ALBERT

Description: Background: Outcome of pts with R/R ALL is poor. Addition of IO to effective low-intensity chemotherapy might improve outcome. CD22 expression occurs in 〉90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve outcome. Methods: Pts ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Pts received IO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. Results: Thirty-five pts (14 men, 21 women) have been treated so far. Pts characteristics and outcome are summarized in Table 1. Median age is 35 yrs (range 9-87). Median follow-up is 10 months (mos). The overall response rate was 71%: 18 (51%) CR, 6 (17%) CRp, and 1 (3%) marrow CR. Four (11%) pts were refractory and early death was reported in 6 (17%) pts. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (1 on study who had prior allogeneic stem cell transplantation, 3 were post transplantation following IO therapy). Four (11%) pts were switched early to maintenance therapy due to poor functional status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Twelve (34%) pts proceeded to receive allogeneic stem cell transplantation; of the rest, 6 (17%) relapsed within 3 mos (range, 1 to 7). At the last follow-up, 17 pts (49%) are alive, 18 (51%) died: 6 early death (3 hemorrhage, 2 sepsis, and 1 unknown cause); 8 were responders (5 died post relapse after subsequent salvage, 2 died post transplantation VOD in 1, and 1 died due to sepsis and multiple organ failure), 4 were refractory and died of disease progression. The 6-month PFS and OS rates were 79% and 58%, respectively. Median survival for pts with CR/CRp/marrow CR was 14 mos versus less than 1 mo in pts with refractory disease. Furthermore, median survival was not reached in pts with S1, 4 mos in pts with S2 and 5 mos in pts with S3+. Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results (71% ORR) in pts with R/R ALL. Pts with previous liver damage and transplant candidate should be considered carefully for this treatment to minimize the risk of VOD.Table 1Patient characteristics and outcomeParameterCategoryN (%)/Median [Range]Follow-up (mos)10 [1-14]Age (yrs)35 [9-87]Performance Status (ECOG)0-130 (86)Salvage StatusS119 (54)S1, primary refractory4 (12)S1, CRD1

Description: Abstract 3567 Background: Acute lymphoblastic leukemia (ALL) is an aggressive lymphoproliferative disorder, responsive to frontline standard induction and consolidation chemotherapy. However, the prognosis of patients (pts) with relapsed/refractory ALL is extremely poor. Deregulation of the PI3K/Akt/mTOR signal transduction pathway is central to leukemic cell growth, proliferation and survival, and has been implicated in ALL pathogenesis. In a recent phase II study of pts with relapsed/refractory non-Hodgkin lymphoma, single agent mTOR inhibitor everolimus showed ORR 30% and acceptable toxicity in 77 heavily pretreated pts (Witzig TE et al, Leukemia 2011; 25,341–7). The purpose of this study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD in pts with relapsed/refractory ALL, and to study effects of everolimus on AKT/mTOR signaling in ALL blasts. Methods: In this single center phase I/II study, pts aged 10 years or older with relapsed/refractory ALL or lymphoblastic lymphoma were treated with oral everolimus at a daily dose of 5 mg or 10 mg in combination with the standard hyper-CVAD regimen (Kantarjian HM et al, J Clin Oncol. 2000 Feb;18(3):547–61) until disease progression or unacceptable toxicity. Primary endpoints were to establish safety (after 2 cycles) and efficacy. Secondary endpoints included assessments of pharmacodynamics and pharmacokinetics. Results: Twelve pts have been enrolled and are evaluable for response. Median was age 24 years (range, 11–59). Five pts had T-ALL and 7 had Philadelphia chromosome negative precursor-B-ALL. Median number of prior treatments was 2 (range, 1–4); 5 pts were 1st salvage attempts. Three pts received everolimus 5 mg/day and 9 were treated with 10 mg/day continuously in combination with hyper-CVAD. Median number of cycles given was 2 (range, 1–4). Median follow-up was 12 months (range, 7–23). Three pts achieved CR (all were 1st salvage attempts) and 1 patient had CRi (second salvage); 2 pts achieved PR. No responses were seen beyond second salvage. Of the 9 pts completing 2 cycles, both EFS and OS were not reached for 3 pts in the 1st salvage, and were 8.5 weeks and 18.5 weeks respectively for pts in second salvage and beyond (P=.01 and P=0.04). Of the 12 pts (including 3 only treated with one cycle), both EFS and OS were not reached for 3 pts in the 1st salvage, and were 10 weeks and 18 weeks respectively for pts in second salvage and beyond (P=0.17 and P=0.05). Treatment-related toxicities in the 9 pts evaluable for MTD (completed 2 cycles) included 3 episodes of grade 3 mucositis, which was a dose-limiting toxicity, 3 episodes of grade 4 infections (sepsis) and 9 episodes of grade 3 infections (neutropenic fever, pneumonia, bacteremia). There was no deaths on-study. Inhibition of mTOR signaling (p-pS6K) was observed in 5 of 8 (62%) patient samples tested, at both the 5 and 10 mg dose levels, suggesting that 5 mg is sufficient to block the pathway. Lack of inhibition of p-pEBP1 and pAKT argues for potential benefit of second generation mTOR inhibitors or dual PI3K/mTOR inhibitors. Conclusions: We conclude that administration of hyper-CVAD plus everolimus is well-tolerated. The study warrants further investigation of next generation mTOR inhibitors in combination with hyper-CVAD for ALL in relapsed and frontline settings. Disclosures: Cortes: Novartis: Consultancy, Research Funding.

Description: Abstract 1486 Background: Corticosteroid therapy is a well-known cause of osteoporosis. Studies have shown that the use of bisphosphonates such as risedronate can prevent bone loss in patients receiving moderate to high doses of corticosteroids. Patients with acute lymphoblastic leukemia and lymphoblastic lymphoma (ALL/LL) are at high risk of bone loss due to both leukemia and high dose steroids used in chemotherapy regimens. Objectives: The primary objective was to determine whether the use of risedronate decreases the amount of bone loss in adult patients with ALL/LL receiving chemotherapy with high dose corticosteroids when compared to placebo. Methods: Adult patients with newly diagnosed ALL/LL receiving Hyper-CVAD or BFM were randomly assigned to receive either risedronate 35 mg weekly or placebo. Both patients and physicians were blinded to the treatment assignment. Patients in both arms were given vitamin D and calcium. Bone mineral density (BMD) using DEXA scan was measured at baseline and at 6 months. Patients who lost more than 10% BMD when compared to baseline measurements were taken off the study and unblinded. We excluded patients with osteoporosis. Results: 36 patients were randomized to each treatment arm. Median age was 29 years in the risedronate arm and 42 years in the placebo arm (p=0.06). 22 patients had an available 6 month DEXA scan in the risedronate arm and 29 in the placebo arm. Patients on the placebo arm had a greater decrease in BMD at the left hip (mean −0.12) and right hip (mean −0.11) when compared to baseline than patients in the risedronate arm (left hip mean −0.08; right hip mean −0.078) and this was statistically significant (p=0.03 and p=0.04, respectively). There were no significant differences observed in the lumbar spine between the two groups. 11/22 (50%) patients in the risedronate arm were taken off study for significant % decrease in BMD at any site, and 18/29 (62%) patients in the placebo arm (p=0.28). Two patients, 1 in each arm, experienced a vertebral fracture during the first 6 months of chemotherapy. Conclusions: Adult ALL/LL patients receiving high dose corticosteroids with HyperCVAD have profound bone loss and should be monitored for this while receiving chemotherapy. Risedronate significantly reduced bone loss at the hips, but did not have a significant effect at the lumbar spine. Despite treatment with risedronate, 50% of patients had profound bone loss during the first 6 months of chemotherapy, thus a more potent bisphosphonate may be necessary to preserve bone mass, particularly at the lumbar spine. Whether a potent bisphosphonate or an agent such as a monoclonal antibody to RANK ligand will reduce fractures and improve quality of life should be studied in future clinical trials. Disclosures: Hu: Amgen: Research Funding, Speakers Bureau. Cabanillas:Procter and Gamble: Research Funding.

Description: Abstract 3851 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, cytopenias and progressive bone marrow fibrosis. Survival in MF is poor, and effective therapy is lacking. Ruxolitinib (INCB18424) is a JAK1 and JAK2 inhibitor with established clinical benefit in patients (pts) with MF (Verstovsek S. J Clin Oncol 29: [suppl; abstr 6500], 2011) by reducing spleen size and improving MF symptoms & quality of life. Objective: Aim was to identify potential correlates of overall survival (OS) of MF pts receiving ruxolitinib. This study was based on a subset analysis of an open-label single-arm phase I/II trial (INCB18424–251; NCT00509899). Methods: 158 adult pts with primary or secondary MF were enrolled in the parent trial; most received ruxolitinib at doses of 10–25 mg PO twice daily. This updated analysis focuses on 107 pts enrolled at MDACC: 63 were high, 34 intermediate (int)-2 and 10 int-1 risk, according to the International Prognosis Scoring System (IPSS), and assesses their survival and correlates thereof. For log-rank survival analysis, events were censored at the later of last dose, last visit, or last follow-up date. Results: Efficacy and safety findings of the parent trial have been published (Verstovsek S. N Engl J Med 363:1117, 2010): ruxolitinib treatment led to a rapid and sustained reduction in splenomegaly and improvements in MF symptoms; anemia and thrombocytopenia were the most common adverse events. After a median follow-up of 32 months, 58 of 107 pts (54%) were still receiving therapy. The corresponding overall survival (OS) was 69% (33 pts died, none due to therapy-related reasons: 14 while on therapy/within 30 days (d) of discontinuation (dc), and 19 off-study). Accounting for deaths occurring on the study, the 2-yr actuarial survival of int-2 and high-risk pts was 92% and 88%, respectively. However, the 2-yr survival of 13 int-2 and 21 high-risk pts who had discontinued therapy and were subsequently followed was 32% and 21%, respectively. MF transformed to acute leukemia in 9 pts: 5 while on therapy/within 30 d of dc, and 4 off-study; the transformation rate was 0.036/pt years. Pts with normal baseline cytogenetics did not have better survival than those with aberrations (Hazard ratio [HR]=1.52; p=0.24). However, pts with a baseline bone marrow fibrosis score of 2 had greater survival than those with a score of 3 (HR=2.21; p=0.031). Other evaluable baseline pt characteristics (gender, age, anemia, WBC and splenomegaly, did not affect survival. Surprisingly, high-risk pts (per either IPSS or dynamic IPSS [DIPSS]) did not have significantly worse survival than int-2 pts. Importantly, reduction in palpable spleen length while on ruxolitinib was noted to be the most robust predictor for survival: pts who had a ≥50% reduction in spleen size (n=62) had significantly prolonged survival vs. those with a

Description: Abstract 1516 Background: Sorafenib is a potent inhibitor of FLT3 kinase with demonstrable clinical activity in patients with acute myeloid leukemia (AML) and FLT3-ITD mutation, but not those with FLT3-D835 mutation. Objectives: To determine the long term outcome of patients with AML treated with the combination of Sorafenib, cytarabine and idarubicin, and in particular those with FLT3-ITD mutation. Method: Between October 2007 to March 2010, 62 patients with newly diagnosed, previously untreated AML, were treated with Sorafenib 400 mg orally twice daily (BID) for 7 days, cytarabine 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if 〉 60 years of age), and idarubicin at 12 mg/m2 IV daily for 3 days on an IRB-approved clinical trial. After achieving remission, patients received up to 5 cycles of consolidation with sorafenib 400 mg BID continuously and abbreviated doses of cytarabine and idarubicin given at approximately one month intervals. Results: 62 patients were treated on the phase II portion of the study. Median age was 53 years (range, 18 – 66) and 12 (19%) patients were 〉 60 years. 23 (37%) had FLT3 mutations including 17 with FLT3-ITD, 4 with FLT3-D835, and 2 with both mutations. Cytogenetics was diploid in 36 (58%), chromosome 5 and 7 deletion in 4 (6%) and 1 (2%) respectively, complex in 8 (13%), miscellaneous in 13 (21%). Median white blood cell count (WBC) at diagnosis was 7.25 × 109/L (range, 0.6 – 225), and 28 (45%) patients had WBC 〉 10 × 109/L; among these, 12 (43 %) had FLT3-ITD. After induction, 49 (79 %) patients achieved CR and 5 (8%) CR with incomplete platelet recovery (CRp). 1 (2%) patient died before response assessment could be performed and 7 (11%) were non responders. Patients with FLT3-ITD were more likely to achieve a CR/CRp than patients without FLT3-ITD [18/19 (95%) patients vs. 36/43 (83%) patients, respectively (p=0.23)]. To date, 32 (59%) of the responders have relapsed including 10 of 18 (56%) patients with FLT3-ITD and 22 of 36 (61%) patients without FLT3-ITD (P=0.86). 35 patients received salvage therapy; 14 died after receiving salvage therapy, 11 achieved a second CR and 10 were refractory. After a median follow up of 40.6 months (range, 5.7 to 50 months), the median DFS and OS were 13 months and 29 months, respectively. Hematopoietic stem cell transplantation (HSCT) was performed in 34 (55 %) patients, including 23 in CR, and 11 with active disease. Stem cell source was from related donors in 15 (44%), unrelated donors in 9 (26%), cord blood in 7 (21%), and haploidentical donors in 3 (9%) patients. Overall, 35 (56%) patients have died; 16 (26%) had infectious complications, 12 (19%) multi-organ failure, 9 (15%) graft versus host disease, and 10 (16%) other causes with some patients having overlapping causes. Three-year disease free survival (DFS)(in patients achieving CR, n=54) and overall survival (OS) (n=62) were 34% and 47%, respectively (Figures 1 and 2). Conclusion: Combination of sorafenib, idarubicin and cytarabine is an effective regimen with durable responses in patients with newly diagnosed AML, particularly those with FLT3-ITD. Disclosures: Ravandi: Bayer: Research Funding; Onyx: Research Funding.

Description: The main therapeutic challenge in the treatment of Acute Lymphocytic Leukemia (ALL) is the development of strategies aimed at overcoming resistance to chemotherapy. Interactions between leukemia cells and microenvironment promote leukemia cell survival and confer resistance to drugs commonly used to treat ALL. Recent reports indicate that the endosteum at the murine bone-bone marrow (BM) interface is hypoxic, and data in a rat model demonstrate that leukemic cells infiltrating bone marrow were markedly hypoxic compared to cells in bone marrow of healthy rats. Hypoxia-inducible factor 1α (HIF-1α) is a key regulator of the cellular response to hypoxia. To characterize expression and function of HIF-1α in the bone marrow from ALL patients, HIF-1α expression was analyzed by immunohistochemistry in the bone marrow specimens from 16 newly diagnosed patients with pre-B ALL. HIF-1α was found to be expressed in 10/16 samples tested (62.5%). Of the 16 patients, 5 patients subsequently relapsed, all of which have expressed HIF-1α at diagnosis. No relapses were seen in the 6 patients with negative HIF-1α levels at presentation. To examine the molecular mechanisms of survival of leukemic cells growing under hypoxic conditions of bone marrow microenvironment, we established a co-culture system of pre-B ALL cells with BM-derived mesenchymal stem cells (MSC). Culture of REH cells under hypoxia (1% O2) resulted in induction of HIF-1α protein which was further increased in leukemia/stroma co-culture. Exposure of cells to hypoxia resulted in robust activation of AKT phosphorylation in leukemic cells. We have recently demonstrated that rapamycin analogs inhibit AKT signaling in AML cells via inhibition of mTORC2 formation (Zeng et al., Blood 109:3509-12, 2007). Likewise, mTOR inhibition by RAD001 completely blocked HIF-1α and pAKT in REH cells. Importantly, REH cells co-cultured with MSC under hypoxia/high glucose environment exhibited significantly lower apoptotic rates (p=0.02) and growth inhibition (p=0.002) in response to vincristine, and these effects were reversed by mTOR blockade with RAD001. We have further demonstrated that inhibition of mTOR signaling reduced expression of the glucose transporter Glut-1 and diminished glucose flux, decreased glycolytic rate and ATP production, both in leukemic cell lines and in primary ALL blasts (n=8). This was associated with decreased mitochondrial membrane potential and inhibition of the hypoxia-induced hexokinase (HKII) in the mitochondrial fraction of ALL cells. In summary, data suggest that mTOR/AKT signaling critically controls HIF-1α expression and function in ALL cells studied under the hypoxic conditions characteristic of bone marrow microenvironment. Hence, mTOR inhibition or blockade of HIF-1α-mediated pro-survival signaling events may reverse microenvironment-mediated chemoresistance and improve clinical outcomes in ALL.

Description: Early results of the fludarabine, cyclophosphamide, and rituximab (FCR) regimen in 224 patients showed that it was highly active as initial therapy of chronic lymphocytic leukemia. In this report, we present the final results of all 300 study patients at a median follow up of 6 years. The overall response rate was 95%, with complete remission in 72%, nodular partial remission in 10%, partial remission due to cytopenia in 7%, and partial remission due to residual disease in 6%. Two patients (〈 1%) died within 3 months of starting therapy. Six-year overall and failure-free survival were 77% and 51%, respectively. Median time to progression was 80 months. Pretreatment characteristics independently associated with inferior response were age 70 years or older, β2-microglobulin twice the upper limit of normal (2N) or more, white cell count 150 × 109/L or more, abnormal chromosome 17, and lactate dehydrogenase 2N or more. No pretreatment characteristic was independently associated with decreased complete remission duration. The risk of late infection was 10% and 4% for the first and second years of remission, respectively, and less than 1.5% per year for the third year onward. In a multivariate analysis of patients receiving fludarabine-based therapy at our center, FCR therapy emerged as the strongest independent determinant of survival.

Description: Existing prognostic models for myelofibrosis (MF) are based on complete blood count parameters and clinical symptoms at the time of initial presentation, with the most widely cited being the Lille score (Blood 88.1013). These models, however, are only applicable to patients at the time of initial diagnosis, and they do not identify the patients at imminent risk of death. In order to identify patients in advanced phase (AP) MF that may be candidates for intensified therapy, we reviewed the records of 371 MF patients for disease features that predict for survival less than twelve months. Median baseline characteristics (range): age 63 yrs (24–86); male 59%; post-PV or post-ET MF 21%; spleen 5cm (0–30); HB

Description: Background: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic neoplasms demonstrating clonal proliferation of myeloid precursors and is typically a disease of older adults. In acute lymphoblastic leukemia (ALL) adolescent and young adult (AYA) patients (pts) have a distinct outcome, possibly influenced by type of therapy (i.e., usually better with more intensive regimens). There is little information about outcome of AML in AYA. Aims: To define the characteristics and outcome of AYA pts with AML treated at MDACC. Methods: We retrospectively analyzed the data of all pts with AML treated at MDACC from 1965 to 2008. Those aged 16 to 21 years were defined as AYA. Results: Among 3934 adult pts seen during this period, 163 (4%) were AYA. The median age was 19 yrs. These included 27 (17%) pts with Core Binding Factor (CBF)-AML [inv(16), t (8:21)]and 19 pts (12%) with acute promyelocytic leukemia (APL). Among other evaluable pts, 50% had diploid cytogenetics, 39% miscellaneous changes, and 11% 5-and/or 7- abnormalities. Antecedent hematologic disorders were present in 33 (20%) and AML was a secondary malignancy in 6%. Among 20 evaluable pts, FLT3 ITD was documented in 4 and mutation in 2. CR rates were 89% for CBF AML, 79% for APL, and 75% for all others. The median survival for the total group was 88 weeks (wks) with 36% alive at 3 yrs, and median CR duration of 67 wks (30% CR at 3 yrs). Outcome is better for pts with CBF leukemias (3-yr survival 56%, CR duration 49%) and APL (3-yr survival 51%, CR duration 36%) compared to other AML (3-yr survival 28%, CR duration 24%). CR rates have improved from 71% in 1965–84, to 85% in 1985–94 and 83% after 1994. Similarly, overall survival (OS) has increased during the same time periods (3-yr survival 18%, 44%, and 53%, respectively) together with CR duration (3-yr CR duration 21%, 32% and 39%, respectively) as early mortality has decreased (11%, 8%, and 4%, respectively). To compare outcome with older adults, we focused on those with diploid cytogenetics (Table 1): Percentage by age group Outcome 16–21 22–45 46–60 〉60 CR 81 75 68 54 Induction mortality 2 11 13 24 3-year survival 46 36 28 16 3-year remission duration 39 32 30 22 Conclusion: The outcome of AYA pts with AML is significantly better than that of older adults with AML. Despite these improvements over time, there is still significant room for improvement in this area, particularly among those with AML other than CBF and APL. Exploration of new treatment options is needed in this patient population.