Cancer Treatment

H. Pylori for lymphoma

H. pylori infection, one of the most common worldwide infections and an important factor linked to the development of peptic ulcer disease, gastric malignancy and dyspeptic symptoms occurs in an estimated 30 percent to 40 percent of the U.S. population. Diagnosis of infection is usually made by checking for dyspeptic symptoms and then doing tests which can suggest H. pylori infection. One can test noninvasively for H. pylori infection with a blood antibody test, stool antigen test, or with the carbon urea breath test.

Nearly all patients with gastric MALT lymphoma are infected with H. pylori, and the risk of developing this tumor is over six times higher in infected people than in uninfected people. Furthermore, up to 80 percent of patients with gastric MALT lymphoma achieve complete remission of their tumors after treatment with H. pylori-eradicating antibiotic therapy.

There are no guidelines that recommend testing for H. Pylori as screening for lymphoma. H. Pylori testing is appropriate for symptoms of peptic ulcer disease or lymphoma but nto screening.

Singapore Ministry of Health. Management of helicobacter pylori infection. Singapore: Singapore Ministry of Health; 2004 Sep. 25 p. [29 references]

Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement Online Jan 7–9;12(1):1-23.

European Helicobacter Pylori Study Group. Current Concepts in the Management of Helicobacter pylori Infection. The Maastricht 2-2000 Consensus Report. Retrieved on September 30, 2006.

Donor lymphocyte infusion to treat chimerism

The donor cell reinfusion in this case is not being used to provide new graft versus leukemia effect but to destroy remaining normal patient cells and to provide engraftment. It ahs been observed that chimerism is risk factor for relapse of the leukemia. The status of DLI to treat disase is still unsettled and the use of DLI to decrease chimerism is even less established. There would have been no objection to a reinfusion of stem cells to re-engraft which I would see as a continuation of the previously approved stem cell transplant. However, using DLI in this fashion is experimental since the contention that it does os is supported by case reports and series only

Because of the large number of acute leukemia patients who relapse after alloBMT, there has been a substantial experience in the treatment of these patients with DLI. Using median doses of >/=108 T cells/kg, DLI alone induces complete remissions in 8% of patients with ALL and 22% of patients with acute myeloid leukemia (AML). When patients who receive chemotherapy prior to DLI are included, complete response rates are significantly higher, ranging from 33% to 37%. However, follow- up of ALL patients reveals few, if any, long-term survivors, although 1 has been reported. Relapse occurs in approximately one quarter to one half of patients with AML in remission after DLI, leaving a long-term survival rate of approximately 10% to 15%.

DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Fewer patients with relapsed myelodysplasia have been treated with DLI. However, because myelodysplasia progresses more slowly than AML, the rate of complete remissions may be higher. The natural history of myelodysplasia patients who enter into a remission following DLI has not been described.

It is not clear whether administration of induction chemotherapy at the time of relapse improves long-term survival following DLI. It is usually thought that it does but without a strong conifrmation in the literature. A randomized trial with analysis performed on an intent-to-treat basis is needed to answer this question.

Litzow, Mark R Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Current Opinion in Hematology. 14(2):130-137, March 2007.

Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.Cancer Control. 2002 Mar-Apr;9(2):123-37.

Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor leukocyte infusion in patients with relapsed acute leukemia using the same donor as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplantation. 2003; 31:1057-1059.

Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002; 20(2):405-412.

E . Orsini , E . Alyea , A . Chillemi , R . Schlossman , S . McLaughlin , C . Canning , R . Soiffer , K . Anderson , J . Ritz Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma . 
Biology of Blood and Marrow Transplantation , Volume 6 , Issue 4 , Pages 375 - 386, 2000

Suradej Hongeng et al, Donor Lymphocyte Infusion Can Eliminate Mixed Chimerism in Nonmyeloablative Stem Cell Transplantation for Correction of Hyper-IgM Syndrome Acta Hematologica Vol. 114, No. 3, 2005

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.

Donor Lymphocyte Infusions (DLI) for CLL

Lay Summary: DLI is well studied in chronic myelogenous leukemia but less so in other hematological conditions.

DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response.
Other hematologic malignancies do not respond to DLI as well as early-stage CM. In general, less than 30% of patients with relapsed acute leukemia,myelodysplasia, and multiple myeloma achieve complete responses to DLI. As many close to half or more of patients who do achieve a complete response may be expected to relapse after DLI. DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Chronic lymphocytic leukemia (CLL) also appears to be responsive to allogeneic donor T cells.However, clinical expereince is limited.  Some patient have obtained a remission following DLI as treatment of persistent disease following alloBMT. Other CLL patients have obtained complete remissions, including molecular complete remissions, following discontinuation of posttransplant immunosuppression. However, there is not much literature credibly supporting routine use of DLI for CLL.

PET to"fish" for a diagnosis

Lay Summary: PET should not be used to "fish" for a diagnosis. On the other hand, when a pathological diagnosis is already established, PET can be useful for follow-up, staging and reassessment after therapy.

PET scanning is an excellent modality to assess tumor size and metabolic activity and it is coming into wider use as supporting data becomes avaialble for various tumor types. Unfortunately, there is no literature to support use of PEt to "fish" for diagnosis when no histologic diagnosis has been obtained. Since lymphadenopathy can be caused by a variety of conditions with different degree of gadolinium uptake and different specificites, sensitivities and accuracies, PET is potentially msileading and even harmful when used in this fashion. A NCT00068146 study is looking at a related question:  the usefulness of FDG-PET scanning in distinguishing autoimmune lymphoproliferative syndrome (ALPS) from lymphoma. Much more investigation will neeed to be done before PET can be used to disitnguish different types of lymphadenopathies.

Ref: http://clinicaltrials.gov/show/NCT00068146

Cook GJR, Fogelman I, Maisey MN. Normal physiological and benign pathological variants of 18-FDG PET scanning: potential for error in interpretation. Sem Nucl Med 1996;26:308–14

Salvage regimens for non- Hodgkin's lymphoma

Lay Summary: I discussed salvage regimens for agressive of intermediate relapsed or refractory lymphoma.

Aggressive non-Hodgkin's lymphoma is difficult to handle once it relapses or becomes refractory to chemotherapy. Various second or third line chemotherapies, which are called salvage chemotherapy, were developed without promising results. Improvement in efficacy by adding relatively new agent, rituximab, to chemotherapy is now widely accepted in non-Hodgkin's lymphoma.

The consensus is that people with relapsed disease should be treated with salvage chemotherapy. The first systematic review identified 22 phase II studies (1210 people overall; individual trials from 20–208 people) using 15 different combinations of cytotoxic drugs for conventional dose second line (salvage) chemotherapy. The most common included drugs were etoposide (20 studies), ifosfamide (14 studies), and methotrexate (11 studies). Other drugs included cisplatin (6 studies), cytarabine (4 studies), mitoxantrone (3 studies), bleomycin (3 studies), and mitoguazone (3 studies). All 22 studies revealed similar results, with second line combination chemotherapy frequently inducing remission in people with relapsed or refractory aggressive non-Hodgkin's lymphoma. The second review also reported the use of rituximab in non-controlled trials (number of trials not reported). The reviews found that overall 60–70% of people with relapsed disease showed objective tumour responses. Complete remission was seen in 20–40% of people. However, these remissions were frequently short lived, with a maximum of 10% of responders remaining disease free after 3–5 years. The authors of the reviews were unable to conclude that any particular salvage chemotherapy regimen was superior to any of the others from the literature reviewed.

There are no randomized controlled trials comparing different conventional dose salvage chemotherapy regimens (PACEBOM, ESHAP, RICE, IVAC) in people with relapsed aggressive non-Hodgkin's lymphoma. The consensus is that people with relapsed disease should be treated with salvage chemotherapy. One systematic review identified 22 phase II trials of various conventional dose salvage chemotherapy regimens. All regimens reported similar response rates and no single superior regimen can be identified. There are likewise no studies confirming or disproving the additive effect of Rituximab but it is a well reported regimen and no clinical trials are currently investigtiong RICE vs ICE chemotherapy.However, it is not proven. A clinical trial (NCT00367497) of R-ESHAP is currently recruiting patients.

MEHMET AKIF ÖZTÜRK et al,  Modified ESHAP as salvage chemotherapy for recurrent or refractory non-Hodgkin's lymphoma: Results of a single-center study of 32 patients Chemotherapy  (Chemotherapy)  2002, vol. 48, no5, pp. 252-258

BMJ - CLinical Evidence - http://clinicalevidence.bmj.com/ceweb/conditions/bly/2401/2401_I5.jsp

Kimby E, Brandt L, Nygren P, et al. A systematic review of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncol 2001;40:198–212. 

Barosi G, Carella A, Lazzarino M, et al. Management of nodal diffuse large B-cell lymphomas: practice guidelines from the Italian Society of Haematology, the Italian Society of Experimental Haematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2006;91:96–103.

http://clinicaltrials.gov/ct/show/NCT00367497;jsessionid=9202040C24BA6886B737A55F632A7F7A?order=3

Kimby E, Brandt L, Nygren P, et al. A systematic review of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncol 2001;40:198–212. 

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,

ASCT for Burkitt's

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. It is associated with HIV in the Western world.

Standard doxorubicin-based combination chemotherapy, such as CHOP, frequently induces remissions of short duration. In an attempt to obtain durable remissions, high-dose therapy (HDT) with autologous stem-cell support was given in a few centers for patients who were in remission upon CHOP-like induction therapy. In the last decade, several paediatric groups have obtained impressive results for BL- and B-cell acute lymphoblastic leukaemia patients by giving blocks of intensified chemotherapy for five to seven consecutive days with 2- to 3-week interval. Five-year disease-free and overall survival >90% in paediatric patients have been reported. In the German Adult Acute Lymphoblastic Leukaemia (ALL) 05/93 protocol, the BFM-90 protocol was adjusted with dose modifications for adult patients.

Ther was only one randomized study to my knowledge in agressive lymphomas that compared standard chemotehrapy and ASCT after remission. The long-term outcome for patients with aggressive non-Hodgkin's lymphoma (NHL) is poor. Consequently, the European Organization for Research and Treatment of Cancer Lymphoma Group designed a prospective randomized trial to investigate whether high-dose chemotherapy plus autologous bone marrow transplantation (ABMT) after standard combination chemotherapy improves long-term survival. Patients aged 15–65 years with aggressive NHL received three cycles of CHVmP/BV polychemotherapy (i.e., a combination of cyclophosphamide, doxorubicin, teniposide, and prednisone, with bleomycin and vincristine added at mid-cycle). After these three cycles, patients with a complete or partial remission and at that time no lymphoma involvement in the bone marrow were randomly assigned to the ABMT arm (a further three cycles of CHVmP/BV followed by BEAC [i.e., a combination of carmustine, etoposide, cytarabine, and cyclophosphamide] chemotherapy and ABMT) or to the control arm (five more cycles of CHVmP/BV). From December 1990 through October 1998, 311 patients (median age = 44 years) were registered and received the first three cycles of CHVmP/BV, and 194 patients were randomly assigned to the treatment arms. Approximately 70% (140 patients) of these patients were of low or low–intermediate International Prognostic Index (IPI) risk. After a median follow-up of 53 months, an intention-to-treat analysis showed a time to disease progression and overall survival at 5 years of 61% (95% confidence interval [CI] = 51% to 72%) and 68% (95% CI = 57% to 79%), respectively, for the ABMT arm and 56% (95% CI = 45% to 67%) and 77% (95% CI = 67% to 86%), respectively, for the control arm. Differences between arms were not statistically significant. A subset analysis on IPI risk groups, although too small for reliable statistical analysis, yielded similar results. They concluded that"standard combination therapies remain the best choice for most patients with aggressive NHL. We recommend that patients with IPI low or low–intermediate risk not be subjected to high-dose chemotherapy and ABMT as a first-line therapy."

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

Betticher, D., Martinelli, G, Radford, J., Kaufmann, M, Dyer, M., Kaiser, U, Aulitzky, W., Beck, J, von Rohr, A, Kovascovics, T, Cogliatti, S., Cina, S, Maibach, R, Cerny, T, Linch, D. (2006). Sequential high dose chemotherapy as initial treatment for aggressive sub-types of Non-Hodgkin Lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17: 1546-1552
   
Stewart, D. A., Bahlis, N., Valentine, K., Balogh, A., Savoie, L., Morris, D. G., Jones, A., Brown, C., Russell, J. A. (2006). Upfront double high-dose chemotherapy with DICEP followed by BEAM and autologous stem cell transplantation for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 107: 4623-4627
A. Krishnan, A. Molina, J. Zaia, D. Smith, D. Vasquez, N. Kogut, P. M. Falk, J. Rosenthal, J. Alvarnas, and S. J. Forman
Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas
Blood, January 15, 2005; 105(2): 874 - 878.

Angioimmunoblastic T-cell

Angioimmunoblastic T-cell lymphoma (AILD) is considered a variety of T-cell lymphoma, which usually occurs in adults.   Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coomb's test, and polyclonal hypergammaglobulinemia. It is quite rare and no standrd approach has beend efined.   Angioimmunoblastic T-cell lymphoma was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma. Opportunistic infections are frequent due to an underlying immune deficiency. Doxorubicin-based combination chemotherapy is recommended as it is for other aggressive lymphomas. Myeloablative chemotherapy and radiation therapy with autologous peripheral stem cell support has been described in anecdotal reports. Occasional spontaneous remissions and protracted responses to steroids only have been reported. A few patients may progress to an EBV-positive diffuse large B-cell lymphoma. I have not found any studies reporting the use of autologous SC for this entity. A recent (2006) retrospective review of ASCT in T-cell lymhomas reported good results in 6 angioimmunoblastic lymphoma patients. All angioimmunoblastic T-cell lymphoma (AILT) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients achieved CR; 5 of 6 have remained disease free for more than 3 years. However, this is a very small sample.

A search of current trials reveals a variety of investigtional approaches to this disease, including stem cell transplant in second remission.

http://clinicaltrials.gov/ct/search?term=%22T-cell+lymphoma%22+%5BCONDITION%5D+AND+angioimmunoblastic+%5BALL-FIELDS%5D&submit=Search

Reimer P, Schertlin T, Rüdiger T, et al.: Myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation as first-line therapy in peripheral T-cell lymphomas: first results of a prospective multicenter study. Hematol J 5 (4): 304-11, 2004.

Pautier P, Devidas A, Delmer A et al. Angioimmunoblastic-like T-cell non Hodgkin's lymphoma: outcome after chemotherapy in 33 patients and review of the literature. Leuk Lymphoma 1999; 32: 545–552

Yamazaki T, Sawada U, Kura Y, et al.
Treatment of high-risk peripheral T-Cell lymphomas other than anaplastic large-cell lymphoma with a dose-intensified CHOP regimen followed by high-dose chemotherapy
ACTA HAEMATOLOGICA 116 (2): 90-95 2006