This is Part III of three lengthily posts involving autoimmune diseases and lymphomas. In the Part I post, I focused on a particular autoimmune disease, Lupus erythematosus, its genetic causes and new therapies intended to address it. The Part II post was concerned with the association between Lupus and other autoimmune diseases with lymphomas, what this association is telling us, and the key role of inflammation. Further, I discussed the key role of NF-kappaB, a cell nuclear factor, in autoimmune-related inflammation. This Part III post focuses on lymphomas, their classification, causes, and conventional and emerging therapies for lymphomas. Finally, I include a few comments and speculations about where lymphoma treatments may be going.
Classifications of lymphomas
Lymphoma is a class of cancers that originates in lymphocytes (particularly, T cells and B cells) of the immune system(ref). One such cancer is Hodgkin’s disease, named after the person who discovered it, and there are 16 other lymphoma cancers known as non-Hodgkin lymphomas (NHL’s). These can affect either T cells or B cells. A classification of NHLs listing the general properties of each can be found here. B cell lymphomas represent about 85% of occurrences of NHLs including those that emerge in patients with autoimmune dysfunctions. “The principal functions of B cells are to make antibodies against antigens, perform the role of Antigen Presenting Cells (APCs) and eventually develop into memory B cells after activation by antigen interaction. B cells are an essential component of the adaptive immune system(ref).” “The human body makes millions of different types of B cells each day that circulate in the blood and lymphatic system performing the role of immune surveillance. They do not produce antibodies until they become fully activated. Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is a membrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell encounters its cognate antigen and receives an additional signal from a T helper cell, it can further differentiate into one of the two types of B cells listed below (plasma B cells and memory B cells)(ref).” So, there is a lot that can go wrong with B cells and their functioning resulting in lymphomas.
The American Cancer Society web site offers excellent summaries of the risk factors for NHL, what is known about causes for NHL, possible preventative measures, and explains treatments, providing information on Surgery, Radiation Therapy, Chemotherapy, Immunotherapy, Bone Marrow or Peripheral Blood Stem Cell Transplantation, Clinical Trials, Complementary and Alternative Methods, Treatment of Specific Lymphomas, and More Treatment Information. This general information is too extensive to repeat here but I touch on a few high points.
Causes of lymphoma
Causes of lymphoma are traditionally viewed as complex and not well understood. There are several known risk factors such as having an autoimmune disease or certain other diseases such as HIV. At the root level, the cause is thought to be involved with DNA errors that are inherited or, in the case of NHLs, mutations or DNA copying errors acquired in the process of living. See the July blog post Gene variations and diseases – far from simple. In that post I said “In some cases gene families are known to indicate increased disease susceptibility, for example as recently reported for non-Hodgkin lymphoma: “Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted(ref).””
According to the ACS web site “DNA mutations related to non-Hodgkin lymphoma are usually acquired after birth, rather than being inherited. Acquired mutations may result from exposure to radiation, cancer-causing chemicals, or infections, but often these mutations occur for no apparent reason. They seem to happen more often as we age, and lymphomas for the most part are a cancer of older people.” – “Translocations are a type of DNA change that can cause non-Hodgkin lymphoma to develop. A translocation means that DNA from one chromosome breaks off and becomes attached to a different chromosome. When this happens, oncogenes can be turned on or tumor suppressor genes can be turned off. Some lymphomas tend to have specific chromosomal defects. For example, most cases of follicular lymphoma have a translocation between chromosomes 14 and 18, which results in the turning on of the bcl-2 oncogene. This stops the cell from dying at the right time(ref).” I expect much more will be learned about the genetics of lymphomas in the next few years and, already, a few genetics-oriented therapies such as targeting the bcl-2 oncogene are in clinical trials.
NHLs vary widely in their etiology, prognosis and available treatment options. For some low-grade lymphomas like Low Grade Diffuse B-Cell Lymphomas and WaldenstrÃ¶m’s macroglobulinemia, there can be good news and bad news for the patient. The good news is that the disease may develop very slowly and not impact seriously on the patient for many years. The bad news is that in several cases there is no good available treatment until the patient takes a turn for the worse. Low-grade disorders may begin to progress rapidly after five to 10 years to become aggressive or high-grade, and at that point effective treatment options could be limited “Taken as a whole, low grade lymphomas (diffuse and follicular, B-cell and T-cell) make up from 20-45% of lymphomas and have a median survival of 5 years or more. Patients are often left untreated until morbidity occurs. While combination chemotherapy usually secures a complete or partial response, the relapse rate is 10-15% per year thereafter(ref).”
Chemotherapy appears to be the mainline traditional approach for treating NHLs, specifically favoring the CHOP and more recently R-CHOP protocols. CHOP consists of four drugs: Cyclophosphamide (also called Cytoxan/Neosar), Doxorubicin (or Adriamycin), Vincristine (Oncovin) and Prednisolone. R-CHOP adds Rituximab.
· Cyclophosphamide “works by slowing or stopping cell growth. It also works by decreasing the immune system’s response to various diseases.” – “Phosphoramide mustard forms DNA crosslinks between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This leads to cell death(ref).”
· Doxorubicin “is a cytotoxic anthracycline antibiotic(ref).” It is used therapeutically against many cancers. “The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication(ref).” The drug has several potentially serious side effects.
· Vincristine is an alkaloid that “ binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types including cancer cells, but also intestinal epithelium and bone marrow(ref). This drug too has potentially serious side effects.
· Prednisolone is a powerful anti-inflammatory. “Prednisolone is a corticosteroid drug with predominantly glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions –(ref)” Again, prolonged therapy with prednisolone can lead to serious side effects.
· Rituximab is a chimeric monoclonal antibody that wipes out B cells by targeting the pan-B-cell surface marker CD20.
Radiation therapy can be useful in certain instances, such as for early-diagnosed low grade localized follicular lymphoma, where it might provide a cure. It can also be used in conjunction with other therapies. Of course, it can have life-shortening side effects.
Stem cell therapy
Recently, stem cell therapies are also being tried as NHL therapies, often in combination with chemotherapies. Normally stem cell therapies involve using hematopoietic stem cells derived from blood or bone marrow and can be of two kinds: autogolous which means using stem cells derived from the patient, and allogeneic which means using cells derived from a donor. There are advantages and disadvantages to each. On the one hand, relapse seems to be a serious issue when using allogeneic stem cells. In one study identifying “Characteristics of relapse after autologous stem–cell transplantation for follicular lymphoma,” looking at the 10-year history of 241 patients, “one hundred and three relapses occurred. The 10-year relapse probability was 47%. Median time from autoSCT to relapse was 20 (2–128) months(ref).” (I comment on this high relapse rate and what will probably be done about it in the future at the end of this post) On the other hand, “Graft-versus-host disease (GVHD) occurs in up to 60 percent of those who have a transplant of blood stem cells — called hematopoietic cell transplantation — from the bone marrow or peripheral blood of unrelated donors. In GVHD, the immune system or T-cells from the donor recognize the recipient’s tissues as foreign and attack(ref).” Various treatments for minimizing the chance of GVHD are under investigation. Sometimes, stem cell therapy may be combined with myeloablative therapy, e.g. a very intense regimen of chemotherapy to destroy all cells that divide rapidly, before transferring in the stem cells.
There is a broad quest underway for improved cancer treatments and cures, and NHL lymphoma is one of the prime targets. A search of clinical trials for treatments on adult NHLs within 500 miles of my home in the National Cancer Institute’s database reveals 243 entries. I note a few of these to illustrate the mix and diversity of what is going on in NHL cancer treatment research.
· This trial, like many others, involves testing combinations of existing chemotherapy agents possibly with additional agents for particular NHL diseases or disease stages: Phase III Randomized Study of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) Versus Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (EPOCH-R) in Patients With Previously Untreated De Novo Diffuse Large B-Cell Non-Hodgkin’s Lymphoma
· Trial of another combination of well-known chemotherapy agents for specific lymphoma conditions: Phase I/II Randomized Study of Bortezomib, Rituximab, Cyclophosphamide, and Prednisone in Patients With Relapsed or Refractory Indolent B-Cell Lymphoproliferative Disorders or Mantle Cell Lymphoma
· One of many trials looking at Rituximab-centered therapy approaches: A Study of Rituximab Alternative Dosing Rate in Patients With Previously Untreated Diffuse Large B-Cell or Follicular Non-Hodgkin’s Lymphoma (RATE)
· This trial looks at a relatively new substance CMC-544 in conjunction with Rituximab. : Study Evaluating CMC-544 Administered in Combination With Rituximab in Subjects With Non-Hodgkin’s Lymphoma (NHL). CMC-544 has previously been shown to be potent against systemically disseminated B-cell lymphoma in mice.
· This trial involves testing a novel monoclonal antibody substances when the patient is refractory to use of a usual one: HuMax-CD20 in FL Patients Refractory to Rituximab
· This trial tests chemotherapy alternatives when used in conjunction with stem cell transplantation, in this case using autologous stem cells: Comparison of Rituxan Versus Bexxar When Combined With Carmustine, Etoposide, Cytarabine and Melphalan (BEAM) With Autologous Hematopoietic Stem Cell Transplantation (ASCT)
· Another study looking at chemotherapy regimens to combine with stem-cell transplantation, allogenic stem cells this time: Tacrolimus/Sirolimus/Methotrexate Versus Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma. The emphasis here is prevention of GVHD.
· Another trial with emphasis on GVHD prevention after allogenic stem cell transplantation is Bortezomib Plus Tacrolimus and Methotrexate to Prevent GVHD After Mismatched Allogeneic Non-Myeloablative Blood Stem Cell Transplantation .
· This trial seems to combine two familiar themes, use of Rituximab and prevention of GVHD: Rituximab for Prevention of Chronic GVHD .
· Fatigue is often an important issue for patients who have undergone intensive cancer chemotherapy. This trial looks at a dietary supplement: Phase III Randomized Study of American Ginseng (Panax quinquefolius) in Patients With Cancer-Related Fatigue. The title is self-explanatory.
· This trial looks at a different “alternative” approach to treating post-chemotherapy fatigue: Acupuncture for the Treatment of Chronic Post-Chemotherapy Fatigue: A Randomized, Phase III Trial
· An early-phase trial of a relatively new potential chemotherapy substance SB-743921: A Study of SB-743921 in Non-Hodgkin’s Lymphoma. Initial clinical findings were recently published(ref).
· Another early-phase trial of yet-another potential chemotherapy agent Phase I/II Study of ABT-263 in Patients With Relapsed or Refractory T-cell or B-cell Lymphoid Malignancies. ABT-263 is an orally bioavailable inhibitor of Bcl-2 family members(ref). This trial is one of several trials concerned with relapsed or refractory lymphomas.
I cannot do justice to all the clinical trials but the list above is illustrative and leads to a few observations:
· A great many of the trials involve alternative combinations of known cancer chemotherapy agents for alternative lymphoma conditions.
· Several trials involve rituximab and other monoclonal antibody therapies, possibly in combination with other conventional chemotherapy agents
· Certain “old favorite” chemotherapy agents show up in the trials over and over again, including prednisolone, rituximab, methotrexate, doxorubicin , mycophenolate mofetil, often variations of R-CHOP or other cancer chemotherapy protocols.
· Stem cell clinical trials for NHLs seem to focus on using chemotherapeutic agents to prevent GVHD in the case of allogeneic transplants and relapses in the case of autologous transplants
· A number of trials are focused on relapsed or refractory lymphomas. Driving these trials is the fact that existing therapies don’t always work and many are subject to relapse.
Comments and speculations
I have no doubt that the existing clinical trials will lead to improved treatment schedules for NHL’s; how much improved I do not know.
My impression is that therapies specifically targeting cancer stem cells have not yet entered clinical trials. As long as cancer stem cells are doing their thing and continuing to differentiate, therapies that mainly kill off normal cancer cells are likely to lead to relapse. See my recent post Update on cancer stem cells and the post On Cancer stem cells.
I speculate that the high rate of relapses in cases of autologous stem cell transplants in treatments of NHLs is due to the fact that the patient’s own stem cells contain the same genetic defects that led to the lymphoma condition in the first place. The transplant takes the patient back to an earlier epigenomic state but the gene-determined cancer susceptibility remains the same. I speculate further that an ultimate therapy might involve restoring selective cells from a patient to induced pluripotent stem cell( iPSC) state, repairing the genetic defect in these iPSCs to remove the cancer susceptibility, and then using these corrected cells for stem cell therapy. This process is described in the August 2009 blog post Treating genetic diseases with corrected induced pluripotent stem cells. I expect at some point to learn about clinical trials of this approach.