Cancer Treatment

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

Stem Cell transplant for Scleroderma

Lay Summary: Stem cell transplantation in the hope of modifying disease activity in scleroderma is under active clinical investigational.

Immunosuppressive agents such as cyclophosphamide have long been used to treat autoimmune disease, but the dose is often limited by bone marrow suppression. Ten years ago several groups considered adopting the oncological approach of myeloablative therapy followed by haematological 'rescue' using either autologous or allogeneic hematopoietic stem cells to treat severe, therapy-resistant autoimmune disease. The concept was supported by animal model data, suggesting tolerance induction in a rat arthritis model and cases of patients receiving an hematopoietic stem cell transplantation (HSCT) for conventional indications and in whom a coincidental autoimmune disease was improved or eradicated.

After several international meetings, consensus guidelines were developed and the first published case of a patient receiving an HSCT as treatment for an autoimmune disease alone was published in October 1996. Since then, over 1000 patients have been transplanted for autoimmune disease, the majority within the context of phase I/II trials and more recently within phase III prospective randomized studies.

SCT for sceroderma are under active clinical investigation.  One such current study is SCOT. SCOT is a clinical research study designed for people with severe forms of scleroderma. SCOT stands for Scleroderma: Cyclophosphamide Or Transplantation. The SCOT study will compare the potential benefits of stem cell transplant and high-dose monthly cyclophosphamide (Cytoxan) in the treatment of scleroderma. These 2 approaches are investigational which means that they are still being tested in research studies and are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of scleroderma. Even less is known about SCT as salvage after cyclophosphamide fails.

McSweeney PA, Nash RA, Sullivan KM, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood 2002; 100:1602-1610.

Nash RA, McSweeney PA, Crofford LJ, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood 2007; 23 April

van Laar JM, Farge D, Tyndall A. Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial: hope on the horizon for patients with severe systemic sclerosis. Ann Rheum Dis 2005; 64:1515.

van Laar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford) 2006; 45:1187-1193.

Alan Tyndall; Daniel E. Furst Adult Stem Cell Treatment of Scleroderma Curr Opin Rheumatol.  2007;19(6):604-610

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

Leukine for melanoma

Lay Summary: Leukine is being explored for treating melanoma.

Leukine (granulocyte macrophage colony stimulating factor, GM-CSF, Sargramostim), which is approved for marketing for hematopoietic reconstitution and reversal of iatrogenic neutropenia, also has activity as a macrophage activator. It has been reported that Leukine stimulates peripheral blood monocytes in vitro to become cytotoxic for human melanoma cells. It has further been shown in clinical trials that in vivo administration of Leukine at low doses also results in monocyte activation as shown by enhanced cytotoxicity. Finally, Leukine causes release of an angiogenesis inhibitor by the macrophages. Becasue of these effects, interest was aroused in its use for melanoma.

A trial of therapy in the adjuvant setting was favourable. The median survival was prolonged over three-fold in patients who received Leukine to 34.3 months compared to matched historical controls (median survival 10.2 months). The observed 2-year survival was 64% in the study patients vs. 15% in the controls, (p < 0.001). Toxicity was minimal, the major side effect being mild fatigue; there were no reports of Grade 4 toxicity or serious adverse events.

An interim analysis of another trial was presented at the 6th International Conference on Admuvant Therapy of Melanoma in Stockholm in 2006 and 5th International Conference on Adjuvant Therapy of Melanoma in Athens in March, 2004. It supports the results of the earlier trial and suggests that Leukine improves survival in this patient population. In addition, one of the cooperative study groups, the Eastern Cooperative Oncology Group, has initiated a Phase III prospective randomized trial to further evaluate this therapy (E4697). Accrual of 800 patients has ben completed, but many patients are still undergoing treatment and results of this study will not be known for several years. Finally, there is a trial to gather additional information about efficacy of this treatment and to determine the immunologic effects of GM-CSF in patients with melanoma.

The therapy is being currently investigated and is clearly experimental/investigational. The only adjuvant therapy approved at this time is interferon.

For metastatic setting, it is even more experimental, since immune mechanisma may not work for metastatic disease. A trial in this setting as well is referenced.

Spitler, LE, Grossbard, ML, Ernstoff MS, et al:  Adjuvant therapy of Stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 18:1614-1621, 2000

http://clinicaltrials.mayo.edu/clinicaltrialdetails.cfm?trial_id=100307

nccn.org, melanoma