Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial.

Minimal residual disease (MRD) negativity is a key prognostic indicator of outcome in acute lymphocytic leukemia. In the INO-VATE trial (clinicaltrials.gov identifier: NCT01564784), patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab versus standard chemotherapy achieved greater remission and MRD-negativity rates as well as improved overall survival: hazard ratio 0.75, one-sided P = 0.0105. The current analysis assessed the prognostic value of MRD negativity at the end of inotuzumab treatment. All patients who received inotuzumab (n = 164) were included. Among patients with complete remission/complete remission with incomplete hematologic response (CR/CRi; n = 121), MRD-negative status (by multiparametric flow cytometry) was defined as <1 × 10-4 blasts/nucleated cells. MRD negativity was achieved in 76 patients at the end of treatment. Compared with MRD-positive, MRD-negative status with CR/CRi was associated with significantly improved overall survival and progression-free survival, respectively: hazard ratio (97.5% confidence interval; one-sided P-value) 0.512 (97.5% CI [0.313-0.835]; P = 0.0009) and 0.423 (97.5% CI [0.256-0.699]; P < 0.0001). Median overall survival was 14.1 versus 7.2 months, in the MRD-negative versus MRD-positive groups. Patients in first salvage who achieved MRD negativity at the end of treatment experienced significantly improved survival versus that seen in MRD-positive patients, particularly for those patients who proceeded to stem cell transplant. Among patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab, those with MRD-negative CR/CRi had the best survival outcomes

Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P \u3c 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P \u3c 0.0001) and CD54 (P \u3c 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy

Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients

Background: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS). Methods: Patients >= 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis. Results: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis. Conclusions: These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL

Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia

Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis

Acute Leukemia in Adolescents and Young Adults

In many areas of medicine adolescents are regarded as a discrete group with specific therapeutic, psychological, educational, and resource needs. In the treatment of acute leukemia age is a predictor of response. Thus, in acute lymphoblastic leukemia (ALL) there is a clearly poorer treatment outcome after puberty, while in acute myeloid leukaemia (AML), which is more common in older adults, age is a continuous variable with poorer outcomes in each successive decade. Much is known about other prognostic factors and their relative incidence in each age stratum. Although there is some segregation of favorable factors with relative youth, age usually remains an independent factor with respect to prognosis. Adolescents may be included in pediatric or adult-oriented treatment protocols. Here we discuss the outcome of acute leukemia in adolescents and young adults, particularly with respect to whether they respond similarly to children or other adults

A Phase 1 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Abstract Abstract 2600 Background: Lenalidomide (Len) is an immunodulatory agent with proven efficacy in lower-risk myelodysplastic syndromes (MDS) and with strong signals of single-agent activity in higher-risk MDS and AML patients (pts). Our preclinical data showed that Len antagonized cytarabine cytotoxicity with simultaneous exposure, while augmenting the effects of anthracyclines and cytarabine with sequential drug exposure. We initiated a phase 1 combination study in patients with AML investigating sequential standard induction chemotherapy followed by Len. Objectives: 1) to determine the safety and maximum tolerated dose (MTD) of Len following idarubicin/cytarabine induction. 2) to assess preliminary signs of efficacy of this regimen in adults with previously untreated AML. Methods: This was a multicenter, open-label, dose escalation phase 1 study with a 3+3 dosing design of idarubicin (12 mg/m2, day 1–3), cytarabine (100 mg/m2, CI day 1–7) + Len (starting dose 5 mg, day 8–21). Len dose was escalated in 5 mg increments up to a maximum of 25 mg/day. Eligibility included pts with AML age ≥60 years or age <60 with associated del 5/5q; or MDS/RAEB-2 with prior hypomethylating agent failure. Other inclusion criteria included: ECOG PS 0–2 and adequate end-organ function (including normal LVEF of ≥ 50%). Pts who achieved CR/CRi after 1 or 2 cycles of induction were eligible to receive post-remission idarubicin/cytarabine/Len (at the same dose level) for up to 2 cycles, followed by Len maintenance 10 mg/day for up to 12 months. The MTD cohort was expanded to 10 patients. Results: Of 23 enrolled and treated pts, 21 have completed at least 1 treatment cycle. Median age was 68 years (range 44–79); males: 18 (78%). Eleven pts had del 5/5q associated karyotype (10 of whom had complex karyotype), and 15 had secondary AML (including 8 who received prior hypomethylating agents). Len dose escalation reached 25mg/day, with MTD determined to be 20 mg/day. Dose-limiting toxicities occurred in 2 of 3 patients treated at Len 25 mg/day (grade 3 rash; grade 4 neutropenia and thrombocytopenia persisting beyond day 56) and in 1 of 8 patients treated at Len 20 mg/day (grade 4 cardiac ischemia). Only 1 of 21 (5%) patients died within 30 days of treatment initiation. The most common therapy-related non-hematologic toxicities (occurring in ≥ 20% of patients, the vast majority of which were grade 1–2) included: diarrhea (76%), infection/febrile neutropenia (71%), rash (62%), nausea (43%), pain (43%), hemorrhage (33%), fatigue (29%), and non-neutropenic fever (24%). Of the 20 patients evaluable for response, 7 achieved CR and 1 CRi, for an overall response rate (ORR) of 40%. Of 11 evaluable patients treated at the MTD (Len 20 mg/day) and higher, the ORR was 55%. CR occurred in 3 out of 10 (30%) patients with associated del 5/5q. Conclusion: Sequential idarubicin/cytarabine + Len was generally well-tolerated in a primarily older population of patients with previously untreated AML, with MTD of 20 mg/day for Len. Clinical activity in this poor-risk population appears promising at the MTD and higher. Further exploration of this regimen in older AML patients is warranted, with plans for a phase 2 expansion underway. Updated toxicity, response, and survival data will be presented. Disclosures: Lancet: Celgene: Research Funding. Off Label Use: Lenalidomide is approved for use in MDS. Its investigational role in AML will be discussed. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Sekeres:Celgene: Advisory Board. List:Celgene: Consultancy

A Phase 1 Trial of Imatinib Mesylate in Combination with Daunorubicin and Cytarabine for Patients for C-kit Positive Relapsed Acute Myeloid Leukemia (AML)

Abstract C-kit is expressed on more than 10% of blasts in 95% of patients with relapsed AML. Imatinib mesylate (IM) inhibits c-kit and is active in relapsed/ refractory AML. We conducted a Phase 1 trial of IM combined with daunorubicin (D) and cytarabine (A) in patients with c-kit+ relapsed AML. Methods: All patients were treated at the Cleveland Clinic from 2003–2007. Cytogenetic (CG) risk was defined by CALGB criteria. Eligibility criteria included: relapsed AML (excluding APL), relapse more than 6 mo from induction therapy, ECOG performance status 0–2, ≥20% c-kit+ blasts (CD117+ by flow cytometry), age ≥18 yrs, not pregnant or lactating, creatinine ≤2 mg/dL, AST and ALT ≤2 x upper limits of normal, bilirubin ≤2 mg/dL. The concurrent use of antimicrobials which significantly interact with IM was prohibited. All patients received D 45 mg/m2 IV for 3 days, and A 100 mg/m2/d continuous infusion for 7 days (7+3). IM dose was escalated using a standard 3 x 3 design. Dose levels were: −1 (300 mg), 1 (400 mg), 2 (600 mg), 3 (800 mg). IM was administered with the first dose of chemotherapy and continued daily until disease progression, intolerance, removal from study for another treatment (including alloBMT), or dose-limiting toxicity (DLT). Initially, patients with persistent leukemia on Day 14 bone marrow were removed from protocol. A later amendment allowed patients with persistent leukemia, but ≥50% reduction in bone marrow blasts to remain on protocol. These patients continued IM and received 5 days of A (100 mg/m2/d) and 2 days of D (45 mg/m2/d). Results: Seventeen patients have been enrolled: median age was 47 yrs (range 30–71) and nine (53%) were male. The average time from CR to relapse was 19.2 mos (range, 7.4–36.2 mos). CG were poor risk in 29%, intermediate risk in 59%, and good risk in 12%. The median percentage of c-kit positive blasts was 86% (range, 52–98%). Nine patients were treated at dose level 1 (400 mg) because 3 patients discontinued IM before DLT could be evaluated (2 due to nausea, 1 due to persistent leukemia on a Day 14 bone marrow). Of the 6 evaluable patients, 2 patients had a DLT. Both of these were ≥Grade 3 hepatotoxicity. One patient had a bilirubin of 6.0 mg/dL (normal range 0–1.5). Therefore, subsequent patients were treated at dose level −1. Eight patients have been treated at dose level -1. Of these, 6 are evaluable for DLT. Only 1 DLT (bilirubin 5.5 mg/dL) was seen, making 300 mg/d the MTD. Fifteen out of 17 patients are evaluable for response, and 9 of these 15 have achieved CR (53%) or CRp (7%). Patients received IM for a median of 35.9 days (range 9–101 days). Three patients discontinued IM when they proceeded to alloBMT. One patient continues on IM and remains in remission on Day 180 of therapy. Enrollment to the expanded cohort at the MTD is ongoing to better evaluate response. Conclusions: The MTD of IM in combination with 7+3 was 300 mg. Since the hepatotoxicity appeared to be reversible with discontinuation of IM, it may be possible to escalate IM doses further and re-challenge. The reason for the elevated bilirubin is unclear but may be due to pharmacokinetic interactions, chemotherapy, and/or the presence of active leukemia. Further pharmacokinetic studies are being performed for further evaluation. Given the preliminary encouraging activity of this Phase 1 combination, a Phase 2 study is planned