Cancer Treatment

Hyper CVAD for BUrkitts

Burkitt's/Burkitt-like lymphoma (BL/BLL) are highly aggressive B-cell lymphomas that most commonly affect children, adolescents and young adults. Left untreated, the disease is rapidly fatal.

Standard doxorubicin-based combination chemotherapy, such as CHOP, frequently induces remissions of short duration. The overall CR rate is 915 and induction-therapy mortality was low (6%). The estimated 5-year CR rate was 38% and the estimated 5-year survival rate was 39%. These results were achieved despite broad entrance criteria (no exclusions by age, performance status, organ dysfunction, or infection status at the time of diagnosis). Median age was 39.5 years, about 10 years higher than that of subjects in published studies of adult ALL, and 22% of patients were 60 years or older. Outcome was significantly superior with Hyper-CVAD therapy compared with the VAD regimens, in terms of both CR rate and long-term prognosis.
Kluin Nelemans H, Zagonel V, Anastasopoulou A et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 2001; 93: 22–30

K. A. Blum, G. Lozanski, and J. C. Byrd
Adult Burkitt leukemia and lymphoma
Blood, November 15, 2004; 104(10): 3009 - 3020.

S. Smeland, A. K. Blystad, S. O. Kvaloy, I. M. Ikonomou, J. Delabie, G. Kvalheim, J. Hammerstrom, G. F. Lauritzsen, and H. Holte
Treatment of Burkitt's/Burkitt-like lymphoma in adolescents and adults: a 20-year experience from the Norwegian Radium Hospital with the use of three successive regimens
Ann. Onc., July 1, 2004; 15(7): 1072 - 1078.

H M. Kantarjian, S. O’Brien, T. L. Smith, J. Cortes, F. J. Giles, M. Beran, S. Pierce, Y. Huh, M. Andreeff, C. Koller, et al.
Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia
J. Clin. Oncol., February 1, 2000; 18(3): 547 - 547.

Treating biphenotypic leukemia

A minority of acute leukemias have features characteristic of both the myeloid and lymphoid lineages and for this reason are designated mixed-lineage, hybrid or biphenotypic acute leukemias (BAL). There have been difficulties in establishing whether BAL represents a distinct clinico-biological entity due to a lack of objective criteria for distinguishing BAL from acute myeloid leukemias (AML) or acute lymphoblastic leukemias (ALL) with aberrant expression of a marker from another lineage. As such, it is often treated as AML but with some component of treatment being taken from acute lymphocytic leukemia regimens.There is no agreement on how the disease should be treated. The majority of patients receive treatment according to the morphology of the blasts, with either AML or ALL induction. Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias. Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4;11)(q21;q23) or other 11q23 abnormalities. Gleevec can be added in such cases.

Brunning RD, Matutes E, Harris NL, et al.: Acute myeloid leukaemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80.

Aribi, Ahmedet al, Acute leukaemia: a case series.British Journal of Haematology. 138(2):213-216, July 2007.

The role of flow cytometry in diagnosis of acute leukemia

Acute leukemia displays characteristic patterns of surface antigen expression (CD antigens), which facilitate their identification and proper classification and hence play an important role in instituting proper treatment plans. In addition to enzyme cytochemical analysis, multiparameter flow cytometric analysis has become commonplace in most laboratories for that purpose. Aside from identification of blasts, flow cytometry is especially useful in the correct identification of AML MO, differentiation of APL from AML M1/M2, and correct identification of TdT-negative ALL and unusual variants, such as transitional B-cell ALL and undifferentiated and biphenotypic acute leukemias. Distinction between lymphoid and myeloid leukemias, most often made by flow cytometry, is crucially important. Several advances in flow cytometry, including availability of new monoclonal antibodies, improved gating strategies, and multiparameter analytic techniques, have all dramatically improved the utility of flow cytometry in the diagnosis and classification of leukemia.

Flow cytometery is very helpful in a diagnosis of any leukemic condition but is most useful for differentiating different leukemia subtypes. Final diagnosis should never relay on one report alone but should be produced by a consideration of clinical findings and history, examination of the peripheral smear and bone marrow morphology, and, if necessary special stains. Flow cytometery represents one of several sources of information that go into making a secure diagnosis. It should not be relied on in isolation to make a diagnosis.

Does the flow cytometry report give a positive diagnosis of Acute Monoblastic Leukemia?
This report is a strong support to this diagnosis but cannot be used exclusively.

Kaleem, Zahid,  Crawford, Eric, Flow cytometric analysis of acute leukemias: Diagnostic utility and critical analysis of data Arch Pathol Lab Med. 2003;127:42-48

Kaleem Z, Crawford E, Pathan MH, Jasper L, Covinsky MA, Johnson LR, White G.
Flow cytometric analysis of acute leukemias. Diagnostic utility and critical analysis of data.Arch Pathol Lab Med. 2003 Jan;127(1):42-8.

Granulocute Transfusions

Lay Summary: An ssessment of the role of granulocyte transfusions in 2008.

Granulocyte transfusions are requested by clinicians for use in patients with refractory infection or at high risk of developing severe infection (Strauss 2003). Most patients prescribed granulocyte transfusions are those with cancer related neutropenia, who are receiving myeloablative chemotherapy with or without haemopoietic stem cell rescue. Interest in the use of granulocytes remains high (Van Burik & Weisdorf, 2002; Price 2006), and requests for granulocyte components for transfusion have steadily increased in England and Wales during the last five years. This has been driven by publications describing transfusion in neutropenic patients both for therapeutic indications, when they have an infection refractory to antimicrobials (Hubel et al. 2002) and for secondary prophylaxis, in patients who have had severe bacterial or fungal infections previously but who require a further cycle of chemotherapy or haemopoietic stem cell rescue (Kerr et al. 2003, Oza et al., 2006). Recent studies with promising but overall inconclusive results have been reported both in adults (Oza et al., 2006) and children (Sachs et al., 2006).

The exact clinical role for granulocyte transfusions (whether derived from whole blood or collected by apheresis) therefore remains unclear. Potential efficacy including a dose dependent effect has been raised by systematic reviews/meta-analyses (Vamvakas et al. 1996; Vamvakas et al. 1997; Stanworth et al., 2004), and in animal studies. The existing literature is, perhaps not surprisingly, otherwise heavily dominated by case reports and small case series, with the significant attendant risk of publication bias. However, it should be acknowledged that anecdotal evidence of benefit in selected patients from physicians in the UK and abroad can be found, and that a number of very recent publications have again pointed to evidence of benefit, including one study based on biological randomisation - although this study was underpowered to detect an effect on mortality (Oza et al., 2006).

History of stem cell and bone marrow transplantation in cancer and leukemia

The history of stem cell research includes work with both animal and human stem cells. Stem cells can be classified into three broad categories, based on their ability to differentiate. Totipotent stem cells are found only in early embryos. Each cell can form a complete organism (e.g., identical twins). Pluripotent stem cells exist in the undifferentiated inner cell mass of the blastocyst and can form any of the over 200 different cell types found in the body. Multipotent stem cells are derived from fetal tissue, cord blood, and adult stem cells.

A prominent application of stem cell research has been bone marrow transplants using adult stem cells. Among early attempts to do this were several transplants carried out in France following a radiation accident in the late 1950's. Since physicans could not isolate stem cells at that time, they transfused bone amrrow with stem cells in it. Autologous marrow means from the same individual while allogeneic marrow is provided by another individual. A bone marrow transplant between identical twins guarantees complete HLA compatibility between donor and recipient. These were the first kinds of transplants in humans, followed by autologous transplants. It was not until the 1960's that physicians knew enough about HLA compatibility to perform transplants between siblings who were not identical twins. In 1973 a team of physicians performed the first unrelated bone marrow transplant. In 1984 Congress passed the National Organ Transplant Act, which among other things, included language to evaluate unrelated marrow transplantation and the feasibility of establishing a national donor registry. This led ultimately to National Marrow Donor Program (NDWP) a separate non-profit organization that took over the administration of the database needed for donors in 1990. The 1990's saw rapid expansion and success of the bone marrow program with more than 16,000 transplants to date for the treatment of immunodeficiencies and leukemia.

Now that stem cells can be harvested from the blood, stem cell transpalntation has largely replaced bone marrow transplantation, although recent trials have revived an interest in bone marrow trnasplantation and its possible advantages over stem cell transplants. Adult stem cells also have shown great promise in other areas. Stem cell transplant for acute myelogenous leukemia. Philadelphia (PA): Intracorp; 2005. Various p. [50 references]

http://www.emedicine.com/med/topic3497.htm

Buckner CD: Autologous bone marrow transplants to hematopoietic stem cell support with peripheral blood stem cells: a historical perspective. J Hematother 1999 Jun; 8(3): 233-6

Overview of treatment options for acute lymphocytic leukemia

Children with acute lymphocytic leukemia (ALL) who undergo treatment have about an 80 percent cure rate. Newer treatments may soon boost the child cure rate to as high as 90 percent. Adults have around a 40 percent cure rate. Individuals who fall in the adolescent group can be elgitimately treated with children's protocols or as adults.

Induction therapy. The purpose of the first phase of treatment is to kill most of the leukemia cells in the blood and bone marrow.
Consolidation therapy. Also called post-remission therapy, this phase of treatment is aimed at destroying the leukemia cells remaining in the brain or spinal cord. Extra spinal taps and radiation therapy are considered crucial during this phase to decrease the risk of relapse.
Maintenance therapy. The third phase of treatment prevents leukemia cells from regrowing. The treatments used in this stage are often given at much lower doses.

Children with acute lymphocytic leukemia typically receive treatment to kill leukemia cells hiding in the central nervous system during each phase of therapy. This is called central nervous system sanctuary therapy, central nervous system preventive therapy or intrathecal chemotherapy. In this type of chemotherapy, anti-cancer drugs are injected directly into the fluid that covers the spinal cord. The drugs used here are methotrexate and Ara-C.

The three phases of treatment typically take two and a half to three and a half years.  Chemotherapy is the major form of remission induction therapy for children and adults with acute lymphocytic leukemia. It usually lasts about four weeks, sometimes longer.

Children with standard-risk ALL usually receive three drugs for the first month of treatment — vincristine, L-asparaginase, and a corticosteroid such as prednisone or dexamethasone. Children in the high-risk group may also receive an anthracycline drug such as daunorubicin. Adults with ALL receive a similar combination that usually includes vincristine, a corticosteroid and an anthracycline drug.

Some of these same medications are also used in the consolidation and maintenance phases. However, the later phases usually rely on less intensive regimens that don't require staying in the hospital.

Gleevec and stem cell transpalntation is not reviewd in this brief post.

Samuel ED, Sakamoto KM.. Topics in pediatric leukemia--acute lymphoblastic leukemia.MedGenMed. 2005 Mar 7;7(1):23

Redaelli A. A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL). Eur J Cancer Care. 2005;14(1):53-62.

Rowe JM. Induction therapy for adults with acute lymphoblastic leukemia (ALL): results of over 1,500 patients from the international ALL Trial: MRC UKALL XII / ECOG E2993. Blood. 2005;Aug 16

Gleevec for acute lymphocytic leukemia

Lay Summary: There is now evidence that GLeevec is very effective in Philadelphia chromosome positive ALL.

Philadelphia-positive ALL is a very difficult disease to treat successfully. In the recent past, the standard approach was to use daunorubicin/vincristine/prednisone-based induction therapy to achieve remission and then, if the patient was a reasonable candidate and a donor could be found, to perform an allogeneic transplant. Now, the use of tyrosine kinase inhibitor therapy may be altering this strategy. Single-agent treatment with imatinib and probably with dasatinib is fairly likely to achieve hematologic responses, but the likelihood of cytogenetic response is lower.

A study reported by Dr. Kirk Schultz on behalf of the Children's Oncology Group (COG) showed that imatinib mesylate could be given safely in combination with chemotherapy in children with Philadelphia-positive ALL. Patients aged 1-21 with Philadelphia-positive ALL who achieved remission with standard COG induction therapy received an intensive multidrug combination chemotherapy regimen, with introduction of imatinib at 340 mg/m2 for 21 days into an increasing number of treatment blocks in successive cohorts of patients. Patients receiving imatinib had a higher incidence of transaminase elevation in first consolidation and maintenance. However, there were few significant additional increased toxicities compared with historical and contemporaneous controls not receiving imatinib. This appeared to be a feasible combination of a targeted therapy with chemotherapy and will be explored further in subsequent trials.

Dr. Deborah Thomas, a pioneer in the use of imatinib mesylate and chemotherapy in adults with Philadelphia-positive ALL,[11] presented her most recent data at ASH 2007. This is the  Phase II Pilot Study of Intensified Chemotherapy With or Without Allogeneic Hematopoietic Stem Cell Transplantation in Children With Very High-Risk Acute Lymphoblastic Leukemia. The chemotherapy backbone was the MD Anderson standard of hyper-CVAD, which is fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and high-dose ara-C. Although a high rate of remission was achieved historically with the use of this regimen in patients with Philadelphia-positive ALL, disease-free survival was brief. Dr. Thomas and colleagues added imatinib at 400 mg per day on days 1 through 14 to each of 8 courses followed by 12 months of imatinib. In later iterations of her work, imatinib was increased to 600 mg per day on days 1 through 14 for courses 1 through 8, with imatinib being given indefinitely after maintenance was completed. Overall, 52 patients with imatinib-naive or minimally treated Philadelphia-positive ALL received therapy from April 2001 to July 2006. With a 3-year treatment follow-up, there were only 7 relapses (14%); however, 12 patients died. The 3-year remission and disease-free survival rates for the combination compared favorably with hyper-CVAD alone (83% vs 24%, and 55% vs 14%, respectively).

1. Schultz KR, Aledo A, Bowman WP, et al. Minimal toxicity of imatinib mesylate in combination with intensive chemotherapy for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in children: a report of the Children's Oncology Group (COG) AALL0031 protocol for very high risk ALL. Blood. 2006;108:87a. Abstract 283.
2. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407

3. Oliver G. Ottmann and Barbara Wassmann Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia  ASH Hematology 2005

   © 2005 The American Society of Hematology
   

IVIG post transpalntation

Lay Summary: Intravenous gammaglobulin is often adminsitered after bone maroow/ stem cells transplantation to prophylax for infections.

Antibiotics and intravenous gamma globulin are often adminstered for at least 100 days months after transplant to decrease the risk of bacterial infection immediately following transplant. Although there are no randomized studies of this strategy, it is recommended by the joint guidelines of CDC, the Infectious Disease Society of America, and the American Society of Blood and Bone Marow Transplantation. For actually hypogammaglobulinemic patients a higher dose is used than than is standard for non-HSCT recipients because the IVIG

half-life among HSCT recipients (generally 1–10 days) is much

shorter than the half-life among healthy adults (generally 18–23

days) (therefore, the IVIG dose for a hypogammaglobulinemic

recipient should be individualized to maintain trough serum IgG

concentrations >400–500 mg/dl (should monitor trough serum IgG concentrations among

these patients approximately every 2 weeks and adjust IVIG doses

as needed

Stanley C. Jordan, Ashley A. Vo, Mieko Toyoda, Dolly Tyan, Cynthia C. Nast (2005)
Post-transplant therapy with high-dose intravenous gammaglobulin: Applications to treatment of antibody-mediated rejection Pediatric Transplantation 9 (2), 155–161.

Antin, JH. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med. 2002; 347(1):36-42.

http://mmserver.cjp.com/gems/bbmt/7-83.pdf

Photopheresis for graft versus host disease

The use of photopheresis as a treatment of graft-versus-host disease (GVHD) after a prior allogeneic stem cell transplant is based on the fact that GVHD is similar to autoimmune disease in that it too is an immunologically mediated disease. Chronic GVHD typically presents with more diverse symptomatology resembling autoimmune diseases such as progressive systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. It may affect the mouth, eyes, respiratory tract, musculoskeletal system, peripheral nerves, as well as the skin, liver, or gut - the usual sites of acute GVHD.

A 2001 BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment, which offered the following observations and conclusions:

For acute GVHD or chronic GVHD in previously untreated patients, or in those responding to conventional therapy, there were no studies that met selection criteria and reported results of extracorporeal photopheresis, alone or in combination with other therapies. Therefore, it was not possible to draw conclusions concerning the effects of this therapy on health outcomes in previously untreated or responsive patients.
Studies focusing on patients with chronic GVHD unresponsive to other therapies reported resolution or marked improvement of lesions in about 50% of patients.
Three studies reported outcomes for 38 patients with acute GVHD that was refractory to standard treatment with steroids and other immunosuppressive drugs. Patients with Grade IV disease were generally unresponsive to photopheresis. While a single study of 21 patients reported responses in a majority of patients with Grade III disease, the small number of patients in this study was not sufficient to permit conclusions concerning the outcomes of photopheresis for treatment-refractory acute GVHD.

2001 TEC Assessment: Extracorporeal photopheresis for graft versus host disease

Halle P, Paillard C, D'Incan M et al. Successful extracorporeal photochemotherapy for chronic graft-versus-host disease in pediatric patients. J Hematother Stem Cell Res 2002;11(3):501-12

Salvaneschi L, Perotti C, Zecca M et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 2001;41(10):1299-305

Umbilical cord stem cells

Lay summary: Cord stem cells have been shown to be equivalent to other allogeneic cells for transplantation in leukemia but not yet for other diagnoses.

Cord blood transplatation ifs a fairly recent but rapidly becoming established technique for transplnatation in leukemia. The first unrelated cord blood transplantations were performed in children. The first 25 unrelated cord blood transplantations were reported in 1996. Since then a number of reports appeared. This work has been followed by several studies, showing similar results in children. The New York Blood Center reported on 562 cases, 82% children, who underwent transplantation in a variety of centers with differing conditioning regimens and graft-versus-host disease prophylaxis. However, there have been retrospective matched pair analyses. Two studies in the New England Journal of Medicine reinforce the role of cord-blood transplantation in the treatment of leukemia in adults. Although this treatment is not recommended over HLA-matched donors from unrelated donor sources, it is a viable alternative that can be effective. (N Engl J Med. 2004;351:2255-2265, 2276, 2328). Although guidelines ahve not yet listed this alternative, more recent review articles and an editorial state that it is an equivalently effective approach, even in adults. Both reports reinforce the role of cord-blood transplantation in the treatment of adults with leukemia. It is realistic to anticipate that the current results for cord-blood transplantation in adults with hematologic cancers will contribute to more extended use in the coming years.

J. Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Br. Med. Bull., October 5, 2006; (2006)

Karen K. Ballen New trends in umbilical cord blood transplantation
Blood, 15 May 2005, Vol. 105, No. 10, pp. 3786-3792

Vikram Mathews, MD and John F. DiPersio, MD, PhD Stem Cell Transplantation in Acute Myelogenous Leukemia in First Remission: What Are the Options? Current Hematology Reports 2004,