CC-486 is safe and well-tolerated as maintenance therapy in elderly patients (≥75 years) with acute myeloid leukemia (AML) in first remission following induction chemotherapy: Results from the phase III QUAZAR AML-001 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7530-7530
Author(s):  
Farhad Ravandi ◽  
Andrew Wei ◽  
Hartmut Dohner ◽  
Hervé Dombret ◽  
Gert J. Ossenkoppele ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Age Distribution ◽  
Age Groups ◽  
Study Drug ◽  
Phase Iii ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
First Remission

7530 Background: About 40-50% of older patients (pts) with AML attain complete remission (CR) with induction chemotherapy (IC) but relapse is common.Effective, well-tolerated maintenance treatment (Tx) is needed for older pts in remission who are not eligible for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/cycle) to sustain therapeutic activity. In the phase III placebo (PBO)-controlled QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance therapy in pts with AML in first remission following IC produced significant improvements in overall and relapse-free survival. Here we report safety and tolerability findings among pt subgroups defined by age at study entry. Methods: Eligible pts were ≥ 55 yrs of age, with de novo or secondary AML, intermediate or poor risk cytogenetics, and ECOG PS ≤ 3; had achieved first CR or CRi after IC ± consolidation; and were not candidates for HSCT. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of repeated 28d Tx cycles. Safety was assessed across 3 age subgroups (≥ 55 to < 65, ≥ 65 to < 75, and ≥ 75 yrs) in pts who received ≥ 1 dose of study drug. Adverse events (AEs) were coded using MedDRA v. 22.0 and graded by NCI-CTCAE v. 4.0. Results: 469 pts ( >99% of all enrolled pts) were evaluable for safety (CC-486 n = 236; PBO n = 233). Median age was 68 yrs (range 55-86). Age distribution was similar between the two Tx arms (Table). Between Tx arms, AE rates within each age stratum were similar to rates in the overall study population. The most common AEs (any grade) with CC-486 were GI events, which were more frequent than in the PBO arm across age groups. Within the CC-486 arm, AE rates were generally consistent across age groups, except for constipation, which was > 20% more frequent in pts aged ≥ 75 yrs, and thrombocytopenia, which was ≥ 20% less frequent in this group (Table). Overall, 13% and 4% of pts in the CC-486 and PBO groups discontinued Tx due to AEs. Conclusions: In QUAZAR AML-001, CC-486 was generally well tolerated in all age groups, including elderly pts aged ≥ 75 yrs. Clinical trial information: NCT01757535 . [Table: see text]

Escalated dosing schedules of CC-486 for patients experiencing first acute myeloid leukemia (AML) relapse: Results from the phase III QUAZAR AML-001 maintenance trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7513-7513
Author(s):  
Hartmut Dohner ◽  
Andrew Wei ◽  
Pau Montesinos ◽  
Hervé Dombret ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Survival Rates ◽  
Study Drug ◽  
Median Number ◽  
Leukemic Cells ◽  
Phase Iii ◽  
Cell Transplant ◽  
Dosing Schedule ◽  
Hematopoietic Stem ◽  
First Onset

7513 Background: A goal of AML maintenance therapy is to decrease the risk of relapse by suppressing growth of residual leukemic cells post-induction. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/28d cycle) to sustain therapeutic activity. In the QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance treatment (Tx) significantly prolonged overall (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following induction chemotherapy (IC), who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/cycle, but pts who relapsed with 5–15% blasts could receive escalated 21d/cycle dosing. We review outcomes of pts who received 21d dosing in QUAZAR AML-001. Methods: Pts were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and had achieved first CR/CRi after IC ± consolidation. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of 28d Tx cycles. CR/CRi status was assessed every 3 cycles. Pts relapsing with 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until > 15% blasts, unacceptable toxicity, or HSCT. Results: 91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were assigned to ≥ 1 21d/cycle dosing schedule. Median time to dose escalation was 9.2 mo (range 1.0-52.7) for CC-486 and 6.0 mo (0.5-19.3) for PBO. Median number of 21d dosing cycles was 2.0 (range 1-45) in the CC-486 arm and 2.0 (1-16) in the PBO arm; 43% and 18% of pts, respectively, received > 3 cycles of 21d dosing. Among 78 evaluable pts, 10/43 (23%) CC-486 pts and 4/35 (11%) PBO pts regained CR/CRi (central review) during dose escalation. Median OS from randomization was 22.8 mo vs. 14.6 mo with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [95%CI 2.1%, 39.7%]). The most common AEs with first onset during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%). Conclusions: Escalated 21d CC-486 dosing was well tolerated and resulted in prolongation of OS and restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with 5–15% blasts. Clinical trial information: NCT01757535 .

Phase III Intergroup Study of Lenalidomide (CC-5013) Versus Placebo Maintenance Therapy Following Single Autologous Stem Cell Transplant for Multiple Myeloma (CALGB 100104): Initial Report of Patient Accrual and Adverse Events.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3416-3416 ◽  
Author(s):  
Philip L. McCarthy ◽  
Kouros Owzar ◽  
Edward A. Stadtmauer ◽  
Sergio Giralt ◽  
David D Hurd ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Progressive Disease ◽  
Study Drug ◽  
Phase Iii ◽  
Cell Transplant ◽  
Grade 5 ◽  
Grade 3

Abstract Abstract 3416 Poster Board III-304 Relapse and/or progression of disease are the primary causes of treatment failure after autologous hematopoietic stem cell transplant (ASCT) for multiple myeloma (MM). The primary objective of CALGB 100104 was to investigate whether adding maintenance therapy would improve the time to progression (TTP). The study was powered to detect an improvement of 9.6 months (prolongation of TTP from 24 months to 33.6 months) in MM patients undergoing a single ASCT. Secondary objectives were the Complete Response conversion rate following maintenance initiation, the Overall Survival and the feasibility of long term lenalidomide maintenance therapy. Eligible MM patients were Durie-Salmon Stage I-III patients within 1 year of diagnosis, receiving at least 2 months of any induction therapy with response (Stable Disease (SD) or better) and ≤ 70 years of age. Patients with progressive disease prior to ASCT were not eligible for study. Patients underwent stem cell mobilization followed by Melphalan 200 mg/m2 and ASCT with a minimum of 2 × 106 CD34 cells/kg for stem cell infusion. Responding patients with SD or better were randomized at day 100 to 110 post ASCT to study drug versus placebo. Patients with progressive disease were not randomized. Randomized patients were stratified by elevated β2 microglobulin at diagnosis and prior thalidomide or lenalidomide use during induction therapy. The starting dose was 10 mg daily with an escalation at 3 months to 15 mg if tolerated. Study drug could be de-escalated by 5 mg daily if not tolerated. Patients could be maintained at 5, 10 or 15 mg as tolerated and were followed with monthly complete blood counts. Drug was held for neutropenia (Absolute Neutrophil Count (ANC) < 500/μl or thrombocytopenia (<30,000/ μl) and restarted after resolution of cytopenia(s). Patients were re-staged by blood and urine testing every 3 months, by skeletal survey and bone marrow testing yearly and remained on maintenance therapy until progression. A total of 568 pts were registered at centers from the following cooperative groups: CALGB (n=377), ECOG (n=132), and BMT-CTN (n=59). The study opened in 12/2004 with increasing annual accrual: 2005, n=33, (6%); 2006, n=62, (11%); 2007, n=137, (24%); 2008, n=214, (38%); 2009, n=122, (21%) and study closure on 07/03/09. The drop out rate before randomization at day 100 to 110 was projected to be 10-15% with an expected randomization of 462 patients. Among the 568 registered patients, 424 have been randomized, 81 have dropped out pre-randomization and 63 are pending randomization as of 08/06/09. Projected final randomization is approximately 475. Pooled Hematologic and Non-Hematologic Adverse Events (AEs) are available from 275 patients in both arms. Individual patients experiencing Hematologic AEs are as follows: Grade 3 (severe) n=43 (16%); Grade 4 (life-threatening) n=26 (9%); and no Grade 5 (lethal). Individual patients experiencing Non-Hematologic AEs are as follows: Grade 3 n=74 (27%); Grade 4 n=9 (3%); Grade 5 n=5 (2%). The most common Non-Hematologic AEs were infection, fever, rash and fatigue. The Data Safety and Monitoring Board (DSMB) will continue to monitor the study for AEs and determination of progression. This large Phase III study has successfully completed patient registration and is nearing completion of patient randomization at day 100 to 110 post ASCT through the cooperation of the Intergroup oncology and transplant clinical research groups. Further analysis will determine if maintenance therapy with lenalidomide (CC-5013) is of benefit for MM patients following single ASCT. Disclosures McCarthy: Celgene: Speakers Bureau. Off Label Use: Lenalidomide for maintenance therapy following autotransplant for multiple myeloma. Stadtmauer:Celgene: Speakers Bureau. Richardson:Millenium (Research Funding and Advisory Board), Celgene, Keryx, BMS, Merck, Johnson and Johnson (All Advisory Board): Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

scholarly journals Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements

2021 ◽  
Vol 11 (9) ◽  
Author(s):  
Ghayas C. Issa ◽  
Jabra Zarka ◽  
Koji Sasaki ◽  
Wei Qiao ◽  
Daewoo Pak ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Adverse Outcomes ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Lysine Methyltransferase ◽  
First Remission ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.

scholarly journals Bispecific T-cell engaging antibodies in B-cell precursor acute lymphoblastic leukemias: focus on blinatumomab

2020 ◽  
Vol 11 ◽  
pp. 204062072091963
Author(s):  
Jose-Maria Ribera ◽  
Eulalia Genescà ◽  
Jordi Ribera
Keyword(s):  
T Cell ◽  
B Cell ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Development Program ◽  
Cell Transplant ◽  
Cell Precursor ◽  
Hematopoietic Stem ◽  
Clinical Development Program

Bispecific T-cell engaging antibodies are constructs engineered to bind to two different antigens, one to a tumor-specific target and the other to CD3-positive T cells or natural killer (NK) cells. Blinatumomab engages CD19 and CD3, performing effective serial lysis. The clinical development program in acute lymphoblastic leukemia (ALL) includes clinical trials in relapsed or refractory (R/R) patients and in B-cell precursor (BCP) ALL patients with measurable residual disease. Several trials are currently being conducted in de novo BCP-ALL, either in induction, consolidation, or before or after hematopoietic stem cell transplant. Combination with other targeted therapies or with other immunotherapeutic approaches are also underway. Several strategies are aimed to optimize the use of blinatumomab either by overcoming the mechanisms of resistance (e.g. inhibition of PD-1/PD-L1) or by improvements in the route of application, among others.

Pharmacokinetics of Ganciclovir Following Oral Valganciclovir Versus Intravenous Ganciclovir in Allogeneic Hematopoietic Stem-Cell Transplant Patients with Stable Graft-Versus-Host Disease of the Gastrointestinal Tract.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2223-2223 ◽  
Author(s):  
Drew J. Winston ◽  
Voravit Ratanatharathorn ◽  
Lindsey Baden ◽  
Christos Emmanouilides ◽  
Don Gabriel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Creatinine Clearance ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Study Drug ◽  
Preemptive Therapy ◽  
Solid Organ ◽  
Cell Transplant ◽  
Hematopoietic Stem

Abstract Cytomegalovirus (CMV) disease can be effectively prevented in allogeneic hematopoietic stem cell transplant (HSCT) patients by ganciclovir (GCV) given as prophylaxis or preemptive therapy. Due to the low bioavailability of oral GCV capsules, GCV is usually administered intravenously (IV) to HSCT patients. Valganciclovir (VGCV) is the valine ester prodrug of ganciclovir. In healthy subjects, HIV-infected patients, and solid-organ transplants, the oral bioavailability of VGCV is about 60%, or 10-fold higher than oral GCV capsules. The bioavailability and total GCV exposure provided by oral VGCV relative to IV GCV in HSCT patients with gastrointestinal (GI) GHVD has not been established. METHODS: HSCT patients were eligible for the study if the following criteria were satisfied: 1) ≥16 years of age; 2) biopsy-proven GHVD of GI tract with nausea and/or diarrhea (300–1500 ml/day) or proven GVHD of skin or liver plus diarrhea with no other explanation; 3) no active CMV infection or disease; 4) neutrophil count ≥1000/μL; 5)creatinine clearance >60 ml/min. Following a standardized breakfast, eligible patients were randomized to receive a single dose of open-label study drug (900 mg of oral VGCV or 5 mg/kg of IV GCV). After a minimum 48 hr. washout period, patients were crossovered to alternate study drug. Blood for levels of GCV and VGCV were obtained predose and then over the 24 hours after dosing. Pharmacokinetic (PK) parameters were derived by noncompartmental methods. RESULTS: Data from 16 patients are currently available. Patient demographics include mean age 45 yrs (range 23 to 58 yrs); males 13, females 3; mean weight 80kg (range 52 to 107 kg); mean creatinine clearance 96 ml/min (range 62 to 184 ml/min). Median time after transplant for study was 303 days (range 102 to 988 days). Mean GCV PK parameters are summarized in the following table. Mean GCV Value (Coefficient of variation in %) Oral VGCV-900 mg IV GCV-5mg/kg Parameter N = 16 N = 16 AUC o -τ (μg•hr/mL) 43.58 (37) 46.74 (40) AUC o-∞ (μg•hr/mL) 46.03 (41) 48.89 (43) C(max) μg/mL) ( 6.45 (30) 12.53 (30) T max (hr) 3.13 (22) 0.97 (8) T½ (hr) 4.97 (31) 5.09 (29) GCV AUC values were similar, although maximum GCV concentrations were higher and acheived earlier with IV GCV. Terminal elimination half-life of GCV with oral VGCV and IV GCV were similar. After 900 mg of oral VGCV, mean plasma Cmax for VGCV was low (0.22 μg/mL), which is consistent with rapid and almost complete metabolism of VGCV to GCV. CONCLUSION: These preliminary results suggest that systemic exposure to GCV after 900 mg of oral VGCV is comparable to that achieved with IV GCV in HSCT patients with stable GI GVHD. Oral VGCV could be a useful alternative to IV GCV in certain HSCT patients requiring prophylaxis or preemptive therapy for CMV.

Phase III Randomized Stem Cell Mobilization Trial Comparing Standard Vs Double-Dose G-CSF Vs Standard Doses of G-CSF Plus GM-CSF in Hard to Mobilize Patients Undergoing An Autologous Hematopoietic Stem Cell Transplant (HSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3228-3228
Author(s):  
Elizabeth Berger ◽  
Christopher Seet ◽  
Mala Parthasarathy ◽  
Tulio Rodriguez ◽  
Scott E. Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
Standard Dose ◽  
Stem Cell Mobilization ◽  
Phase Iii ◽  
Control Group ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Cell Mobilization

Abstract Abstract 3228 Poster Board III-165 Introduction Using standard dose G-CSF (10 μg/kg) for stem cell mobilization, 25-40% of patients, deemed to be hard to mobilize based on prior therapy, will not collect sufficient HSC (> 2-2.5 × 106 CD34/kg) to proceed to a prompt autotransplant. Strategies to improve CD34/kg yields have included dose escalating G-CSF up to 30 μg/kg or combining G-CSF and GM-CSF. While dose escalated G-CSF is effective in increasing CD34 yields in normal donors as is the combination of G-CSF and GM-CSF, their comparative value in pre-treated patients has not been tested. To determine the value of these strategies, we performed a randomized comparison of high dose G-CSF (30 μg/kg as 2 doses 12 hours apart), to the combination of simultaneous single daily doses of G-CSF (10 μg/kg) plus GM-CSF (5 μg/kg), to a control group receiving G-CSF at an equivalent total dose of cytokine to the combination arm (15μg/kg) as a single dose. Patients and Methods Patients were eligible if heavily pre-treated, defined as: a minimum of 10 total cycles of combination chemotherapy and two prior regimens, or a total of 6 chemotherapy cycles if the patient also received RT to marrow bearing sites, platinum-based chemotherapy or 2 or more cycles of any BCNU or fludarabine containing regimen. Baseline WBC had to be > 3000/μl, ANC > 1500/μl and a platelets > 100,000/μl. Twelve liter aphereses began on day 5 of mobilization, and continued until ≥ 4 × 106 CD34/kg were collected or a maximum of 5 aphereses. Patients typically proceeded to transplant if they had ≥ 2.5 × 106 CD34/kg collected and were always re-mobilized if they collected < 2.0 × 106 CD34/kg. CD34 subsets (CD34+/CD33- and CD34+/CD38-) were also assessed for the 3 groups to determine if more primitive HSC were mobilized by the 2 novel strategies. The sample size was calculated based as follows: 60% of the control group would collect 2.5 × 106 CD34/kg and this would rise to 90% in one or both study arms. The detection of such differences with a power of 80% and a 2-sided alpha level of 0.025 required a total sample of 120 patients. Results A total of 120 patients were randomized; 119 were eligible. Patient demographics, shown in the Table, were matched among the three groups: The % of patients collecting ≥2.5 × 106 CD34/kg was: standard G: 60%, high dose G: 57% (p = 1.0), G + GM: 41% (p = 0.1). Median CD34 collected in first mobilization were, 3.6 × 106/kg, 3.0 × 106/kg (p = 0.22) and 2.0 × 106/kg (p = 0.05) respectively in a median of 4, 4, and 5 aphereses (p = NS). Re-mobilization rates: standard G; 37.5%, high dose G: 35%; G + GM: 50% (p = NS). Total median CD34 collected from first and any second mobilizations were: standard G: 4.8 × 106/kg, high dose G: 3.9 × 106/kg, and G + GM: 3.5 × 106/kg. One patient in the standard G arm and 3 in high dose G did not proceed to transplant due to poor initial mobilization and progression in 2, and one each for progression or poor mobilization alone. There were no significant differences in median engraftment times: for ANC, 10, 11 and 15 days respectively for the standard G-, high dose G- and G + GM arms and for platelets, 11, 13 and 14 days respectively. The overall survivals @ the median f/u time of 37 months were 59.8%, 61.8% and 48.1% respectively (p = 0.272) for the three groups. The % primitive HSC (CD34+/CD33- and CD34+/CD38-) from the first mobilization were identical in the 3 patient groups. Conclusions We found no advantage to dose escalated G-CSF nor to the combination of G-CSF and GM-CSF to mobilize HSC for autotransplantation in heavily pre-treated patients. We also did not find higher numbers of more primitive CD34 subsets mobilized by these newer strategies. Alternative approaches, e.g. the combination of plerixifor + standard dose G-CSF (Stiff et al: BBMT; 15:249-56, 2009) would appear to be the preferred method of initial HSC mobilization for heavily pre-treated patients. Disclosures Stiff: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Unexpected High Mortality Rate Due to Acute Respiratory Distress Syndrome Among Infants with AML Enrolled on JPLSG AML-05 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2146-2146 ◽  
Author(s):  
Daisuke Tomizawa ◽  
Akiko Moriya Saito ◽  
Takashi Taga ◽  
Souichi Adachi ◽  
Hideki Nakayama ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Tumor Lysis Syndrome ◽  
Age Groups ◽  
The Other ◽  
Cell Transplant

Abstract Abstract 2146 Background: Infants (age <1 year) with AML are naturally vulnerable to intensive cytotoxic therapy, however, usually treated with the same protocol as older children with or without dose modification. We report here the unexpected high treatment-related mortality (TRM) mainly due to acute respiratory distress syndrome (ARDS) observed among this age subgroup in the JPLSG AML-05 study. Patients & Methods: AML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, opened on 11/1/2006 for children (age ≤18 years) with de novo AML excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome. The study stratifies patients by the specific cytogenetic characters and treatment response into 3 risk groups. All patients receive two common induction courses; the first induction course (Ind-1), “ECM,” is based on the predecessor trial AML99, consisted of etoposide (150 mg/m2 i.v. on days 1 to 5), Ara-C (200 mg/m2 for 12-hour i.v. on days 6 to 12), mitoxantrone (5 mg/m2 i.v. on days 6 to 10), and a single dose of triple IT on day 6. For patients <2 years old, drug dosages are reduced by calculating on body weight basis. TRM among infants in AML99 was as low as 7.4% (2/27). Nine early deaths (= deaths of any cause before initiating the second induction course) were reported among the first 275 patients enrolled on AML-05, and mortality was exceptionally high in infants (7/32, 21.8%). This prompted suspension of the protocol accrual for this age subgroup on 4/2/2009 and comprehensive review of induction adverse events (AEs) were carried out. Results: Among the 7 early deaths in infants, 4 deaths occurred during Ind-1 phase, and the other 3 after being off protocol therapy due to severe Ind-1 AEs. The causes of deaths were as follows; one of resistant disease, 4 of ARDS, one of interstitial pneumonia, and one of bacterial sepsis after receiving haploidentical stem cell transplant because of prolonged pancytopenia. Among the 4 ARDS cases, two had preceding RS virus infection, and the other 2 developed ARDS during marrow recovery with G-CSF use. We also evaluated grade 3 and 4 AEs in all age groups, of which 248/275 cases were evaluable. When comparing the infant group (N=27) and the older age group (≥ 1 year, N=221), there were no difference in hematological toxicities, however, non-hematological toxicities, such as renal, cardiac, pulmonary, neurological complications, and tumor lysis syndrome were significantly more common in the infant group. Conclusions: Early death rate among infants in AML-05 study was unacceptably high, and we decided to make the following changes to the AML-05: 1) additional dose reduction by 33% in Ind-1 for infants; 2) enhancing supportive care guidelines regarding infection prevention; 3) close prospective monitoring of induction toxic death. The enrollment of infants was re-opened on 8/11/2009, and no fatal cases are observed since then. Disclosures: No relevant conflicts of interest to declare.

Tandem Autologous Stem Cell Transplants (auto-auto) with or without Maintenance Therapy Versus Single Autologous Transplant Followed by HLA-Matched Sibling Non- Myeloablative Allogeneic Stem Cell Transplant (auto-allo) for Patients (pts) with High Risk (HR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 526-526 ◽  
Author(s):  
Edward A Stadtmauer ◽  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Cell Transplant ◽  
Primary Analysis ◽  
Hematopoietic Stem

Abstract Abstract 526 The prognosis of patients with high-risk myeloma (HR MM) continues to be dismal, despite the early incorporation of novel agents. Early phase trials of allogeneic hematopoietic stem cell transplant (alloHCT) suggest the possibility of an immunologic graft-versus-myeloma effect that might favorably affect survival. Less toxic reduced-intensity HCT preparative regimens now allow more widespread use of alloHCT in the MM population. BMT CTN 0102 is a phase III multicenter clinical trial that biologically assigned patients to either melphalan 200mg/m2 (MEL 200) auto-auto without (obs) or with 1 year of thalidomide and dexamethosone (ThalDex), or an auto-allo approach using MEL 200 followed by alloHCT using 2 Gy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. Patients were stratified by biological prognostic factors that were considered to be high risk at the time of the trial design: chromosome 13 deletions by metaphase karyotype and beta-2 microglobulin ≥4 mg/dl. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled, and 85 fulfilled the criteria of HR MM. Among them, 48 were assigned to auto-auto (24 Thal-Dex and 24 obs) and 37 to auto-allo. Groups differed in age (median 57 y and 51y, p=0.02) but were otherwise balanced. Compliance with second transplant was 65% for auto-auto and 78% for auto-allo. Compliance with ThalDex was poor, so the two auto-auto arms were pooled for the primary analysis. Three-year PFS was 33% (95% Confidence Interval (CI), 22–50%) and 40% (95% CI, 27–60%, p=0.74) and 3-year OS was 67% (95% CI, 54–82%) and 59% (95% CI, 49–78%, p=0.46) for auto-auto and auto-allo, respectively. Corresponding probabilities for 3-year progression/relapse was 53% and 33% (p=0.09), and 3 year treatment-related mortality was 8% and 20% (p=0.3). Among auto-allo patients, probabilities of grade 3–4 acute and chronic GVHD were 9% and 48%, respectively. Among the 59 (31 auto-auto, 28 auto-allo) patients who received second transplant, 3 year PFS was 35% and 46% (p=0.6). Disease response at day 56 after second transplant was 57% for very good partial response (VGPR) or better and 37% for complete response (CR) and near CR (nCR) in the auto-auto group; and 48% (VGPR or better) and 41% (CR+nCR) in the auto-allo group. In conclusion, this planned secondary analysis of a cohort of HR MM patients demonstrated equivalent 3-year PFS and OS for auto-auto and auto-allo in both intention-to-treat and as-treated analyses. However, trends in late PFS and time to progression/relapse suggest further follow-up is needed before final conclusions regarding the utility of auto-allo in this HR cohort can be made. Finally, this study shows the feasibility of an alloHCT approach for HR MM patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects. Disclosures: Stadtmauer: Celgene: Speakers Bureau. Krishnan:Celgene: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy for Patients Younger Than 61 Years with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1550-1550
Author(s):  
Aziz Nazha ◽  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Phase Iii ◽  
Molecular Profile ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Elevated Bilirubin

Abstract Abstract 1550 Background: Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in AML relapse showed higher response rates and better event-free survival with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. We have also reported the feasibility and safety of the addition of idarubicin to CA (CIA) in a previous phase I and II study. To explore this combination further, we conducted a phase II study of CIA in pts</= 60 years with previously untreated AML. Patients and Methods: Patients (Pts) were eligible if they were </=60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m2 iv daily (days 1–5), Idarubicin 6 mg/m2 daily (days 1–3), and Cytarabine 0.75 g/m2 daily (days 1–5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m2 × 5, Idarubicin 10 mg/m2 × 3, and Cytarabine 1 g/m2 × 5. Pts who have not achieved a complete remission following the induction could receive one re-induction course. Pts in CR or CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m2 × 3, Idarubicin 6 mg/m2 (days 1–2), and Cytarabine 0.75 g/m2 × 3, subsequently amended to Clofarabine 15 mg/m2 × 3, Idarubicin 8 mg/m2 × 2, and Cytarabine 0.75 g/m2 × 3. Supportive care was standard. Pts ≥ 50 yrs were admitted to a laminar air flow room for the duration of the induction. Results: From April 2010 until August 2011, 51 pts have been accrued with a median age of 49 yrs (range 19–59): 33 pts (65%) with de novo AML and 18 pts (35%) with secondary AML (18 related to MDS, 7 related to therapy). Three pts (5%) had a PS of 2. Median WBC at diagnosis was 3.4 × 109/L (0.6-92.3). Thirty-three (65%) pts had abnormal cytogenetics (21/33[64%] poor risk and 5/33 [15%] intermediate risk). Molecular profile: 6 pts (11%) had FLT3/ITD, 3 pts (6%) CEBPA, and 8 pts (16%) NPM1 mutations. Thirty-five pts (69%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 71%. 61% pts (31/51) achieved CR following one induction cycle. 18% (9/51) pts required a re-induction and 44% (4/9) of them responded after the re-induction. Responding pts received a median of 2 courses (1–8) courses. With a median follow-up of 23 weeks (3–36+) median remission duration has not been reached with a 1-yr remission probability of 85%. Ten pts (19%) died on study including 2 (4%) who died < 28 days from treatment start (one from septic shock and multi-organ failure, and one from Steven Johnson syndrome). Median overall survival (OS) for responding pts has not been reached (2–36 weeks). One-yr survival probability is 65%. Sixteen pts (31%) proceeded with an allogenic stem cell transplant in CR1. Most toxicities were </= grade 2 and included rash (41 %), nausea (29%), diarrhea (23%), elevated transaminases (21%), and elevated bilirubin (17%). Toxicities > grade 2 included elevated bilirubin (4%), hypokalemia (4%), cellulitis (4%) and seizure (1%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. 76 % (39/51) pts had neutropenic fever. Conclusion: Clofarabine, Idarubicin and Cytarabine achieve a response rate of 71% in patients </=60 yrs with previously untreated AML. Induction mortality was low and the toxicity profile was expected and manageable. Longer follow up and comparisons with standard induction therapy will be needed to further assess the role of this combination in AML therapy. Disclosures: Off Label Use: Clofarabine, use of Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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