ASH 2013

Dr Laurence Cooper talks to ecancer at the 2013 ASH Annual Meeting in New Orleans about using a patient's T cells to target the specific antigen, CD19, to target malignant B cells. This process of gene therapy has a number of issues, including persistence and toxicity. Dr Cooper commented, "One remaining challenge is determining why some patients benefit and others have less durable responses. Does ‘one size fits all’ therapy work or do we need personalised or individualised T cell treatments? Further, we need to extend these studies to other tumour types, particularly solid tumors, to evaluate their potential in other clinical settings.”

Acute promyelocytic leukaemia is a subtype of acute myeloid leukaemia. There has been great success using a chemotherapy free regimen of retinoic acid combined with arsenic trioxide. Dr Mazzarella also discusses chronic vs cure, risk factors such as obesity - which can also influence outcomes - and further investigation of the biology of the disease using mouse models.

Dr Gribben talks to ecancertv at ASH 2013 about a session covering the latest for CLL treatment. This session focused on recent advances in the management of chronic lymphocytic leukaemia (CLL). The most recent, targeted drugs for CLL, as well as therapeutic concepts for elderly, non-fit patients with CLL and immunotherapeutic approaches to achieve long-lasting remissions were discussed. Dr Michael Hallek reviewed the currently available diagnostic and therapeutic tools and give an integrated recommendation of how to manage CLL in 2013, for example use of veltuzumab. Dr Gribben himself reviewed some of the clinical key features of CLL, which induces a state of immunosuppression, causing increased susceptibility to infections and failure of an anti-tumor immune response. Hef further reported the state of the art on allogeneic stem cell transplantation and other immunotherapeutic approaches such as CLL vaccines, CXCR 4 antagonists, adoptive cellular immunotherapies (e.g., chimeric antigen receptor (CAR) modified T-cells), CD 40 ligand gene therapy, and the immunomodulatory drug lenalidomide. Dr Tait Shanafelt discussed how CLL is a leukaemia of advanced age, and how the management of patients with CLL is more complex than in many other malignancies. He addressed several key questions in the management of elderly patients with CLL, including why the classification of the 'fitness' of CLL patients is necessary, what criteria should be used to classify patient fitness, when elderly patients should be treated, how therapy should be selected for elderly patients, and which therapy is best for each individual patient.

Dr Smita Bhatia talks to ecancertv at ASH 2013 about her study: Full-Intensity Transplantation and Short Telomeres Increase The Risk Of Cognitive Impairment After Allogeneic Hematopoietic Cell Transplantation (HCT) – Results Of a Prospective Longitudinal Study. The team demonstrated several new findings in this study: patients receiving full-intensity HCT are at risk for cognitive impairment in executive functioning, processing speed, verbal speed and visual memory; those receiving reduced-intensity HCT are generally spared. In addition, telomeric shortening prior to HCT is associated with poorer executive function, processing speed, verbal speed and working memory in females after HCT, and not males. Identifying vulnerable subpopulations will facilitate implementation of prevention strategies.

Prof Deininger talks to ecancertv at ASH 2013, New Orleans. Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Despite shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy.

Dr Sharman talks to ecancertv at ASH 2013 about the study: "Phase 2 Trial Of GS-9973, a Selective Syk Inhibitor, In Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL)" Spleen tyrosine kinase (Syk) is an essential mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, small-molecule, selective inhibitor of Syk. GS-9973 was generally well tolerated. At the initial 8-week response assessment GS-9973 demonstrated activity in subjects with CLL/SLL, including those with poor prognostic features. Dr Sharman also covers ibrutinib and idelalisib.

Dr Taussig talks to ecancertv at ASH 2013 about his study "Arginine Deprivation With Pegylated Arginine Deiminase Induces Death Of Acute Myeloid Leukaemia Cells In Vivo". Malignant cells require amino acids for a wide range of core functions. Amino acid deprivation using enzymatic degradation has been used to induce remission in acute lymphoblastic leukaemia for decades. Amino acid deprivation may also benefit patients with acute myeloid leukaemia (AML). We have previously shown that AML cells lack of argininosuccinate synthetase 1(ASS1), a key enzyme in the pathway that produces arginine. Here we tested the effect of an arginine depleting agent, pegylated arginine deiminase (ADI-PEG 20) on primary AML cells in a xenograft model of AML. The experiments showed that arginine deprivation by ADI-PEG 20 can decrease the leukaemic burden in mice transplanted with primary AML cells. The combination of ADI with cytarabine had a greater effect than cytarabine alone in half the experiments. These results provide the rationale to test ADI-PEG 20 with cytarabine in clinical trials.

Dr Kalos talks to ecancertv at ASH 2013 about data on an overview of patient response in a clinical research program evaluating treatment of paediatric and adult leukaemia patients with experimental CAR genetically engineered T cells. A series of treatment cohorts were included in the analysis, including paediatric and adult patients with high-risk, treatment-resistant acute lymphocytic leukaemia and adult patients with advanced relapsed and/or treatment-resistant chronic lymphocytic leukaemia.

Dr Furman talks to ecancertv at ASH 2013 about his study: "A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)" Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. This Phase 3 study evaluated the efficacy and safety of Idelalisib plus rituximab vs placebo plus retuximab in patients with previously treated CLL. Idelalisib plus rituximab demonstrated statistically significant improvement with acceptable safety over placebo plus rituximab in PFS, ORR, LNR and OS in heavily pretreated patients with relapsed CLL, including those with adverse genetic features.

Dr Levis talks to ecancertv at ASH 2013 about novel agents for FLT3-ITD positive acute myeloid leukaemia (AML) The relapse rate for FLT3-ITD positive AML is worse than normal AML, and when relapse does occur cure is near to impossible. Activating mutations in the receptor tyrosine kinase FLT3 occur in roughly 30% of acute myeloid leukemia patients, implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin (PKC412) shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Besides its mere presence, the allelic ratio as well as ITD insertion site within the FLT3 gene had been reported as prognostic factors in FLT3-ITD positive AML. Pharmacokinetic analyses revealed clinically important interactions between potent CYP3A4 inhibitors, such as azoles, and midostaurin. Allogeneic transplant remains the best option.

Dr. Stephen A. Grupp talks to ecancer at the 2013 ASH Annual Meeting in New Orleans about results from a group of cell therapy trials using the chimeric antigen receptor (CAR) cell engineering approach to manipulate the T cells of 22 children and five adults with relapsed, treatment-resistant acute lymphocytic leukaemia. After treatment with their own cells re-engineered to seek, attack, and kill leukaemic cells, 24 patients (19 children, five adults) achieved a complete response.

Dr Strasser talks to ecancertv at ASH 2013. Impaired apoptosis is considered one of the prerequisites for the development of most, if not all, cancers, but the mechanisms that guarantee the sustained survival of most cancer cells remain unknown. Members of the Bcl-2 family are key regulators of apoptosis and include proteins essential for cell survival and those required to initiate cell death. Studies with transgenic mice have shown that over-expression of Bcl-2 or related pro-survival family proteins, such as Bcl-xL or Mcl-1, can promote tumorigenesis, particularly in conjunction with mutations that deregulate cell cycle control, such as deregulated c-myc expression. It is, however, not known whether expression of pro-survival Bcl-2 family members under endogenous control is required to maintain the survival of cells undergoing neoplastic transformation. Using Eµ-myc transgenic mice, a well-characterized model of human Burkitt’s lymphoma, we investigated the role of endogenous Bcl-2 in lymphoma development. Bcl-2 was found to be dispensable for the development of Eµ-myc pre-B/B lymphoma. In contrast, loss of Bcl-xL and even, more remarkable, loss of a single allele of Mcl1 greatly impaired lymphoma development. Experiments with inducible knockout mice demonstrated that Mcl-1 but not Bcl-xL is essential for the sustained survival and expansion of Myc-driven malignant pore-B/B lymphoma. Remarkably, even loss of one Mcl1allele greatly impaired lymphoma growth. These findings were translated into using lymphoid malignancies by using inducible expression of selective antagonists of distinct pro-survival Bcl-2 family members. Such studies showed that Mcl-1 is also critical for the sustained survival and expansion of Burkitt Lymphoma, a Myc-driven malignancy. These observations indicate that (even relatively weak) targeting of Mcl-1 may be an attractive strategy.

Dr Miller talks to ecancertv at ASH 2013 about research presented on the increased risk of cognitive impairment with transplantation and short telomeres. While a hematopoietic stem cell transplant (HSCT) is often a lifesaving procedure, previous reports have associated transplant-related chemotherapy and radiation as having a negative impact on cognitive function. Seeking to explore whether transplants – and specifically the intensity of transplant-related chemotherapy and radiation – might be associated with cognitive decline, investigators conducted a prospective study, measuring cognitive function in transplant patients and healthy controls at similar intervals.

Dr Lown talks to ecancertv at ASH 2013. It is well accepted that patients of ethnic minorities who lack a sibling donor are poorly represented on the international unrelated donor panels. As recently as 2000, only 30% of such patients were able to find an unrelated donor suitable for transplantation. Continued expansion of the international donor inventory, and the advent of cord blood and haploidentical transplantation has improved the prospects for transplantation for such patients and, through the expertise of search staff within donor registries and histocompatibility laboratories, transplant centres are increasingly able to identify early on those patients who are unlikely to find a well-matched unrelated adult donor. Surprisingly, however, few contemporary data have been published to show the impact of these search strategies and alternative stem cell sources on provision of transplant to those of non-white Northern European origin. Dr Lown's study has shown that the chance of receiving a transplant for patients of a non-white Northern European (WNE) descent has improved considerably compared to historical literature. The majority of non-WNE patients were able to find a 9 or 10/10 matched donor, and many of those who could not were afforded the option of a cord blood or haploidentical donor transplant within a similar timescale. Whilst times to transplant do remain slightly longer for non-WNE patients, mainly due to a more protracted CT stage, they now stand an equal chance of reaching transplant. However, whether survival following transplant is similar between ethnic groups remains to be seen.

Dr Thierry Facon talks to ecancertv at ASH 2013 about the FIRST trial: Frontline Investigation of Revlimid Dexamethasone Versus Standard Thalidomide. This Phase III trial was designed to compare the efficacy and safety of a combination of two oral drugs, lenalidomide and low-dose dexamethasone (Rd), to a standard combination therapy including melphalan, prednisone, and thalidomide (MPT) used worldwide to treat patients with newly diagnosed multiple myeloma (NDMM). A total of 1,623 NDMM patients ineligible for stem cell transplant due to age or other factors were randomised into three treatment arms: continuous Rd until disease progression, Rd for 72 weeks, or MPT for 72 weeks. After a median follow-up period of 37 months, the study met its primary endpoint by demonstrating that those patients treated with continuous Rd were more than a quarter (28%) less likely to experience disease progression or death than those patients treated with MPT. Further, patients in both Rd treatment arms showed improvements in overall survival, overall response rate, and duration of response. While the safety profiles of the two treatment regimens were similar, patients treated with Rd showed fewer secondary hematologic malignancies than those treated with MPT.