ALBERT

Description: Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. The prevalence of Ph-like ALL increases with age and accounts for over 25% of patients with B-progenitor ALL between the ages of 21-39 years. However, the frequency, outcome and genetic basis of Ph-like ALL in adults over the age of 39 is unknown. The goals of this study were to define the prevalence of Ph-like ALL across the adult age spectrum, assess response to conventional chemotherapy, and define the genetic landscape of Ph-like ALL in adults. Methods: We studied 692 adults with B-ALL obtained from multiple groups including the Alliance (Cancer and Leukemia Group B), ECOG-ACRIN, MD Anderson Cancer Center, Northern Italy Leukemia Group, Princess Margaret Cancer Centre, SWOG and UK NCRI. The cohort was divided into three age groups: 21-39 years (median age 28±6 years, n=333), 40-59 years (median age 47±6 years, n=246) and 60-79 years (median age 67±7 years, n=101). RNA samples were screened using a Taqman low density array (LDA) card that identifies patients with the Ph-like ALL gene signature, in addition to BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, MLL-rearranged and ERG altered ALL. Cytogenetic data was also available for the majority of cases. High expression of CRLF2 was determined by the LDA card, and CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CFRLF2) was confirmed using fluorescence in situ hybridization. Total stranded transcriptome sequencing (RNA-seq) using the Illumina platform was performed on 99 cases and sequencing data was analyzed using FusionCatcher and CICERO. Results: The overall prevalence of ETV6-RUNX1, TCF3-PBX1 and ERG ALL in adults was low (1.3%, 3.6% and 3.1%, respectively), whilst the prevalence of patients with BCR-ABL1, Ph-like and MLL-rearranged ALL was 20%, 24% and 14%, respectively. Ph-like ALL comprised 26% of patients between 21-39 years of age and 20% of patients aged 40-79. Patients with BCR-ABL1 and Ph-like ALL presented with higher white blood counts at diagnosis compared to non Ph-like ALL patients (57.7 and 65.0 vs 28.5 x 109/L). Patients with Ph-like ALL were also more likely to be male compared to patients with BCR-ABL1 and non Ph-like ALL, with 66% vs 50% and 50%, respectively(p

Description: Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.

Description: Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML. The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS. With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts. A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo. This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p

Description: At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients.

Description: Key Points In this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.

Description: Background: Stem cell mobilization (SCM) with G-CSF is efficient but - although overall safe - inconvenient because of the five-day injection regime and certain contraindications. Side effects, sometimes severe, are frequent. These disadvantages fuel the quest for alternative mobilizing agents. Mobilization with the CXCR4-inhibitor plerixafor is rapid, albeit insufficiently efficacious on its own. POL6326, a potent 2nd generation macrocycle CXCR4 antagonist, has demonstrated rapid mobilization kinetics and efficacy in mice. We herein report the results of a Phase IIa dose escalation trial where SCM in response to POL6326 was compared with G-CSF in healthy volunteer stem cell donors. Methods: In this Phase IIa open label trial, healthy volunteer stem cell donors with average mobilization (121±7 CD34+ cells/μL, MW±SEM)after a five-day course of G-CSF, and a wash-out period of at least 6 weeks, received POL6326 at 500-2500 µg/kg as a single 2-hour i.v. infusion. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) were assessed in 3-10 subjects/dose group. Subgroups received two doses of POL6326, 1000 and 2500 µg/kg or 1500 and 2500 µg/kg, at least 2 weeks apart (paired intra-individual analysis). For PK and PD blood samples were collected before (0) and at 2, 3, 4, 6, 8 and 24 hrs after infusion start. Complete blood count, CD34+, CFU-C count and PK were assessed at all time points. At 0, 4, 8 and 24 hrs extensive phenotyping of mobilized mature and immature leukocyte subsets was performed. Eight to 14 days after treatment volunteers underwent extensive clinical and laboratory follow-up. Results: POL6326 was very well tolerated. Several volunteers experienced a mild urticarial or itchy macular rash which responded well to H1/H2 blockade. Rating of tolerability/adverse events by volunteers (questionnaire) compared favourably with G-CSF administration. Exposure (Cmax, AUC) was dose-linear. At all doses tested POL6326 mobilized CD34+ progenitor cells and colony-forming cells (CFU-C, Figure 1) exceeding reported peak mobilization with plerixafor in donors at all except the lowest dose levels. In this dataset mobilization after doses of 2000 or 2500 µg/kg did not appear meaningfully stronger than after 1500 µg/kg. The SCM response for CD34+ cells to doses ≥1500 µg/kg was 36.9±2.4/µL (mean±SEM), or 1/3 that of G-CSF (y=0.324x). Good SCM with G-CSF was predictive of good SCM with POL6326 (r=0.63). One/5.7 POL6326-mobilized CD34+ cells was clonogenic (G-CSF: 1 CFU-C/3.4 CD34+ cells) possibly indicating a more immature phenotype of CD34+ cells mobilized by POL6326. POL6326 caused mixed leucocytosis with peak values in the mid-20K/µL. B-lymphocytosis was more and neutrophilia and monocytosis were less pronounced after POL6326 than G-CSF. Compared to G-CSF the subset of plasmocytoid dendritic cell progenitors (pDC) was enriched to a distinct population within the CD34+ cells following SCM with POL6326 as previously described for plerixafor. At the 24 h time point, blood values were well on their way towards normal, and at follow-up all laboratory values had normalized. Summary/Conclusions: The novel CXCR4-antagonist POL6326 is safe, well tolerated, and provides efficient mobilization of HSPCs. Based on the number of mobilized CD34+ cells at higher doses in this study, we conclude that a standard dose of 4x10E6 CD34+ cells/kg can be extracted with a single apheresis for most recipients unless their body weight significantly exceeds the donor weight. However, exploration of alternative dosing regimens may provide even higher mobilization responses. POL6326 can be an effective mobilizing agent for allogeneic donors, including subjects with contra-indications to G-CSF. Figure 1. Mobilization of CD34+ cells (left) and CFU-C (right) over time is shown (mean±SEM for each dose level of POL6326). Figure 1. Mobilization of CD34+ cells (left) and CFU-C (right) over time is shown (mean±SEM for each dose level of POL6326). Figure 2. Figure 2. Disclosures Escot: Polyphor Ltd.: Employment. Douglas:Polyphor Ltd.: Employment. Romagnoli:Polyphor Ltd.: Employment. Chevalier:Polyphor Ltd.: Employment. Dembowsky:Polyphor Ltd.: Consultancy. Hooftman:Polyphor Ltd.: Employment. Bonig:Polyphor Ltd.: Research Funding.

Description: Background: Patients aged 15 to 39 years old constitute the Adolescent Young Adult (AYA) population. In the US, leukemias represent ~6% of all cancers in this population with the incidence of Acute Lymphoblastic Leukemia (ALL) gradually decreasing with age as the incidence of acute and chronic myeloid leukemias (AML, CML, respectively) increase; ALL occurs at approximately twice the rate of AML in 15- to 19-year olds. Further studies are needed to define the unique features of leukemia in AYA patients, and to better assess and optimize treatment regimens. Marqibo®, vincristine sulfate liposome injection, uses a novel sphingomyelin and cholesterol nanoparticle that facilitates vincristine dose intensification without exacerbation of its toxicity, i.e., it has a wider therapeutic index than standard formulation vincristine. This formulation has also been shown to enhance the penetration and concentration of vincristine into tumors, and prolong plasma circulation time in non-clinical experiments. Marqibo is approved in the US for the treatment of adult patients with Philadelphia chromosome negative (Ph-) ALL in second or greater relapse, whose disease has progressed following two or more previous lines of therapy. We performed a retrospective analysis of data from the Phase 2 RALLY clinical trial (n=65) to examine the effects of Marqibo in the subgroup of the AYA population. The Phase 2 study results of the entire study demonstrated that treatment with single-agent Marqibo resulted in an Overall Response Rate (ORR) of 35%, with 20% of patients achieving a Complete Response (CR) or CR with Incomplete Blood Count Recovery (CRi) (O'Brien, S., 2012 J Clin Oncol). Methods: Data from the RALLY Phase 2 study of Marqibo were analyzed retrospectively to examine only the relapsed or refractory Ph- ALL patients 39 years of age and younger (n=44). In this study, Marqibo (2.25mg/m2) was administered via IV over 60 minutes without dose capping, once per week until response, progression, toxicity or hematopoietic transplant. Results: The median age of the 44 patients was 27 (range: 19-39), 57% were male, 82% had B-cell ALL and 18% had T-cell ALL. 84% had ECOG performance status of 0 or 1. The number of previous treatments ranged from 2-6. 41% had 2 prior lines of treatment, 41% had 3 prior lines of treatment, 16% had 4 prior lines of treatment and 2% had 6 prior lines of treatment. In addition, 59% of patients had previously received a hematopoietic cell transplant. The ORR in the AYA population was 39%, with 25% of patients achieving a CR or CRi. Overall, the safety profile of Marqibo was similar to that in the older adult population, with 35 (79.5%) patients having a treatment-related adverse event, of any grade, on study. The most common treatment-related adverse events, of any grade, in the AYA population were constipation (34%) and peripheral neuropathy (32%). Conclusions: Marqibo (vincristine sulfate liposome injection) was shown to have clinical benefit in AYA patients with relapsed or refractory Ph- ALL with similar safety and efficacy profiles compared to the entire adult population (range: 19-83). Disclosures Schiller: Sunesis: Honoraria, Research Funding. Damon:Atara: Consultancy; Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Sigms Tau: Research Funding. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre:Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Douer:Gilead: Consultancy.