Melissa L. Larson

Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML.

CPX‐351 is a liposome‐encapsulated fixed‐molar‐ratio formulation of cytarabine and daunorubicin that exploits molar ratio–dependent drug‐drug synergy to enhance antileukemic efficacy.

Aggressive disease defined by cytogenetics is associated with cytokine dysregulation in CLL/SLL patients.

Early treatment of CLL/SLL does not impact survival‐reflecting limitations in detecting progression early and identifying asymptomatic patients likely to benefit from early treatment. Improved understanding of CLL/SLL biology would identify better prognostic/predictive markers. This study attempts to address these issues by determining the relationship between cytokine aberrations and poor clinical outcomes in CLL/SLL in the context of a genetic–based prognostic model. Fifty‐nine serum cytokines/chemokines were measured in 28 untreated CLL/SLL patients. Patients were stratified as GR or int/PR using cytogenetics. Comparison of CLL/SLL with 28 HCs revealed increased expression of Th2 cytokines (IL‐10, IL‐5, sIL‐2Rα; P≤0.01) and decreased levels of Th1 cytokines (IL‐17, IL‐23, IFN‐γ; P≤0.003). In a multivariate analysis of GR versus int/PR groups, differential expression of sIL‐2Rα maintained significance with increased expression in int/PR CLL/SLL. With median follow‐up of 54.3 months after diagnosis, four patients incurred disease progression, with an IL‐17/sIL‐2Rα model predicting need for treatment in all cases. In summary, specific cytokine signatures are associated with genetically defined aggressive disease and predict need for therapy. This suggests utility in detecting disease progression early, identifying those likely to incur a survival advantage with early treatment, and directing future therapy.

Granulocyte-macrophage colony stimulating factor-induced immune priming of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab chemoimmunotherapy in previously untreated patients with diffuse large B-cell lymphoma and mantle cell lymphoma

Abstract Granulocyte-macrophage colony stimulating factor (GM-CSF) has been shown to enhance CD20 antigen expression, augment antibody-dependent cell-mediated cytotoxicity, and stimulate immune cell proliferation. This may lead to an improved anti-tumor effect of rituximab while reducing the severity of chemotherapy-induced myelosuppression. We evaluated the safety and efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in sequential combination with GM-CSF priming and rituximab in previously untreated patients (n = 39) with diffuse-large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). CHOP was administered every 21 days on day 1, GM-CSF 250 μg/m2/day on days 9 through 15, and rituximab 375 mg/m2 on day 15 of each cycle. The overall response rate was 87%, with complete response in 64%. At a median follow-up of 84.3 months, the overall and progression-free survival rates were 54% and 49%, respectively. The most common toxicity was myelosuppression. Sequential combination of CHOP with GM-CSF priming and rituximab was feasible and effective, warranting further evaluation.

Clofarabine: a new treatment option for patients with acute myeloid leukemia

Clofarabine is a rationally designed, second-generation deoxyadenosine analog that incorporates characteristics of two other purine analogs, fludarabine and cladribine. It has shown efficacy in hematologic malignancies such as acute lymphoblastic leukemia, acute myeloid leukemia and myelodysplastic syndrome. It has already been approved for use in pediatric acute lymphoblastic leukemia after two lines of previous therapy. Clinical trials have also shown clofarabine to have activity both as a single agent and in combination with other cytotoxic drugs in adult myeloid leukemia. This compound seems to have efficacy in older patients, as well as those with adverse cytogenetics.

Bone Marrow and Peripheral Blood AML Cells Are Highly Sensitive to CNDAC, the Active Form of Sapacitabine

Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, CNDAC, compared to current chemotherapeutic drugs Ara-C and mitoxantrone using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from AML patients. Cell lines were exposed to compound for 3–6 days and primary cells for 4 days. The viability of primary cells was additionally evaluated 3, 7, and 31 days after removal of tested compound to determine the durability of the response. Our studies indicate that CNDAC and mitoxantrone have a greater impact on viability than ara-C in primary AML cells and AML cell lines. CNDAC is more effective at reducing viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line, which is defined as displaying resistance to ara-C. As sapacitabine has shown in vivo activity at clinically achievable doses, future studies are warranted to assess the potential for combining it with ara-C and/or mitoxantrone, with an emphasis on cells and patients insensitive to ara-C treatment.

Phase 2 study of CHOP‑R‑14 followed by 90Y‑ibritumomab tiuxetan in patients with previously untreated diffuse large B‑cell lymphoma

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.

Impact of insulin-like growth factor 1 and insulin-like growth factor binding proteins on outcomes in acute myeloid leukemia.

Our objective was to explore associations of circulating factors implicated in insulin-like growth factor- 1 receptor (IGF-1R) signaling with clinical outcomes of patients with acute myeloid leukemia (AML). Pretreatment blood samples from patients with non-M3 AML (n = 30) were collected prospectively and levels of IGF binding proteins (IGFBPs) 1–7 and IGF-1 (free and total) were established at diagnosis and statistically evaluated. Baseline levels of IGFBP-1 and -6 below respective thresholds of 8.8 ng/mL and 237 ng/mL were associated (p = 0.0347 and 0.0099, respectively) with superior progression-free survival, whereas baseline levels of IGFBP −1, −2, −6 and −7 below the respective thresholds of 8.8, 28.8, 237 and 119 ng/mL were strongly associated (p = 0.0004, 0.0085, 0.0031, 2.46 × 10− 7, respectively) with improved overall survival. These findings provide promising evidence that IGFBP signatures could be used as predictive tools in AML, with applications in remission surveillance and the development of IGFBP-directed biologic therapy.

The relationship between ehrlichiosis and the development of hematologic malignancies

Viral and bacterial infections cause chronic inflammation and produce bacterial metabolites that may lead to carcinogenesis. Ehrlichiosis is an intracellular infection that primarily infects white blood cells. Given that infections can lead to cancer, and that Ehrlichia has tropism for white blood cells, it can be deduced that Ehrlichia may cause hematologic malignancies, such as acute leukemia. A prospective study was performed that tested the blood of ten patients with acute leukemia for prior exposure to Ehrlichia. The RT-PCR that was performed did not detect Ehrlichia DNA in any of the ten samples. Therefore, based on this small study, one cannot conclude that Ehrlichia can lead to hematologic malignancies.

Abstract 4668: Patient AML cells and AML cell lines are highly sensitive to CNDAC, the active form of sapacitabine

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, 2′-C-Cyano-2′-deoxy-1-α-d-arabino-pentofuranosylcytosine (CNDAC, Cyclacel Ltd, Dundee, UK), as compared to current chemotherapeutic drugs Ara-C (Cytarabine) and Mitoxantrone (Mit, synthetic anthracenedione) using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from 5 AML patients. Methods: Cells lines and AML patient cells were treated in vitro with Ara-C (1-100 µM), CNDAC (1-100 µM) or Mit (0.005-0.5 µM) for 4 days. During treatment, HL-60, THP-1, and PB AML cells were cultured in suspension. BM AML cells were co-cultured with M2-10B4 mouse stromal cells. Cell lines were assessed immediately. BM and PB AML cells were assessed after an additional 3, 7, or 31 days of co-culture on M2-10B4 cells. Treated cells were assessed for sensitivity (cell death by trypan blue and apoptosis by 7AAD/Annexin V) as compared to untreated cells and IC50 values (50% of maximum possible effective response) were calculated. Results: In HL-60 cells, the amount of cell death was greater with CNDAC compared to Ara-C at all doses tested (p≤0.05, n=3). In THP-1 cells, CNDAC and Mit, but not Ara-C, induced a significant apoptotic response. At a 10-fold lower seeding density, which correlates to higher proliferation rates, the response of THP-1 cells to Ara-C, CNDAC and Mit reached significance compared to untreated cells (p≤0.05, n=3). However, the IC50 values for the 3 drugs in THP-1 cells reflect the observation that this cell line is in essence resistant to AraC (IC50 = 7.77 µM) but sensitive to CNDAC (IC50 = 0.929 µM) and Mit (IC50 = 0.003 µM). Using PB AML cells, a significant response to 1 µM CNDAC and 0.005 µM Mit but not 1 µM Ara-C was observed, as compared to untreated cells at all days post drug removal (p≤0.05, n=5). A significantly greater apoptotic response to CNDAC was observed compared to Ara-C at low doses (p≤0.05, n=5). At higher doses, all 3 drugs induced significant cell death (p≤0.05, n=5). In BM AML cells, overall survival with 1 µM CNDAC or 0.005 µM Mit, but not 1 µM Ara-C, was significantly less than untreated cells 31 days post-treatment (p≤0.05, n=5). Higher doses induced cell death (p≤0.05, n=5) with all 3 drugs. Conclusion: Low dose CNDAC and Mitoxantrone induce a greater response than low dose Ara-C in patient AML cells and AML cell lines. CNDAC also exhibits a greater activity in cell lines (THP-1) that are less sensitive to Ara-C. The in vitro sensitivity of AML cells to CNDAC supports the ongoing clinical evaluation of sapacitabine in AML patients. Future studies are warranted to assess the potential for combining sapacitabine with Ara-C and/or Mitoxantrone, with an emphasis on cells and patients insensitive to Ara-C treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4668. doi:1538-7445.AM2012-4668