood, 2007). The dual Src and Abl inhibitor dasatinib has a significantly higher in vitro kinase inhibition against BCR-ABL and has demonstrated potent clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL with over 50% complete cytogenetic responses (CG CR) in phase I and II trials but with median progression free survival of only 3 to 4 months. We are conducting a phase II trial in which patients with newly diagnosed or relapsed Ph+ ALL or CML-LB receive dasatinib 50 mg po bid for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in complete remission (CR) continue to receive maintenance dasatinib 50 mg po bid daily and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 15 newly diagnosed patients with Ph+ ALL (cohort I) and 4 patients with relapsed Ph+ ALL or CML-LB (cohort II) have received a median of 4 cycles (range 1 – 8); 4 patients are receiving maintenance in CR. Median age for cohort I is 55 years (range 23 – 79) and for cohort II, 43 years (range 26 – 69); 13 and 3 patients were older than 50 years, respectively. Median WBC at diagnosis for cohort I was 4.3 × 109/L (range, 0.8 – 203.4 x 109/L). Three patients had CNS involvement. Fourteen and 3 patients in the 2 cohorts are evaluable for response to induction; 2 are too early. Thirteen patients (93%) in cohort I and all evaluable patients in cohort II have achieved CR after the first cycle; 1 patient in cohort I died on day 20 from infections before response assessment; her bone marrow exam on day 14 showed no detectable disease. Ten of 11 (91%) patients in cohort I have achieved CG CR after 1 cycle; 3 are too early. Three of 4 patients in cohort II have achieved CG CR after 1 cycle; 1 had a new CG abnormality and 1 is too early. Six patients have achieved complete molecular remission after the first cycle with the lowest BCR-ABL/ABL in the other patients ranging from 0.01 to 1.91. Median time to neutrophil and platelet recovery for cohort I is 18 and 25 days and for cohort II 18.5 and 30.5 days. Grade 3 and 4 toxicity has included 7 episodes of GI bleeding as well as infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and acute renal failure unrelated to treatment. With a median follow up of 4 months (range, 0 – 10), 15 patients are alive and in CR; 1 died at induction, 1 died in CR from an unrelated cardiac event, and 2 are too early. No patient has relapsed and no patient has received an allogeneic transplant. We conclude that the combination of the hyperCVAD regimen with dasatinib is feasible and can achieve early molecular remissions in patients with Ph+ ALL and CML-LB.

Anti-CD19 BiTE Blinatumomab Induces High Complete Remission Rate In Adult Patients with Relapsed B-Precursor ALL: Updated Results of An Ongoing Phase II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 252-252 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Goekbuget ◽  
Gerhard Zugmaier ◽  
Andreas Viardot ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Complete Remission ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Adult Patients ◽  
Quantitative Detection ◽  
Hematopoietic Stem ◽  
Dismal Prognosis

Abstract Abstract 252 Adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) have a dismal prognosis with low complete remission (CR) rates with intensive salvage chemotherapy which are not durable. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that directs cytotoxic T-cells to CD19 expressing B-cells. In collaboration with the German Multicenter Study Group for Adult Lymphoblastic Leukemia (GMALL), an open-label, multicenter, single-arm, exploratory phase II trial is being conducted to evaluate efficacy and safety of blinatumomab in adult patients with relapsed/refractory B-precursor ALL. The primary endpoint for this trial is the rate of patients who reach CR or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment. Secondary endpoints are the rate of minimal residual disease (MRD) response (defined by an MRD level below the quantitative detection limit of 10−4), time to hematological relapse and overall survival. Blinatumomab is administered by continuous intravenous infusion for 28-days followed by a 14-day treatment-free interval. Responding patients could proceed to allogeneic hematopoietic stem cell transplantation (HSCT) or receive a total of up to 5 cycles of blinatumomab treatment. Three dose levels have been explored as shown in Table 1.Table 1.Summary of Dose Cohorts and OutcomesCohortPatients TreatedInitial Dose Week 1, Cycle 1 μg/m2/dayDose Week 2, Cycle 1 μg/m2/dayDose Weeks 3–4, Cycle 1 μg/m2/dayMaintenance Dose, Subsequent Cycles μg/m2/dayCR or CRh*Serious Adverse EventsnPts171515151551562a551515154222b65153030354310 planned5151515n.a.n.a.n.a. As of June 30, 2011, 43 cycles have been administered to a total of 18 patients (range 1–5; median 2). Twelve out of 18 patients have reached a complete remission within the first 2 cycles of single agent blinatumomab corresponding to a response rate of 67%. Of these 12 responding patients, 75% had complete hematologic recovery of peripheral blood counts. All 12 responders reached MRD negativity within the first 2 cycles and included 3 patients with t(4;11) and 1 patient with Ph-positive B-precursor ALL. Four responders proceeded to allogeneic HSCT; one experienced a CD19-negative hematological relapse after HSCT. Two responders relapsed during treatment; one had a CD19-positive extramedullary, and one a CD19-negative bone marrow relapse. The remaining 6 non-transplanted responders are still in hematological complete remission. The most common adverse events were pyrexia and chills. In cohort 1, one patient with a high tumor burden developed disseminated intravascular coagulation (DIC)/cytokine release syndrome (CRS) leading to treatment discontinuation. The implementation of a cytoreductive pre-phase and a lower initial dosing at 5μg/m2/day during the first week prevented further treatment discontinuations in such patients. Four patients had fully reversible CNS serious adverse events that led in 1 patient to discontinuation of treatment, and in 3 patients to temporary interruption of treatment. These 3 patients resumed treatment at a lower dose without further interruptions during the following cycles. There were no deaths related to blinatumomab. Blinatumomab as single agent induced an unprecedented high rate of complete hematological and MRD responses in adult patients with relapsed/refractory B-precursor ALL. A lower dose of 5μg/m2/day for the initial week of treatment, as tested in cohort 2a, demonstrated a favorable safety profile while maintaining efficacy. A maintenance dose of 30μg/m2/day, as tested in cohort 2b, did not further improve the already high efficacy but increased the number of adverse events. Therefore, the dosing of cohort 2a was selected as the basis for cohort 3 and will be applied to further clinical development in this patient population. Updated results of the study will be presented. Disclosures: Topp: Micromet: Consultancy, Honoraria. Goekbuget:Micromet: Consultancy. Zugmaier:Micromet: Employment. Klappers:Micromet AG: Employment. Mergen:Micromet Inc: Employment. Bargou:Micromet: Consultancy, Honoraria.

Ruxolitinib Before Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Patients With myelofibrosis : a Preliminary Descriptive Report Of The JAK ALLO Study, a Phase II Trial Sponsored By Goelams-FIM In Collaboration With The Sfgmtc

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 306-306 ◽  
Author(s):  
Marie Robin ◽  
Sylvie Francois ◽  
Anne Huynh ◽  
Bruno Cassinat ◽  
Jacques-Olivier Bay ◽  
...  
Keyword(s):  
Renal Failure ◽  
Performance Status ◽  
Tumor Lysis Syndrome ◽  
Conditioning Regimen ◽  
Safety Data ◽  
Disease Free Survival ◽  
Inclusion Criteria ◽  
Hematopoietic Stem ◽  
Prophylactic Measures ◽  
The Impact

Abstract Ruxolitinib (RUXO) is a JAK inhibitor recently approved in France in patients (pts) with myelofibrosis (MF) because of its efficacy on splenomegaly and constitutional symptoms. Although no prospective safety data are available, many centers have started to use RUXO before HSCT to improve general performance status and decrease splenomegaly (influencing the engraftment). This academic study (ClinicalTrials.gov: NCT01795677) was designed to assess the impact of RUXO in pts with MF candidates for HSCT. Primary objective is the achievement of a disease-free survival at 1 year post HSCT > 50%. A total of 53 pts should be transplanted in order to reach this endpoint. Secondary objectives include: probability to be transplanted in pts with donor, overall survival, non-relapse mortality, hematological response, rate of pre-HSCT splenectomy, quality of life and MF-associated symptoms (through questionnaires). Inclusion criteria are: pts with MF, < 70 years, with either an intermediate or high risk MF according to Lille or IPSS score, or poor prognostic cytogenetics: complex karyotype, abnormalities of chromosomes 5, 7 or 17. Pts with platelets < 50 G/L, blasts ≥ 20% or previously treated with RUXO are excluded. After inclusion, RUXO is started at 15 mg BID in pts with platelets > 100 G/L or 10 mg BID in pts with platelets < 100 G/L and the search for a donor is started. If a donor is identified (related or unrelated HLA matched), the patient should be transplanted within 4 months. Pts without donors are prospectively followed on RUXO therapy in a parallel group. Conditioning regimen (CR) consists in melphalan and fludarabine, started after RUXO tapering and discontinuation. In May 2013, as some unexpected severe adverse events (SAE) were reported, investigators decided to stop enrollment of pts and to amend the protocol with new prophylactic measures. Twenty-three pts have been enrolled between Dec 2012 and May 2013 (1 pt excluded for inclusion criteria violation). Median age was 59 years (45-67). MF was primary in 19 and post essential thrombocytemia or polycythemia vera in 3 pts. All pts had splenomegaly (median: 23 cm). 12 pts had the JAK2V617F mutation. Cytogenetics were normal in 7, abnormal in 10 (poor prognostic in 2), missing or failed in 5 pts, respectively. Lille score was low in 5, intermediate (int) in 13 and high in 4 pts, resp. Age adjusted dynamic IPSS was low in 1, int-1 in 7, int-2 in 9, and high in 5 pts, respectively. Median follow-up was 149 days (69-229). Response after 2 months of RUXO was assessable in 16 pts: 50% partial remissions (- 25% in spleen size and improvement of constitutional symptoms) and 50% had stable disease. 8 pts have been transplanted (3 splenectomies before HSCT), 8 are waiting for HSCT, 4 pts have no donor identified yet and 2 pts were excluded from HSCT because of onset of comorbidities. Tolerance of RUXO was generally good and 3 SAEs were reported: febrile pancytopenia (n=2), multiple cranial nerve injury (n=1). The other SAEs (n=10) were reported within 21 days after RUXO discontinuation. Among the 10 pts who stopped RUXO, 7 had SAEs: multiple SAEs in 4, life-threatening in 7 and fatal in 2 pts, resp. Unexpected SAEs occurring after RUXO withdrawal included febrile cardiogenic shocks before HSCT not due to coronaropathy in 2 pts, and tumor lysis syndrome (TLS) with acute renal failure during CR in 1 pt. The 2 deaths were due to severe acute grade III-IV graft-versus-host disease refractory to steroids. The protocol was amended in May 2013 with TLS prophylaxis, modification of RUXO tapering with a shorter duration (10 days) systematically associated with steroids (0.5 mg/kg/day) and slight CR change (started with melphalan instead of ending). Despite this amendment, 2 other pts experienced TLS (but without renal failure) and 1 patient had a cardiogenic shock 9 days after HSCT. After review of the data with the Data Safety Monitoring Board, ethics committee and health authorities, the protocol is continued for the 22 pts already enrolled, but new inclusions are on hold until safety is confirmed. This preliminary report of the first prospective study assessing the impact of RUXO before HSCT in MF pts aims at highlighting unexpected SAEs, namely TLS (n=3) and cardiogenic shocks (n=3), that should be carefully considered in other prospective trials and clinical practice. According to the study design, all included pts should be transplanted before Oct 2013, and more information will be available for Dec 2013. Disclosures: Robin: NOVARTIS: gives ruxolitinib and a financial support for the JAK ALLO study Other. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees.

NCCTG N057K phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: A North Central Cancer Treatment Group trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2031-2031
Author(s):  
Daniel Ma ◽  
Evanthia Galanis ◽  
David Schiff ◽  
Wenting Wu ◽  
Patrick J. Peller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Methylation Status ◽  
Mtor Inhibitors ◽  
Outcome Data ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Drug Induced ◽  
Flt Pet ◽  
Grade 3

2031 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.

Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4530-4530
Author(s):  
Angela Q. Qu ◽  
Susanna J. Jacobus ◽  
Sabina Signoretti ◽  
Edward C. Stack ◽  
Katherine Maragaret Krajewski ◽  
...  
Keyword(s):  
Tumor Markers ◽  
Phase Ii ◽  
Residual Disease ◽  
Excision Repair ◽  
Elevated Serum ◽  
Disease Free Survival ◽  
Logrank Test ◽  
Tumor Biopsy ◽  
Serum Tumor Markers ◽  
Post Surgery

4530 Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least >50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p<T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score <0.1 (negative) vs. >0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p=0.146). Those achieving RaR had a significantly longer DFS (p=0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(+) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(+) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(+) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.

CULMINATE: A phase II study of cusatuzumab + azacitidine in patients with newly diagnosed AML, ineligible for intensive chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS7565-TPS7565 ◽  
Author(s):  
Geralyn Carol Trudel ◽  
Angela J. Howes ◽  
Neelum Jeste ◽  
Jeffrey J. Tryon ◽  
Liang Xiu ◽  
...  
Keyword(s):  
Phase Ii ◽  
De Novo ◽  
Phase Ii Study ◽  
Standard Dose ◽  
Intensive Therapy ◽  
Moderate Hepatic Impairment ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Hematopoietic Stem

TPS7565 Background: AML, the most common acute leukemia in adults, is a heterogeneous malignancy characterized by uncontrolled clonal expansion of hematopoietic progenitor cells. Median diagnosis age is ~67 yrs. Despite current therapies prognosis is poor with 5-yr OS ~25% for patients (pts) ≥65 yrs. For pts unable to receive intensive chemotherapy, survival rates are worse, indicating a critical need to develop better treatments. CD70 is expressed on >95% of AML blasts harvested from newly diagnosed AML pts but not on normal hematopoietic stem cells nor most normal tissues. Cusatuzumab is a first-in-class, high-affinity anti-CD70 monoclonal antibody with multiple mechanisms of action, including Fc-mediated cytotoxicity with enhanced ADCC and inhibition of CD70/CD27 signaling, resulting in leukemia blast and stem cell cytotoxicity. As cusatuzumab and azacitidine target distinct pathways of myeloblast propagation, a combination may have a synergistic therapeutic effect and overcome treatment resistance. Initial data from a Phase I study (NCT03030612) with cusatuzumab (1–20 mg/kg) + standard dose azacitidine in AML pts ineligible for intensive chemotherapy showed no dose-limiting toxicity and a CR/CRi (CR with partial/incomplete hematologic recovery) in 10 of 12 pts (ASH 2019, Abs #234). This abstract describes a follow-on Phase II study (NCT04023526). Methods: CULMINATE is a 2-part study of cusatuzumab + azacitidine to determine the optimal dose of cusatuzumab (Table). Inclusion criteria: ≥18 yrs with de novo or secondary AML unfit for intensive therapy (≥75 or <75 yrs with a comorbidity [i.e. ≥1 of: ECOG 2, severe cardiac/pulmonary or moderate hepatic impairment]). In Part 1, pts are randomized 1:1 to cusatuzumab 10 or 20 mg/kg (IV, on Days 3 and 17 of each 28-day cycle) + azacitidine (75 mg/m2 SC or IV on Days 1–7). Data will be reviewed after 15, 30 and 50 pts are enrolled into each arm to select the cusatuzumab dose for the Part 2 expansion cohort in which efficacy and safety will be further evaluated. Follow-up continues until death, loss to follow-up or study end. The primary objective is to determine CR rate. Secondary objectives include rate of CRi/CRh, rate of MRD-negativity, ORR, time to and duration of response, pharmacokinetics, immunogenicity, transfusion independence and safety. Enrollment began in Sept 2019 and is currently two-thirds complete. Clinical trial information: NCT04023526 . [Table: see text]

scholarly journals A clinically relevant population of leukemic CD34+CD38− cells in acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3571-3577 ◽  
Author(s):  
Jonathan M. Gerber ◽  
B. Douglas Smith ◽  
Brownhilda Ngwang ◽  
Hao Zhang ◽  
Milada S. Vala ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Clinical Relapse ◽  
Aldh Activity ◽  
Immunodeficient Mice ◽  
Minimal Residual ◽  
Acute Myeloid

Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34+CD38− cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34+ subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34+CD38− cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34+CD38−ALDHint leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34+CD38− cells and identifies those AML cells associated with relapse.

Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (36) ◽  
pp. 4134-4140 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Gökbuget ◽  
Gerhard Zugmaier ◽  
Petra Klappers ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Hematopoietic Stem ◽  
Dismal Prognosis ◽  
Bispecific T Cell Engager

Purpose Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. Patients and Methods Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). Results Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. Conclusion The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.

scholarly journals Outcome of (Novel) Subgroups in 1257 Pediatric Patients with KMT2A-Rearranged Acute Myeloid Leukemia (AML) and the Significance of Minimal Residual Disease (MRD) Status: A Retrospective Study By the I-BFM-SG

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Romy E. Van Weelderen ◽  
Kim Klein ◽  
Bianca F. Goemans ◽  
Christian M. Zwaan ◽  
Hester A. De Groot-Kruseman ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Board Of Directors ◽  
Cox Regression ◽  
Residual Disease ◽  
Remission Rate ◽  
Disease Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
The Past ◽  
Poor Risk

Introduction Outcome of KMT2A-rearranged (KMT2A-r) pediatric AML (pAML) is in general poor with a 5-year probability of event-free survival (5y-pEFS) and overall survival (5y-pOS) of 44% and 56%, respectively (Balgobind et al., 2009). However, over the past decades, the heterogeneity of KMT2A-r pAML has emerged, showing differences in outcome between subgroups based on translocation partners. The predictive value of MRD in KMT2A-r pAML is undefined. This retrospective study aimed to confirm the outcome of pediatric KMT2A subgroups (Balgobind et al., 2009) in a more recent era and to study the significance of MRD status during and after induction. Methods Outcome and MRD data of 1257 KMT2A-rde novo pAML patients from 15 AML groups affiliated with the I-BFM-AML study group, diagnosed between 2005 and 2016 were retrospectively collected. Patients were assigned to KMT2A subgroups, or to the KMT2A-other group in case of unknown translocation partner. Flow cytometry MRD levels &lt;0.1% were considered negative, and levels ≥0.1% positive. Kaplan-Meier methods were used to estimate probabilities of disease-free survival (pDFS), pEFS and pOS. Cox regression analyses were performed to study the independent impact of KMT2A subgroups and potentially prognostic factors: white blood cell count (WBC), age and MRD status. Results The 1257 patients were assigned to 13 KMT2A subgroups, or the KMT2A-other group. Two novel subgroups were identified: t(X;11)(q24;q23) (n=21, 2%) and t(1;11)(p32;q23) (n=12, 1%). The median age was 2.5 years (range, 0-18.9). The median WBC was 21.4 x 109/L (range, 0.2-727). Overall complete remission rate was 91%. The 5y-pEFS was 46% [SE, 2%] and the 5y-pOS was 62% [SE, 2%]. Differences across subgroups in 5y-pEFS (Figure 1) ranged from 24% [SE, 5%] to 76% [SE, 9%], and in 5y-pOS from 25% [SE, 13%] to 92% [SE, 8%] (both p&lt;0.0001). The median follow-up time of patients at risk was 5 years. The subgroups t(10;11)(p12;q23) (HR 1.7, p&lt;0.0001), t(6;11)(q27;q23) (HR 1.9, p&lt;0.0001), t(4;11)(q21;q23) (HR 2.9, p=.003) and t(10;11)(p11.2;q23) (HR 2.7, p&lt;0.0001), WBC of &gt;100 x 10^9/L (HR 1.3, p=.006), and age &gt;10y (HR 1.3, p=.005) were revealed as independent predictors of poor EFS. These factors also predicted OS. MRD data after induction course one were available for n=635 (MRD-positivity (range, 0.1-94) n=126, 20%) and after course two for n=527 (MRD-positivity (range, 0.1-88) n=51, 10%). In the four KMT2A poor-risk subgroups, MRD-positivity was not significantly more common after induction course one (p=.0232) or two (p=.066), compared with the other subgroups. MRD-positivity was associated with inferior 5y-pDFS after both induction course one (36% [SE, 4%] vs 48% [SE, 2%]; p=.002) and course two (28% [SE, 6%] vs 49% [SE, 2%]; p&lt;0.0001) (Figure 2). Within the t(9;11)(p22;q23) subgroup, MRD-positivity after induction course one, and within the t(10;11)(p12;q23) subgroup after course two, was associated with inferior 5y-pDFS (36% [SE, 8%] vs 56% [SE, 4%]; p=.004, and 0% [SE, 0%] vs 35% [SE, 5%]; p&lt;0.0001, respectively). After induction course one, the subgroups t(10;11)(p12;q23) (HR 1.7, p&lt;0.0001) and t(10;11)(p11.2;q23) (HR 4.0, p&lt;0.0001), and MRD-positivity (HR 1.5, p=.003) were revealed as independent predictors of poor DFS. After induction course two, the subgroups t(10;11)(p12;q23) (HR 1.8, p&lt;0.0001), t(4;11)(q21;q23) (HR 4.9, p=.008) and t(10;11)(p11.2;q23) (HR 3.2, p&lt;0.0001), MRD-positivity (HR 2.0, p&lt;0.0001), and age &gt;10y (HR 1.5, p=.002) were revealed as independent predictors of poor DFS. Within the group of patients with MRD-negativity after induction course two, the subgroups t(10;11)(p12;q23) and t(10;11)(p11.2;q23) were independent predictors of poor EFS (5y-pEFS 35%, HR 1.7, p=.003 and 5y-pEFS 18%, HR 2.7, p=.004, respectively). Conclusion Outcome for KMT2A-r pAML patients has improved slightly, but similar subgroups were identified as poor risk (Balgobind et al., 2009), including t(10;11)(p12;q23), t(10;11)(p11.2;q23) and t(6;11)(q27;q23). In our study, t(4;11)(q21;q23) was poor risk as well. These subgroups should be considered for high-risk pAML therapy protocols. The favorable risk of t(1;11)(q21;q23) could not be confirmed in our cohort. MRD status is highly predictive of outcome within KMT2A subgroups. In MRD-negative patients after induction course two, both t(10;11) KMT2A subgroups were associated with poor outcome. Disclosures Guest: Syndax Pharmaceuticals: Consultancy. Locatelli:Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Rubnitz:AbbVie Inc.: Research Funding. Kaspers:Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months; AbbVie: Ended employment in the past 24 months.

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