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PROVISIONER'S SELECTION MAY 2001 Gregory I. Berk, MD Cornell Medical College, New York; New York Presbyterian Medical Center Dr. Gregory Berk is an Attending Physician at the New York Hospital-Cornell Medical Center and a Clinical Assistant Professor of Medicine at the Cornell University Medical College. He is Board Certified in Internal Medicine and Medical Oncology. Dr. Berk is a member of the Cancer and Leukemia Group B (CALGB), the American Society of Hematology, and the American Society of Clinical Oncology. Dr. Berk served as a resident and fellow at the New York Hospital-Cornell Medical Center. He earned his medical degree in 1984 from Case Western Reserve University School of Medicine, where he was inducted into the Alpha Omega Alpha honor society. Dr. Berk received his Bachelor of Science from Tulane University, where he graduated Summa Cum Laude. He was inducted into the Phi Beta Kappa Society and was chosen as a Tulane scholar from 1977 through 1980. Prior to attending medical school, Dr. Berk also attended Cambridge University, England, where he was a member of Churchill College. Dr. Berk maintains an active private practice in New York City. He teaches Cornell medical students as well as New York Hospital residents and fellows, and he is also the Associate Director of the Cancer Research and Treatment Fund. Indolent Non-Hodgkin's Lymphoma Indolent non-Hodgkin's lymphoma and its subtypes fall into a class of their own. They are different from other lymphomas in that they are slow-growing. Because physicians do not view the indolent lymphomas as "curable" in the complete sense, the goal of treatment is often "palliative”. This means is that the goal is to extend life for as long as possible and improve the person’s quality of life during that time. In contrast to the more fast-growing (aggressive) lymphomas, indolent lymphoma usually gives the patient and the doctor plenty of time to fully assess the best possible treatment of this disease if one becomes necessary. Also, because of the nature of this disease, there is very much an art to the care of these patients. Each patient is approached individually, even though there are basic principles in the management of all cancer patients. The first step is to determine what type of indolent lymphoma the patient has. Staging of Low-Grade Lymphoma There are several types of low-grade, or indolent lymphomas, (based on the appearance and size of cells found in each group). The initial approach to all of these types of lymphoma, however, is to determine the extent of the disease, what is referred to as "staging." In non-Hodgkin's lymphoma, staging is usually described according to the "Ann Arbor" system. In this system, there are four stages. Stage I (early disease): The cancer is found only in a single lymph node, or in the area immediately surrounding that node, or in a single organ Stage II (locally advanced disease): The disease involves more than one lymph node area on one side of the diaphragm (the breathing muscle separating the abdomen from the chest) Stage III (advanced disease): The disease involves lymph node regions above and below the diaphragm. For example, there may be swollen lymph nodes under the arm and in the abdomen Stage IV (widespread disease): The disease involves one or more organs. Because of the chronic, indolent nature of the disease, most people are unaware that they have cancer and as a result, patients are usually first diagnosed with an indolent lymphoma in the advanced stages—usually stage III or IV. Many patients also have bone marrow involvement (cancer that has spread to their bone marrow). Occasionally, some patients with indolent lymphoma will be diagnosed with lymphoma that has not spread (localized) and is in Stage I. While this is relatively rare, many of these patients can be effectively treated with radiation therapy alone. Treatment Strategies Once the specific stage is determined, the oncologist then prepares a set of treatment goals. The oncologist knows that the goals of therapy must be specific for this patient, and may be quite different from those for patients in different age groups. This is especially true when considering the side effects that are likely to occur with different treatments. Oncologists are always aware of the toxicities of therapy (side effects) and are constantly weighing the benefits of a treatment against its risks. In doing so, the physician will take into account the age of the patient, other medical problems, overall performance status of the patient, and the extent (stage) of disease. As mentioned previously, most patients with indolent lymphoma will have advanced disease. Although cure is not likely at this stage, many patients can still live excellent lives with no therapy; from a health care standpoint, this is called the "watchful waiting" approach. This approach is particularly difficult for some patients to accept: when a patient is told he or she has cancer, the idea that it should go untreated can be very unappealing. However, there are good reasons for this approach. Since this patient may enjoy a long period of time (sometimes many years) without clear progression of the disease or any noticeable symptoms of worsening, and since the cancer therapy would likely cause side effects of its own and is not likely curative, why not wait till the patient really needs treatment? In fact, earlier treatment has never been proven to increase the length of time that patients with this lymphoma survive. The "watchful waiting" approach may be more acceptable for elderly patients who are likely going to have more trouble with chemotherapy. It is particularly difficult to take this approach in younger patients with low-grade lymphoma, such as those in their 30s or 40s. The disease will likely progress in these patients while they are still young, so even though we do not have any information on the advantage of early treatment, oncologists will often treat a younger patient earlier with the hope of some survival benefit. So when is indolent lymphoma usually treated? A physician will treat the disease when patients suffer from large, bulky lymph nodes (adenopathy), as these nodal masses may be hurting normal tissues and organs. The oncologist will also treat low-grade lymphoma if patients are tired all the time (anemic) due to a large number of lymphoma cells in their bone marrow, or when there is significant enlargement of the spleen. Types of Treatments Once a decision has been made to treat the patient, the next decision is which treatment to use for this particular patient. Chemotherapy is usually used, and there are effective regimens that use only one drug, such as cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), fludarabine (Fludara®), or cladribine (Leustatin®). Oncologists will often use a combination of drugs together, especially in younger patients and in those patients where the physician is hoping for a "faster" response. The most common combinations are those referred to by the acronyms "CHOP" (which consists of Cytoxan®, Adriamycin®, vincristine, and prednisone) and "CVP" (Cytoxan®, vincristine and prednisone). The most significant side effect of all these treatments involves a slowing down of the production of normal white and red blood cells in the bone marrow (bone marrow suppression), with subsequent low blood counts. This leads to anemia and increases the risk of infection for the patient. Because of this, many patients are also given blood cell growth factors, such as erythropoietin (Procrit®) or G-CSF (Neupogen®), which can increase the number of blood cells to lessen this toxic effect. Other forms of treatment for low-grade lymphoma include monoclonal antibodies (see related article) and vaccines. Rituximab (Rituxan®) is the first monoclonal antibody approved and is currently being used as part of treatment. Another monoclonal antibody Bexxar® has not yet been approved, but early testing, especially when it is combined with CHOP chemotherapy, shows promising results in the treatment of patients with indolent lymphoma. Lastly, since our own immune system plays a major role in fighting cancers such as lymphoma, the development of lymphoma vaccines has become a major area of interest. Preliminary tests in which patients are immunized against their own lymphoma cells have shown exciting results in the ability to prevent recurrence of disease. Summary The approach to the treatment of the patient with indolent non-Hodgkin’s lymphoma is highly individual. While chemotherapy remains the standard treatment, we are now incorporating biologic therapy (monoclonal antibodies, vaccines) into our treatment plan. Intermediate and High Grade Lymphomas Intermediate-Grade NHL In contrast to the low-grade, indolent lymphoma patients (see related article), patients with intermediate-grade lymphoma have more aggressive disease and all require therapy; nevertheless, intermediate-grade lymphoma is far more curable than indolent lymphoma, and the major goal of treating patients with intermediate-grade lymphoma is cure. There are four recognized types of intermediate-grade non-Hodgkin's lymphoma (NHL), each of which differ in such factors as the kinds of cells involved and how they grow and spread (aggressiveness). By far, the most common subtype is diffuse large cell lymphoma, meaning larger cells spread evenly through the lymph node. Another example would be "follicular large cell", meaning large cells clustered in groups. At present, physicians generally treat all subtypes of intermediate-grade lymphoma the same; therefore, a major area of lymphoma research has concentrated on determining which types should require more intensive therapy than others. Staging The oncologist’s first task in the evaluation of patients with intermediate-grade lymphoma is to determine the extent of their disease, or “stage” of the lymphoma. In non-Hodgkin's lymphoma, staging is usually described according to the "Ann Arbor" system. In this system, there are four stages. Stage I (early disease): The cancer is found only in a single lymph node, or in the area immediately surrounding that node, or in a single organ. Stage II (locally advanced disease): The disease involves more than one lymph node area on one side of the diaphragm (the breathing muscle separating the abdomen from the chest). Stage III (advanced disease): The disease involves lymph node regions above and below the diaphragm. For example, there may be swollen lymph nodes under the arm and in the abdomen. Stage IV (widespread disease): The disease involves one or more organs. The staging evaluation will typically include a physical exam, blood tests, chest x-ray, computer-assisted views (CT scans) of the chest/abdomen/pelvis, and bone marrow examination. Other tests that an oncologist might use to look for tumors or cancerous cells include such specialized tests as gallium scanning, positron-emission test (PET), and magnetic-resonance imaging (MRI). If a patient has central nervous system (CNS) symptoms (like headaches dizziness, or visual abnormalities), a spinal tap will be performed. Treatment Occasionally, patients will be diagnosed with local, or Stage I, disease. If the subtype of the lymphoma is diffuse large cell lymphoma, then the patient is treated with chemotherapy followed by radiation therapy for 3 or 4 “cycles,” with a cycle often meaning monthly treatments. The specific chemotherapy treatment usually given is referred to by the acronym "CHOP" by physicians, and includes Cytoxan®, hydroxydaunomycin (Adriamycin®), vincristine (Oncovin®), and prednisone). This approach results in cure in more than 80% of patients. More often though, patients have more advanced disease, usually stage III or IV, by the time they are diagnosed. Combination chemotherapy, usually CHOP, will again be the treatment used. Many alternative chemotherapy regimens have been used successfully in patients with diffuse large cell lymphoma. These include combination treatments like MACOP-B, m-BACOD, and ProMACE-CytaBOM. However, none of these other treatments has been shown to have an advantage over CHOP. High-risk patients with diffuse large cell lymphoma, primarily those with many tumor cells, are unlikely to be cured by standard therapy. However, many of these patients benefit from treatments given at higher doses (dose-intensive therapy) and bone marrow transplantation. Oncologists are also now beginning to use monoclonal antibody therapies. Two types of monoclonal antibody treatments, Rituxan® and Bexxar® are currently being evaluated for use in combination with chemotherapy. High-Grade NHL A high-grade NHL may often be suspected when patients present with rapidly growing and rapidly spreading disease. The diagnosis is made by taking a biopsy (a sample) of an involved lymph node. The pathologist will examine the specimen under the microscope, paying special attention to the cell shapes, sizes and distribution within the sampled lymph node. There are three different types of high-grade NHL (large cell, immunoblastic; lymphoblastic; and Burkitt’s, small non-cleaved cell). These categories are based on the features of the cells that make up the lymphoma. While these three varieties do have unique features which distinguish them from each other, they are all considered highly aggressive in nature and warrant “intensive” therapeutic approaches. The first type, large-cell, immunoblastic, is initially managed like an intermediate-grade NHL, using similar chemotherapeutic regimens like CHOP. Since it is one of the high-grade types, however, much higher dosages are used (“dose-intensive therapy”). Furthermore, this dose-intensive approach often involves a bone marrow transplant during the course of treatment. The management of patients with lymphoblastic lymphoma, the second type of high-grade NHL, also begins with initial dose-intensive therapy. Following initial therapy, patients often are continued with less intensive treatment regimens, which are given over longer periods of time, usually over two years. This milder, longer course of treatment is called “maintenance therapy”. Finally, the third type, Burkitt’s lymphoma, is again managed with dose-intensive chemotherapy. For this type, successful regimens have been developed for children by the National Cancer Institute (NCI) and the Pediatric Oncology Group (POG), which are organizations which focus on cancer research and treatment. These regimens include high doses of a certain cancer drug called methotrexate. The highly successful results seen in children with lymphoma have been duplicated in adult patients. Oncologists now regard Burkitt’s lymphoma as a highly curable disease.
SELECTION SEP 2000 David A. Bader MD J. Stevan Nagel MD January 17, 1995 Case Presentation: Bone Scintigraphy in Multiple Myeloma A 48 year old male with no significant past medical history fell onto his right shoulder at home. A radiograph was obtained and revealed a pathologic fracture of the proximal humerus through a lytic lesion. A bone scan was requested to evaluate for fibrous dysplasia. Findings: Bone scan revealed no significant activity corresponding to the known fracture site. There were several foci of anterior rib activity and an additional focus of mild to moderate increased activity in the left distal medial femur. Plain films of the ribs and left femur were obtained for comparison at the time of the nuclear medicine study and revealed a diffuse lytic process involving essentially all of the visible bones. The mild increased activity in the left femur on bone scintigraphy activity was noted to correspond to periosteal reaction at a site of pathologic fracture. All of the above imaging findings were consistent with the diagnosis of multiple myeloma. Imaging Technique: A whole body bone scan was performed following the administration of 25 mCi of Tc-99m MDP utilizing 3 hour delayed regional planar images on a Siemens body scan (dual head) with a low energy high resolution collimator. Course: A bone marrow biopsy and aspirate performed at an outside institution revealed markedly hypercellular marrow with increased numbers of plasma cells, including atypical forms, consistent with multiple myeloma. Discussion: Bone scintigraphy is a sensitive and efficient method of measuring metabolic activity of the entire skeleton. Tc-99m labeled diphosphonates are well established in screening for most bony metastatic disease. Bone scanning makes up greater than 1/3 of the procedure volume in most nuclear medicine departments, a large proportion of which is screening for metastatic disease. The role of scintigraphy in evaluation of the patient with multiple myeloma is less well defined. Recent developments which necessitate reevaluation of the role of scintigraphy in multiple myeloma with respect to treatment. Bone scan mechanism of uptake is directly related to blood flow and degree of osteoblastic activity. Autoradiographic studies have shown the deposition of radiolabeled phosphates at sites of osteoid mineralization with Tc-99m labeled bone tracers exchanging with ions in the actively forming hydroxyapatite complex. Bony metastatic disease results in carcinomatous osteodysplasia which refers to a histologic alteration resulting in a variable increase in osteoblasts, osteoclasts, blood vessels, and other stromal tissues. More often than not this will result in increased activity on a bone scan. Over 80% of bony metastases originate from breast, prostate, lung and, much less frequently, thyroid and kidney. The osteoblastic response is less likely with the round cell group of tumors (lymphomas, leukemias, myeloma) and with highly vascular or anaplastic tumors (thyroid and kidney often placed in this category). The round cell group of tumors have been shown to produce osteoclast-activating and osteoblast-inhibiting factors. The highly vascular or anaplastic tumors are associated with very little osteoblastic activity. However, thyroid and renal cell cancer often present with solitary metatases, rapid progression and associated soft tissue masses. Although scintigraphy may be false negative, these tend not to be clinically occult lesions. In addition, one study demonstrated that 42% of radiographically occult renal cell metastases were scintigraphically positive (Cole). Renal cell cancer also has been shown to not uncommonly present as a cortical metastasis, usually scintigraphically positive (Hendrix). Multiple myeloma is the most common primary bone tumor. It is of plasma cell origin, most commonly presents in the 40-70 year age group, female more frequently than male. The radiographic findings are characterized by round, punched out, clean cut areas of destruction with no surrounding sclerosis. However, radiographs may be normal or show only diffuse osteopenia. The sensitivity of radiography versus bone scanning for detecting multiple myeloma has been reported from 75-91% for radiography and 46-60% for scintigraphy (Ludwig, Woolfenden). A Mayo Clinic study (Whaner) concluded that, for multiple myeloma, scintigraphy is of limited value for initial evaluation, adds little additional information to follow-up studies, and, may show limited usefulness in evaluating bone pain with negative radiographs. With respect to the latter, there have been reported cases where a painful region is radiographically negative, scintigraphically positive, and subsequently develops classic lytic changes for myeloma. However, the clinically utility of this has been questioned with regard to radiation therapy because the decision to radiate is clinical, and no difference in effect of treatment has been shown in scintigraphically positive versus negative painful sites (Whaner). A recent case report of the successful palliation of painful multiple myeloma lesions with Sr-89 raises a new issue regarding the role of bone scanning in multiple myeloma (Edwards). The mechanisms responsible for positive scintigraphy in multiple myeloma may be an increase in bone surface area (Whaner), or osteoblastic activity present at the edge of a lytic lesion. The presence of such lesions in patients with myeloma might select a subgroup that will respond to Sr-89 therapy. However, fractures and infractions (local breakdown of trabecular structure) are the more common etiology for osteoblastic activity (Whaner) and pain from fractures will not respond to Sr-89 therapy (Edwards, Silberstein). Conclusions: The role of bone scanning in metastatic disease from the most common primaries remains clear. Bone scanning in multiple myeloma, while not classically done, should be considered in patients who have negative plain films with a clinically painful site. A potential new role for bone scanning in myeloma may also be in predicting response to Sr-89 therapy; however, this role needs further evaluation. References: 1. Ludwig H, Kumpan W, Sinzinger H. Radiography and bone scintigraphy in multiple myeloma: a comparative analysis. The British Journal of Radiology 1982; 55:173-181. 2. Eagel BA, Stier SA, Wakem C. Non-osseous bone scan abnormalities in multiple myeolma associated with hypercalcemia. Clinical Nuclear Medicine 1988; 14:869-873. 3. Robbins S, Cotran R, Kumar V. Pathologic Basis of Disease. Diseases of white cells, lymph nodes, and spleen. W. B. Saunders Company 1988; p. 690. 4. Palmer, Scott, Strauss. Practical Nuclear Medicine. Bone Imaging. W.B. Saunders Company 1992. 5. Woolfenden JM, Pitt MJ, Durie B, Moon TE. Comparison of bone scintigraphy and radiography in multiple myeloma. Radiology 1980; 134:723-728. 6. Juhl JH, Crummy AB Eds. Essentials of Radiologic Imaging, 5th edition. Chapter 4, Bone tumors and related conditions by Rogers, L. J. B. Lipponcott Company, Philadelphia. 1987; pp160-161. 7. Edeiken J, Dalinka M, Karasick D. Roentgen Diagnosis of Diseases of Bone. 4th Edition, Volume 1. Chapter 4. Bone tumors and related conditions. Williams and Wilkins, Baltimore 1990 . 8. Cole AT, Mandell J, Freid FA, Stabb EV. The place of bone scan in the diagnosis of renal cell carcinoma. The Journal of Urology. 1975; 114:364-365. 9. Wahner HW, Kyle RA, Beaubout JW. Scintigraphic evaluation of the skeleton in MM. Mayo Clinic Proc. 1980; 55:739-746. 10. Hendrix RW, Rogers LF, Davis TM. Cortical bone metastases. Radiology 1991; 181:409-413. 11. Edwards GK, Santorno J, Taylor A. Use of bone scintigraphy to select patients with multiple myeloma for treatment with strontium-89. J Nucl Med 1994; 35:1992-1993. 12. Silberstein EB, The treatment of painful osteoblastic metastases: What can we expect from nuclear oncology? (Editorial). J Nucl Med 1994; 35:1994-1995. J. Anthony Parker, MD PhD, Tony_Parker@bih.harvard.edu
PEEK AT PICTURES in turn: AML, ET marrow, HA marrow, IMN, IDA, M-5, MDS marrow, Monocyte phagocytosis and HA, TTP
SELECTION OCT 2001 David G Savage, MD New York Presbyterian Hospital, Columbia University Transplantation for Chronic Myeloid Leukemia Introduction Almost all of the cells circulating in the bloodstream originate from a small population of producer cells called stem cells, which reside primarily in the bone marrow. As all the branches of a plant are derived from their stem, so are the cells of the bone marrow and bloodstream derived from their stem cells. Occasionally a mutation occurs in one of these stem cells giving rise to an abnormal chromosome called the Philadelphia (Ph) chromosome. The Ph chromosome contains an abnormal gene called BCR-ABL, which is grossly unregulated and which causes an immense increase in marrow and white blood cells. This process is the basis of a disease called chronic myeloid leukemia (CML). CML is characterized by a progressive increase in white cells in the marrow, blood and spleen, which becomes enlarged. All of the leukemic cells contain the Ph chromosome and are termed “Ph-positive”. The Ph-positive leukemic cells dominate normal, non-leukemic cells (which are Ph-negative). Although out-numbered, these non-leukemic, Ph-negative cells do persist. The goal of treatment of CML is the suppression or elimination of the Ph-positive leukemic cells and restoration of normal numbers of non-leukemic, Ph-negative cells in the bone marrow and blood. Natural History of CML CML is usually diagnosed in the initial chronic phase, in which the disease is relatively stable and responds to therapy. After a period of about three to six years, the leukemic cells behave more aggressively and the disease evolves into a blastic phase. There may be an intermediate phase of acceleration in which increased treatment doses are needed to control the leukemia. Blastic phase responds poorly to treatment and tends to be fatal within weeks or months. The survival of newly diagnosed patients with CML is typically about five years, but the range is very broad. In some patients with an aggressive form of chronic phase disease, survival may be measured in months. Other patients may live ten years or longer with stable or slowly progressive CML that responds well to drug therapy. Conventional Drug Treatment The two drugs commonly used to treat chronic phase CML are hydroxyurea and interferon-alpha. Hydroxyurea is an inexpensive drug that can be taken by mouth, and which typically returns the blood count to normal, shrinks the spleen, and causes few side effects. In contrast, interferon-alpha is expensive, must be administered by injection, and produces good control in only about two-thirds of patients. The remaining patients fail to respond or are unable to tolerate the drug’s side effects. About one of every four patients receiving interferon-alpha demonstrates a major disappearance of the Ph-positive cells. In about one of every ten patients the Ph chromosome disappears completely. Patients who demonstrate Ph negativity on interferon have a survival advantage of about one to two years over patients receiving hydroxyurea. The addition of a second injectable drug, cytarabine, may provide some further benefit. As interferon-alpha is able to reduce the Ph-positive leukemic cells and improve survival, it is the drug of choice for patients with CML who are unable to undergo allogeneic transplantation of healthy stem cells from a compatible donor. STI-571 (Gleevec) is a new drug that can be taken by mouth and appears to be even more potent than hydroxyurea and interferon. It is not known whether STI-571 prolongs the survival of patients with CML. It is also not known whether its administration might somehow reduce the chance of a good outcome if it is taken before a patient undergoes allogeneic stem cell transplantation. Once CML evolves into the blastic phase, it becomes resistant to hydroxyurea and interferon-alpha. Intensive chemotherapy induces responses in only a minority of patients. Responding patients typically relapse quickly and die in weeks or months because of progressive disease, although there is growing evidence that STI-571 therapy can induce significant remissions in this setting. As blastic phase CML is generally resistant to chemotherapy and fatal, patients are given maximal treatment early in their disease when the leukemia is still in chronic phase and able to respond. In a newly diagnosed patient, the hope is that the leukemia can be cured. Unfortunately, hydroxyurea and interferon-alpha do not cure CML. At the present time, there is no evidence that STI-571 is curative either. The only known curative treatment is allogeneic stem cell transplantation. Allogeneic Transplantation Administration of high dose therapy is one method of reducing the number of Ph-positive leukemic cells and increasing the Ph-negative population in patients with CML. When high dose therapy is given, however, the damage to the bone marrow is so severe that the patient will not be able to survive if nothing more is done. A stem cell transplant given after completion of the high dose therapy will allow the patient to survive the treatment’s lethal effects. Hence, the stem cell transplant rescues the patient. For CML, two types of transplants are possible: allogeneic stem cell transplantation (alloSCT), when cells of another person are used, or autologous (autoSCT), when the patient’s own cells are used. AlloSCT offers the possibility of cure, whereas autoSCT does not. AlloSCT may not be appropriate for patients who are elderly or have other serious conditions (for example, heart or kidney disease), or if their CML is in blastic phase. Finding a compatible donor The patient who is a candidate for alloSCT must have an acceptable stem cell donor. The most suitable donor is a brother or sister who has the same tissue type, which is known as HLA type, as the patient. Potential donors must also demonstrate negativity for HIV and hepatitis viruses. A person’s HLA type is defined by certain molecules on the surface of his or her cells. HLA molecules determine whether cells can be transplanted successfully from one person to another. The HLA type consists of six major molecules, of which three are inherited from each parent. To determine a suitable donor for a patient, HLA typing is performed on blood samples taken from the patient and all his or her siblings. For a given patient and sibling, there is a one in four chance that both will have the same HLA type. If a patient has many siblings, the chance that at least one will be a matched sibling increases. In North America and Europe, because family size is usually small, most patients lack a compatible sibling. Family members who are not siblings have occasionally served as donors with acceptable results. For patients lacking an HLA-matched family member, the transplant physician may initiate a search for a matched donor outside the patient’s family through the large computerized registries of volunteer adult unrelated donors. Such transplants are often effective in younger patients. Allogeneic stem cells can also be collected from the umbilical vein of a newborn baby, then stored for later use in an alloSCT performed in another person. Because the numbers of cells in umbilical cord blood (UCB) are generally small, UCB transplants have been performed predominantly in young patients, including children, with CML. Since most patients with CML are adults and require large numbers of cells in their transplants, UCB transplantation is usually not feasible in CML patients. Potential donors for allogeneic stem cell transplantation: Identical twin HLA-identical sibling HLA-identical or mismatched: other family member volunteer unrelated donor umbilical cord blood Donor stem cell collections Stem cells can be collected from either the donor’s bone marrow or from his or her blood. In current practice, stem cells are usually obtained from the donor’s blood by means of a process known as leukapheresis. Prior to undergoing leukapharesis, the donor is treated with a drug called G-CSF (Neupogen) by daily injection for 5-6 days. Like insulin, G-CSF is a naturally occurring hormone in the body that has become available as a medication in recent years. It stimulates production of white blood cells in the bone marrow and promotes the release of large numbers of stem cells from the marrow into the bloodstream. After five days of treatment with G-CSF, a double-channel intravenous catheter is inserted to collect the blood stem cells. Blood passes out of the donor via one of the catheter’s channels and circulates through a cell separator machine. The fraction of the blood containing stem cells is separated from the blood that is not required for the transplant; the latter blood fraction is then returned to the patient through the catheter’s second channel. Leukapheresis is performed continuously for a period of several hours. Oftentimes the donor is asked to return for a second day of stem cell collection. The stem cells are transfused directly into the patient, or processed and frozen in a specialized laboratory if the transplant is being performed at a later date. After freezing, the cells remain viable for several years. When stem cells are to be collected from a donor’s marrow, the procedure is generally done in an operating room with the donor lying prone on the operating table under general or spinal anesthesia. Approximately one liter of liquid marrow is removed from both sides of the pelvic bone over a period of one to two hours. The marrow is then handled as described for the cells collected by leukapheresis. The primary difficulty with the marrow harvest is the pelvic discomfort that can arise after the anaesthetic wears off; this discomfort usually subsides after a few days. One theoretical concern relative to obtaining stem cells from the blood is that the large doses of G-CSF might stimulate the donor’s marrow cells enough to render them defective. It is conceivable that this could lead to abnormal blood counts and even lead to leukaemia in later years. However, this complication has not been seen in any donor thus far, and recovery after the transplant tends to be faster with blood SCT. For this reason, and because of its convenience and the relative lack of discomfort, obtaining blood stem cells from the donor’s blood is generally preferred over marrow harvesting. Conditioning and transplant Patients undergoing alloSCT are usually admitted to hospital for their preparative conditioning therapy. This consists of very high doses of chemotherapy or chemotherapy combined with radiation. Either type of conditioning is usually given over about six days. The goal is to eliminate the leukemia permanently. The conditioning must also suppress the patient’s immune system such that he or she does not reject the donor’s stem cells at transplant. For the latter reason additional immunosuppressive medication (cyclosporine or tacrolimus) is started just prior to the transplant. These doses of chemotherapy and/or radiation are so high that the patient’s marrow and blood counts will not recover unless the patient receives stem cells as ‘rescue’; failure to receive the stem cells would be fatal. Thus, the stem cell transplant must be given once the chemoradiotherapy has been completed. The transplant procedure itself resembles a blood transfusion. Direct inoculation into the bone marrow is not required. The donor’s cells are brought to the bedside and transfused into the patient intravenously, usually over a period of 30 to 60 minutes. If the cells were previously frozen, they must be thawed. The thawing usually results in a garlic-like odor, which is due to a preservative (DMSO) that is used at the time of stem cell storage. The stem cells have a homing capacity. In other words, they are able to find their way through the bloodstream to the bone marrow cavity where they take up residence. Complications of alloSCT In the two to three weeks following the conditioning therapy, almost all patients develop some degree of sore mouth, nausea, vomiting and diarrhea related to damage to the lining of the gastrointestinal tract. Until the donor’s stem cells have begun making new blood cells, which usually takes about 10-20 days, the blood counts are extremely low. Blood and platelet transfusions are required. As the patient is immunosuppressed, infectious complications are common. A variety of preventive measures (single room, antibiotics) are taken to reduce this risk. Most infections are treatable; occasionally, severe infections (especially fungal disease) do not respond to treatment and prove fatal. Patients may suffer problems directly related to the transplanted cells or ‘grafts.’ That a donor and recipient are “HLA-identical” means that their immune systems are sufficiently similar that a transplant is feasible. Only if they are identical twins, however, will there be no disparity. All other donor/recipient pairs will inevitably be disparate. As a result, when the donor’s cells enter the recipient’s (or host’s) body, the recipient’s immune system may see the donor cells as being foreign and attempt to eliminate them. This is termed the ‘host-versus-graft’ reaction and may lead to graft rejection. It occurs after approximately one percent of HLA-matched sibling alloSCTs, and somewhat more often following mismatched or unrelated transplants. The opposite reaction is ‘graft-versus-host disease’ (GVHD). In this process the donor stem cells grow in the recipient (or host). Accompanying the donor stem cells, however, are donor immune cells called T-cells. These cells may see the recipient’s tissues as foreign and attack them, causing GVHD. Acute GVHD occurs after most alloSCTs, usually in the first 2-6 weeks following the transplant, and affects the gastrointestinal tract causing nausea, vomiting, and diarrhea, the skin, and the liver causing jaundice and bleeding. In most patients GVHD responds to immunosuppressive therapy, such as cyclosporine, tacrolimus, and steroids, but in about 10-20 percent the problem is severe and unresponsive, leading eventually to the patient’s death. GVHD improves for most patients who survive the first 120 days of the transplant. In about 20 percent of patients, however, ‘chronic GVHD’ develops. This condition also tends to involve the GI tract, skin, and liver, but may affect additional organs, such as the eyes, mouth, and lungs, and is sometimes seriously disabling and disfiguring. Chronic GVHD usually responds to treatment, but the therapy may have to be continued for many months or years. Preventive therapy against GVHD Combinations of immunosuppressive drugs are given to prevent GVHD. However, the most effective means of preventing GVHD is ‘T-cell depletion’ of the transplant. In this procedure, after the donor cells are collected as described above, they are then manipulated in the laboratory to remove the T-cell fraction. Unfortunately, T-cell depletion also increases the patient’s risk of graft rejection. Most importantly, T-cell depletion increases the risk of later relapse of the leukemia. Therefore, at most centers, T-cell depletion is reserved for patients at increased risk of GVHD, such as older individuals and those receiving grafts from unrelated or mismatched donors. Results of alloSCT Outcome of alloSCT for CML is determined by several factors. Patients generally have a better outcome if they are: 1) young, 2) undergo transplantation in chronic phase or 3) the first two years following diagnosis, and 4) receive grafts from HLA-matched sibling donors rather than unrelated or mismatched donors. CML can be cured by alloSCT performed while the patient is in chronic phase. Many survivors of alloSCT have normal bone marrows and blood counts for periods that now extend beyond ten years. Such patients have no Ph chromosome. The odds of leukemia-free survival following HLA-matching sibling alloSCT is about 60 percent at five years beyond the transplant. Graft rejection, GVHD and early death are more common in recipients of unrelated and mismatched transplants. However, excellent results have been noted in younger patients transplanted with unrelated donors within one year of diagnosis of CML. Graft-versus leukemia (GVL) effect AlloSCT is thought to cure CML by two mechanisms: 1) the anti-leukemic effects of the high dose chemoradiotherapy and 2) an immunologically mediated ‘graft-versus-leukemia’ phenomenon which accompanies GVHD. As mentioned, donor T-cells may attack the patient’s normal tissues as being foreign, causing GVHD. Similarly, donor T-cells may attack residual leukemic cells (cells that are not killed by pre-transplant chemoradiotherapy), conferring a GVL effect. One of the primary challenges for the transplant physician is to maximize GVL while minimizing GVHD. Minimal residual disease Depending on many factors, relapse following alloSCT occurs in about 20 percent of patients undergoing HLA-identical sibling alloSCT and perhaps 10 percent of those receiving mismatched or unrelated transplants. In patients receiving T-cell depleted grafts, the risk of relapse is 60-80 percent. These different rates reflect the variable potency of the GVL effect associated with different types of transplant: the greater the disparity between donor and recipient, the greater the GVL effect and the less the relapse risk. Relapse typically becomes manifest first by detection of an active BCR-ABL gene in the blood or marrow using a laboratory method called PCR, the most sensitive method of detecting leukemic activity. Subsequently, by different method called cytogenetic analysis and fluorescence in situ hybridization (FISH), Ph-chromosome positive cells are detected. When Ph-positivity reaches 100 percent, the patient demonstrates a high white blood cell count, spleen enlargement, and other features of CML, which may have been present at the original diagnosis. Treatment of relapse There are various approaches to the management of relapse. To unleash potential GVL effects, one might reduce or eliminate immunosuppressive cyclosporine or tacrolimus treatment, allowing donor T-cells to attack the relapsed leukemia. Alternative approaches include STI-571, interferon-alpha or a second allogeneic transplantation. However, the most effective known treatment is the transfusion of lymphoid cells from the original stem cell donor, a procedure called donor lymphocyte infusion (DLI). This approach should not require any chemotherapy or radiation. The efficacy of DLI depends entirely on the GVL effect. DLI induces complete remission in 60-80 percent of patients who relapse into chronic phase. The procedure is most successful when performed in the first two years following allogeneic transplantation for patients whose only evidence of relapse is PCR positivity or detection of the Ph chromosome. Patients in whom relapse is associated with a high white cell count tend to respond less well. Remissions with DLI are more common in patients who develop acute and chronic GVHD following lymphocyte infusion. However, in occasional patients the GVHD is severe and fatal. Numerous groups are attempting to develop methods to maximize the GVL effect while reducing the capacity of the transfused lymphocytes to cause GVHD, but these methods remain relatively experimental. Novel Conditioning Regimens In the past few years it has been demonstrated that donor cells will engraft in their recipients without the prior administration of the standard high doses of chemotherapy and radiation. Several groups have described exciting preliminary results of allogeneic transplantation following conditioning with so-called non-ablative regimens (also termed ‘mini-allografting’ or ‘mini-transplants’). In this procedure just enough chemotherapy or radiation is given to allow engraftment of donor cells, but not so much that major treatment-related toxicity is seen. The goal is to allow engraftment of donor T-cells such that effective GVL will be conferred. Donor engraftment can be achieved in many patients who would not be able to tolerate conventional high dose chemoradiotherapy (for example, patients older than 65 years of age). However, the safety and effectiveness of the procedure are not known, as long-term follow-up observations are not yet available. It is clear that GVHD may occur following non-ablative conditioning. Autologous Transplantation When alloSCT is not advisable, autoSCT is one of several therapeutic options. As discussed, non-leukemic Ph-negative stem cells are difficult to detect but present in patients with newly diagnosed CML. Different investigators have successfully increased normal Ph-negative marrow and blood cell production by administering moderate doses of chemotherapy. AutoSCT allows the hematologist to administer much higher doses of chemotherapy (similar to those used prior to standard alloSCT, as described above). The goal of autoSCT is to increase the Ph-negative state for a longer period. Autologous stem cells may be collected from a patient's blood or marrow in chronic phase, frozen and stored, and used later to reconstitute a patient’s bone marrow and blood after high dose therapy. The theoretical disadvantage of ‘autografting’ such cells is that the original harvest comprises predominantly Ph-positive leukemic cells, so that relapse is inevitable. Nevertheless, many patients recover with partial or even complete Ph-negative marrow and blood. The Ph-negative state usually lasts only weeks or months, but on occasion can be prolonged. How would autoSCT lead to a predominantly Ph-negative state? By some undefined mechanism, the process of freezing, storage, and thawing appears to provide a survival advantage to the Ph-negative stem cells in the original cell collection. In theory, additional manipulations might further eliminate the Ph-positive clone. A variety of methods have been used to ‘purge’ Ph-positive leukemic cells from the blood or marrow. The method of in vivo purging involves treating the patient with drugs (for example, interferon) which increase Ph-negativity in the body; once a Ph-negative state is achieved, marrow or blood cells are harvested, frozen, and stored, then used in a subsequent transplant. In the method of ex vivo purging, the patient does not receive any specific chemotherapy; instead, his or her cells are harvested, then manipulated in a research laboratory (for example, with drugs) to increase the percentage of Ph-negativity. The manipulated cells are then frozen and stored and given back to the patient in a later autoSCT. Many patients have undergone various types of autografting procedures, and some appear to have derived considerable benefit. AutoSCT has the obvious advantage that it does not lead to GVHD. In general, it is a far safer procedure than alloSCT. However, the exact role of autoSCT remains undefined. There is no evidence that autoSCT prolongs the survival of patients with CML. It is quite possible that STI-571, either for in vivo or for ex vivo purging, will increase the effectiveness of this approach, but this has not yet been tested.
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