ASH Meeting Notes
March 31, 2004
by Suzanne Burr
Editor's Note: Many of us have wondered what goes on in the professional meetings where the experts get together to discuss the latest in therapies and technology. For those of us who remain curious about that and for those who simply want to keep up with developments, here is a report prepared by Suzanne Burr on her experience at the ASH (American Society of Hematology) meeting in San Diego in December 2003. As a medical technologist with twenty-odd years experience in hematology, blood bank and flow cytometry, she jumped at the opportunity to attend the ASH conference and what's more, took the trouble to report on her experience. Thanks, Suze!
Forty-fifth Annual Meeting and Exposition, December 6-9, 2003
This is the meeting if you are into hematology. There were people attending and presenting from all over the world. It was a great experience. I took full advantage of the opportunity to attend all the CLL sessions I could and read the abstracts of those that I missed.
The Friday night session I attended was titled ‘Risks and Benefits of Moving toward a Cure in the Treatment of CLL’. It was the least technical and most ‘user-friendly’ of the sessions. It was sponsored by WoltersKluwer Health and Ilex Products, Inc. but they did not promote any products. It consisted of an overview of treatment options and prognostic indicators and highlighted how they are put into practice.
Steven Coutre, MD Stanford University, CA
Dr. Coutre gave an overview of the current therapies, beginning with chlorambucil. He detailed monotherapy and combination therapies, describing dosages and lengths of treatment in various studies and gave the statistics on CR’s, PR’s and OR. It was a good overview of many combinations of treatment regimens and the response rates, depth and duration of remission. Best in show was the latest FCR studies done at MDA. I feel sure they will be presented at the Saturday session in more detail. He also spoke about MRD and how to use follow-up therapy to keep patients in remission. He compared NCI CR and MRD negative responses to different drugs. He also spoke about the redefinition of MRD and how the values have been trending toward zero due to the increased sensitivity of testing methods.
The statistic that stuck with me was that survival time has NOT increased significantly. We have more choices but apparently treatment strategies are not more effective in this important respect.
Andrew Rawstron, PhD Leeds, England
Dr. Rawstron was my favorite. He detailed the work being done on the prognostics front, defining the markers of poor prognosis and methods of testing them. He went into a little detail on the sensitivity of the methodologies and addressed ZAP-70 issues. He explained why ZAP-70 may not correlate but didn’t discount its usefulness, commenting that more research needed to be done. He was a big fan of separating patients and identifying those that would benefit from intensive therapy from those whose disease is truly indolent. He also spoke about clonal evolution. He advocated retesting for markers after therapy. I wondered why he didn’t follow a group of ‘indolent’ patients and test for clonal evolution as WBC increases.
He explained the test methodologies – flow cytometry, FISH, PCR, etc and how sensitive each one is. He spoke about development to make this testing more sensitive down to the very last CLL cell. This also speaks to the definition of CR and MRD. As testing gets more specific, the parameters for remission get correspondingly narrower.
Nicholas DiBella, MD Rocky Mountain Cancer Center, CO
Dr. DiBella is the doctor on the front lines. He presented three case studies of patients with CLL and different treatment scenarios. He considered usage of prognostic indicators and when to get them done. He favored leaving the ‘indolent’ cases alone and testing for CD38 and zap70 if refractory disease becomes a problem. He defended this strategy based on the expense of testing. (I wonder if you can compare the cost of this testing to the cost of poor treatment decisions due to not having this information.)
He mentioned FCR response statistics and a study replacing fludarabine with pentostatin (making it PCR instead). This trial is being conducted by US Oncology network. I believe he also mentioned a study being conducted in Europe on stage A high-risk patients. They are being divided into two groups: one wait and watch and the other FCR. It will be a long-term study. I hadn’t heard about this study and hoped to get more information the next day.
He also favored using Campath. He thought that physicians hadn’t learned how to manage this agent yet, likening the process to the early days of Rituxan. He thinks that since there are more binding sites involved which might make it more useful. (That makes sense but they need to fine tune the dosage and watch for infections.)
David Rizzieri, MD Duke University Medical Center, NC
Dr. Rizzieri is a transplant expert. He complained that patients aren’t referred to him until all else has failed. He thinks that sending patients to him earlier would lead to better outcomes. He prefers the nonmyeloablative method and gave statistics showing less people died from this procedure than the ablative one. He favors identifying high-risk patients as candidates for transplant before they are worn out with rounds of chemotherapy. He has a point but not the statistics with regard to getting ‘patients of last resort’. It’s kind of a catch-22. Who would choose this option given the chance of dying from it if you haven’t exhausted all the other possibilities? But he might well have better statistics if he saw patients that weren’t already suffering from fungal infections, PCP, etc. His area is very cutting-edge, which means he doesn’t have duration of survival statistics that go beyond 2-3 years. This appears to be a promising area. He was the only one to mention the C word. He impressed me as optimistic and very excited.
The first session I attended was about DNA vaccines, peptide vaccines and T-cell mediated therapies: all extremely technical. My understanding is that they are all promising therapies, but new and still being tested. DNA vaccines and T-cell therapies hold the most promise for CLL while peptide vaccines are being researched for AML and CML. They are still working on the best vector, insertion point and delivery mechanisms. I’m sure we’ll be hearing more about these therapies as the kinks are worked out. Some of us will probably participate in the studies.
Freda K. Stevenson, DPhil, FRCPath, Southampton, England
Dr. Stevenson’s presentation on DNA vaccines was not specific to CLL but offers a promising treatment area for malignancies. The goal of vaccination is to stimulate CTL’s (cytotoxic T-lymphocytes) to kill tumor cells. It is preferably given after a round of chemotherapy to eradicate the remaining tumor cells. This approach can incorporate a number of target antigens, thus hoping for eradication of malignant cells and establishment of immune system memory. The discussion focused on delivery methods, delivery sites, whether to target antigens or proteins. Care must be taken not to induce autoimmunity in the patient. These vaccines work best if the patient hasn’t been immunocompromised by too much chemotherapy. The preliminary results of small studies involving patients with follicular lymphoma have been encouraging.
Helen E. Heslop, MD Baylor College of Medicine, Houston, TX
Much attention has been focused on T-cell mediated therapies. The concept of having T lymphocytes target and kill malignant cells is in clinical trials. There are still a number of limitations that must be overcome. These include the establishment of such a population and the persistence of this population over time, elimination of GVHD in the case of transplants and overcoming alloreactivity. It seems to have been most successful in conjunction with stem cell transplants to augment the graft versus leukemia effect and in the case of a viral induced malignancy. Another limiting factor is the source of antigen presenting cells. Various approaches are being investigated. This presentation highlighted a number of studies but focused on none.
My next session was “Biology and Treatment of Chronic Lymphocytic Leukemia”. This was the showcase presentation for CLL. It was divided into three sections; “Unraveling the Biology of CLL”, “Immune Biology and Therapy of CLL” and “Do We Have the Tools to Cure CLL”?
Nicholas Chiorazzi, MD North Shore-LIJ Research Institute
“Unraveling the Biology of CLL”
Dr. Chiorazzi was the presenter though there were many names in the program book. He began with one common misconception: B-CLL cells are antigenically active and mature; not immunologically incompetent and immortal as was previously thought. A very technical explanation followed. To oversimplify, B-CLL cells express antigens on their cell surface, may respond to antigenic stimulation, and have telomere shortening which indicates ongoing cell division. Clonal evolution is an indication that these cells are actively dividing not merely accumulating. He further explained zap70 and cd38 testing and went into the significance of the mutational status of the IgV gene and how it relates to survival statistics. The genetic deletions i.e.,13q14, 17p13, that take place in CLL were briefly discussed. More attention was given to the theory that certain B-cell receptors (BCR) are responsible for the development of CLL. (I much prefer the theory of ‘one cell gone bad’ but it is probably not as simple as that.)
Thomas J. Kipps MD, UCSD
“Immune Biology and Therapy of CLL”
Dr. Kipps began his lecture with statistics on the incidence of CLL-like cells in the general population. ZAP-70’s role in the progression of CLL was next. He continued where Dr. Chiorazzi left off and ended with the speculation that BCR signaling capacity may be a more reliable prognostic indicator than mutational status. He spoke about the role that nurse-like cells play in protecting CLL cells from apoptosis. This is accomplished by mechanisms that require cell-to-cell contact. Interruption of one of these mechanisms was proposed as a possible means of treatment of the disease. He postulated that these nurse-like cells may be protecting CLL cells in lymph nodes from Mab therapeutic agents. He reviewed monoclonal antibodies available as treatment and the effectiveness they bring to CLL therapies. Campath was credited with the ability to clear p53 negative cells; hence its usefulness in treating MRD. Briefly mentioned were new monoclonals under development (anti-cd23, anti HLA-DR and anti-cd25). He ended with a synopsis of the development of vaccines and activated T-cell therapy. He mentioned studies that were underway but gave no statistics.
Michael J. Keating, MB, BS MD Anderson Cancer Center, TX
“Do We Have the Tools to Cure CLL?”
Dr. Keating began by defining aggressive and non-aggressive forms of the disease based on prognostic indicators such as mutational status, cd38 and beta-2-microglobulin. He reviewed the definition of complete remission and how it has narrowed over the years. He proposed that the criteria to use now for minimal residual disease (MRD) should be flow cytometry and PCR negativity.
To achieve these complete remissions, four ‘tools’ were offered: chemotherapy, monoclonal antibodies, chemo-immunotherapy and stem cell transplants. Chlorambucil was the original chemotherapy drug of choice but is now being replaced by Fludara. Fludara offers a higher rate of complete remissions. Combinations of fludarabine and cyclophosphamide and fludarabine, cyclophosphamide and mitoxantrone are now being studied and compared to just fludarabine. The combinations appear to have better response rates. The monoclonal antibodies Rituxan and Campath are being studied to bring maximum effectiveness to CLL patients. Rituxan has good response rates for previously untreated patients. Campath has had success in fludarabine refractory patients. Subcutaneous administration has been very effective. Campath has been effective in managing minimal residual disease. A combination of chemotherapy with monoclonals has given the best CR and OR rates yet. Fludara, cyclophosphamide and Rituxan (FCR) is the classic example with a 95% OR and 69% CR in a study at MD Anderson. Currently under study is the combination of Campath with fludarabine. Stem cell transplants, allogeneic or autologous, are the final therapy choice. They are reserved for relapsed patients. The survival rates for ablative and non-ablative are similar, at approximately 40%.
He tied it together with the therapy choices. He was upbeat and convinced that we can effect a cure by using combination therapy combined with stem cell transplant for patients with aggressive and refractory disease. He, too, favors the non-ablative technique right after therapy as the best chance for a CR (the other C word). Achieving MRD negative status is key to long term survival. Cure? Not yet, but wider therapy options will hopefully result in longer survival times for relapsed patients.
I attended a session on ZAP-70/Mutational status. A number of papers were presented investigating the correlation of ZAP-70 to mutational status of the IGVh gene. There were a number of approaches to measuring ZAP-70 and much disagreement about whether this indicator correlates to mutational status. I came away from that session with the feeling that while ZAP-70 will have its use in the diagnosis and staging of CLL patients, it may not correlate to mutational status as tightly as we would like. As it is likely that this will be the test that makes it into the laboratory near you, I would like to see large scale studies done to establish ranges within the CLL population.
There were sessions on CLL therapy and biology, but I missed them since I flew home. Being the good Girl Scout that I am, though, I have perused the abstracts and have attempted to summarize them below along with a little editorial comment.
CLL Therapy I and II
Abstract 243: This abstract presented a paper on treatment regimens. Fludara alone was compared to a combination of fludarabine and cyclophosphamide. This study was done by the German CLL Study Group. They found the combination of FC to be more effective than F alone. The incidence of leukocytopenia was more severe in the FC group but not severe enough to preclude it as a better treatment option.
Abstract 244: Another study measured ZAP-70 expression in a different group of untreated patients randomized to receive FC or F alone. Their purpose was to assess different genetic abnormalities to see if ZAP-70 could predict time to treatment in these subgroups. It was found to correlate with the different cytogenetic abnormalities and the conclusion was that they were powerful tools to predict time to disease progression.
Abstract 245: This was a retrospective analysis of two studies comparing survival in groups treated with Fludara monotherapy and Fludara/Rituxan combination. The combination group fared better in overall survival and progression-free survival.
Abstract 246: Ways to turn CLL cells into antigen presenting cells for T-cells to kill were described. The aim of this study is to augment allogeneic stem cell transplants by generating cytotoxic T-cell lines programmed to kill CLL cells, I think. Just reading this abstract left me a little confused as to whether this was meant to augment SCT or as a stand-alone adoptive immunotherapy.
Abstract 247: The next paper presented combined an amphipathic peptide to an anti-CD19 monoclonal antibody and tested it against CLL cells in vitro. This would be a targeted treatment that does not result in T-cell depletion. They reported promising results but this is a very preliminary study. Stay tuned for more advanced studies.
Abstract 248: Results were presented from a phase I study of lumiliximab (anti-CD23 or IDEC-153). Six groups are involved at different intervals or dose escalation. Four of the six groups were analyzed with respect to adverse events and decreasing absolute lymphocyte count. The preliminary results are encouraging. The trial will continue and results will be updated.
Abstract 369: The German study group presented another paper. This one compared therapy with Fludara to Chlorambucil in older patients (>65 yrs). The Fludara group had a better overall response rate and quality of life but had more severe leukocytopenia. Overall, the study concluded that Fludara was a viable alternative to Chlorambucil in older patients.
Abstract 370: Preliminary results of a Phase I/II trial for Xcellerated T cells was presented. Four patients have been treated so far; only one at the second of three dose escalations. The results were encouraging but very preliminary.
Abstract 371: The effect of alemtuzumab (Campath) on minimal residual disease was presented. Patients who had MRD after chemotherapy were treated with Campath. They found that a course of Campath was most successful in clearing the bone marrow, less successful in lymph nodes and some patients achieved a complete remission.
Abstract 372: Reactivation of CMV following Campath treatment and SCT was the next topic. This paper proposed screening those considered to be at risk. CMV in immunosuppressed individuals can be life threatening and so must be monitored and treated promptly.
Abstract 373: A study from MDACC was presented using previously treated patients and comparing response rates to FP(Fludara/prednisone), FC (Fludara/cyclophosphamide), and FCR (Fludara/cyclyphosphamide/Rituxan). It concluded that the FCR regimen achieved the longest survival rate. This study looked at historical data using older studies and compared them with their results using FCR.
Abstract 374: The next paper produced evidence that cytotoxic action of Rituxan is complement-dependent. The researchers observed a rise in the malignant population shortly after Rituxan infusion. However, these cells exhibited little cd20 in patients formerly positive for cd20. They postulated that these cells may be taken up by phagocytic cells in the liver and spleen, had their Rituxan-complement-cd20 complexes removed and returned to circulation. They postulated that altered treatment paradigms such as lower dose or alternative anti-cd20 could avoid this phenomenon. I don’t think this is even close to being tested.
CLL Biology I and II
Abstract 649: Array-based comparative genomic hybridization (array CGH) was used to investigate chromosomal abnormalities in CLL patients in the hope of finding additional prognostic markers. The results were compared to FISH analysis for reference. The researchers are investigating 14q32 deletion in patients with a deletion at 13q14 as having prognostic significance.
Abstract 650: The next study presented studied the VH gene structure and light chain rearrangement. It was way too technical for me but I think the essence of the research was that they have identified a variant of the VH gene that is associated with poor prognosis. They gave statistics associated with this variant and postulated that there was antigen involvement. I have no idea what the significance of this antigen involvement would be.
Abstract 651: Antigen involvement was also the theme of the next paper presented. I was hoping for clarification on the subject but this one, too, was beyond me. They studied the genetic structure of a group of patients with stable CLL. That was about all I got out of reading the abstract.
Abstract 652: Proliferation centers (lymph nodes and bone marrow) were studied to characterize the cells involved. They described the characteristics of these cells in this paper and postulated that better understanding of this mechanism of CLL proliferation could lead to therapies that interrupt this process.
Abstract 653: The next paper dealt with genetic subgroups. They studied the subgroups of the disease (13q-, 17p-, etc.) to see if they could identify common genes. In turn, they hope to identify common pathologic mechanisms.
Abstract 654: This study tried to ascertain whether monoclonal B cell populations are a normal aspect of aging. They studied a group of over 65 patients and phenotyped their B cells. They found clonal abnormalities in approximately 4% of these patients with no presence leukocytosis or lymphocytosis. They need to ascertain whether this is a normal aspect of aging or a premalignant state in this group of patients.
Abstract 655: This paper focused on familial CLL. It was a retrospective study of 549 patients with regard to the incidence of all types of cancer found in their immediate families. It is not stated in the abstract how the rates quoted compared to the general public.
Abstract 656: This paper asks the question “What level of disease is clinically relevant?” Their answer is that progression, not the level at initial presentation is what matters. This answer comes in the face of better technology that is able to detect smaller and smaller population of cells. This paper also seems to be a counterpoint to the one above that sought to ascertain whether monoclonal B-cell populations are a normal aspect of aging. This paper followed a group of patients that presented with a small population of CLL cells that were less than the NCI definition of absolute lymphocytosis in CLL. They concluded that the lymphocyte count was less important than the phenotype of the cells.
Abstract 809: This study looked at some of the research necessary to develop vaccines. It dealt with cytotoxic T-lymphocytes (CTL) and the properties of the peptides to which they will respond. I believe they were looking at small structures that can be incorporated into immunotherapy but it was too technical for me.
Abstract 810: Stat3 is a protein that is associated with poor prognosis in hematological malignancies. This paper described work done to find an inhibitor to prevent stat3’s activation. The initial work appears promising but again, preliminary.
Abstract 811: Signaling pathways that affect apoptosis were described in this paper. That is all I really gleaned from this highly technical piece.
Abstract 812: This paper described a study in which patients are infused with autologous B cells that have an adenovirus that codes for cd40-ligand attached. These patients experienced a drop in leukemic cells within a few days of infusion. The remainder of the paper describes the process by which apoptosis is thought to be induced.
Abstract 813: This paper studied the effect of different antigens on B-cell CLL and normal B-cell samples. They found a difference in the way each responded to different antigenic stimuli.
Abstract 814: The abnormalities associated with T-cells from CLL patients were enumerated. Analysis compared T cells from normal individuals and those with CLL. It was postulated that these abnormalities were in response to substances released by CLL cells. Ways to repair immune function need to be investigated.
Abstract 815: XIAP, or X-linked inhibitor of apoptosis protein, was the subject of this paper. Resistance to apoptosis is controlled by these proteins. Reading the abstract gave me very little information that I could use. It was highly technical in an area in which I am unfamiliar.
Abstract 816: Dendritic cells derived from monocytes are being studied for use in immune therapy. The first step in this process is to determine if they are immunologically competent. This study concluded that they are, after a phenotypic comparison of CLL donors with normal donors. They also showed that T-lymphocytes are capable of antigenic recall when tested with tetanus toxoid in vitro. This has implications for the use of these cells in developing immunotherapy for CLL.