Cancer Treatment Today » Immunotherapy

DLI for T cell leukemia and lymphoma – pro

M Levin, MD — Fri, 10 Jan 2014 16:27:04 +0000

Donor lymphocyte infusions are designed to awaken some degree of graft versus host reaction, which contains within it also the graft versus disease effect. It is a modality that can be used after allogeneic transplantation to treat relapse by “awakening” an immune response. . Almost all work on DLI was in B cell leukemias and lymphomas. How it affects T cell malignancies is not well studied and most of what is known was in Adult T-Cell leukami/Lymphoma. Many questions remain. For example, achieving hematologic remission with DLI is not an easy task, especially in patients with a high tumor burden and rapidly proliferating leukemic cells.. Cytoreductive therapy before DLI is thought to improve effectiveness of DLI. Unfortunately, which regimens to use for this cytoreduction has not been defined. How to induce and manage graft versus host reaction has not been defined. Even the very effectiveness of allogeneic transplantation in T-Cell Leukemias continues to be studied. To conclude, DLI remains experimental for T Cell malignancies due to lack of reliable information on how to do it and how effective it is.

Hidehiro Itonag et al, Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience Blood January 3, 2013 vol. 121 no. 1 219-225

Gabriel IH. Graft versus lymphoma effect after early relapse following reduced-intensity sibling allogeneic stem cell transplantation for relapsed cytotoxic variant of mycosis fungoides. Bone Marrow Transplant 2007;40(4):401-403.

Herbert KE, . Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant 2004;34(6):521-525.

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Intravenous Gamma Globulin and/ or plasma excange for Gullain-Barre syndrome – pro

M Levin, MD — Wed, 26 Jun 2013 15:15:22 +0000

Guillain-Barr syndrome is a disorder in which the body’s immune system attacks part of the peripheral nervous system. Symptoms include varying degrees of weakness or tingling sensations in the legs. Sometimes, the weakness and abnormal sensations spread to the arms and upper body and progress to paralysis. There is no known cure for Guillain-Barr syndrome, but therapies can lessen the severity of the illness and accelerate the recovery in most patients. Currently, plasmapheresis and high-dose immunoglobulin therapy are most often used.

Both plasma exchange (PE) therapy and intravenous immune globulin (IVIG) have proven effective for Guillain-Barr syndrome (GBS). They are both thought to diminish autoantibody production and increase solubilization and removal of immune complexes. Both have been shown to shorten recovery time by as much as 50%. IVIG is easier to administer and has fewer complications than PE and is usually the initial treatment.

Randomized trials in severe disease show that IVIG started within 4 weeks from onset hastens recovery as much as plasma exchange. Combination therapy of both, does not improve outcomes or shortened illness duration over one or the other.

1. Shahar E. Current therapeutic options in severe Guillain-Barre syndrome. Neuropharmacol. Jan-Feb 2006;29(1):45-51

2.Bascic-Kes V, Kes P, Zavoreo I, Lisak M, Zadro L, Coric L, et al. Guidelines for the use of intravenous immunoglobulin in the treatment of neurologic diseases. Acta Clin Croat. Dec 2012;51(4):673-83.

3.[Best Evidence] Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barr syndrome. Cochrane Database Syst Rev. Jun 16 2010;6:CD002063

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For Rituxan for Gullain-barre see here

Zevalin and Rituxan for relapsed large cell lymphoma or for consolidation – pro

M Levin, MD — Fri, 14 Sep 2012 15:11:19 +0000

Zevalin, 90Y-ibritumomab tiuxetan, is a novel radioimmunotherapeutic agent approved forthe treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL). Zevalin is also indicated for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.

90Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates 111In for imaging and 90Y for therapy. It is often used for other than first line of treatment for lymphoma.

A recent guideline states experts’ consensus: “It is the opinion of the Hematology Disease Site Group that the benefit of 90Y-ibritumomab tiuxetan radioimmunotherapy may be generalizable to other relapsed or refractory indolent non-Hodgkin’s lymphomas previously treated with rituximab….but not CLL.

F. Morschhauser, T. Illidge, D. Huglo et al., “Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation,” Blood, vol. 110, no. 1, pp. 54–58, 2007.

Leung M, Haynes AE, Stevens A, Meyer RM, Imrie K, Hematology Disease Site Group. Ibritumomab tiuxetan in lymphoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Jul 17. 42 p. (Evidence-based series; no. 6-17). [44 references]

Giulia Motta, Michele Cea, Eva Moran, Federico Carbone, Valeria Augusti, Franco Patrone, and Alessio Nencioni Monoclonal Antibodies for Non-Hodgkin’s Lymphoma: State of the Art and Perspectives Clinical and Developmental ImmunologyVolume 2010 (2010),

Yang DH, Kim WS, Kim SJ, Kim JS, Kwak JY, Chung JS, Oh SY, Suh C, Lee JJ. Pilot trial of yttrium-90 ibritumomab tiuxetan consolidation following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy in patients with limited-stage, bulky diffuse large B-cell lymphoma. Leuk Lymphoma. 2012 May;53(5):807-11.

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Thalidomide for liver cancer – pro

M Levin, MD — Fri, 31 Aug 2012 01:35:35 +0000

Lay Summary: Thalidomide can get an occasional response in hepatocellular cancer.

Thalidomide has poorly understood mechanisms of action, and it might exert its therapeutic properties through antiangiogenic activity and modulation of cytokines, including tumor necrosis factor-, interferon, interleukins 10 and 12, cyclooxygenase-2, and nuclear factor B. Several studies have examined the efficacy and toxicity of thalidomide in HCC . Hsu and colleagues conducted a study using thalidomide in 68 HCC patients. Of the 63 evaluable patients, one complete and three partial responses were seen, for a response rate of 6.3% (95% CI, 0%–12.5%). Ten patients had a dramatic decrease in their AFP levels. Interestingly, all responders received thalidomide at 300 mg or less per day. In another study, involving 99 patients with advanced HCC, responses were seen in six patients in response to single-agent thalidomide]. Several recent phase II studies from the U.S. have examined the use of thalidomide either as a single agent or in combination with epirubicin or interferon and have shown limited activity in HCC. Fatigue and somnolence were the most common side effects associated with thalidomide administration.

Eleutherakis-Papaiakovou V, Bamias A, Dimopoulos MA. Thalidomide in cancer medicine. Ann Oncol 2004;15:1151–1160.
Hsu C, Chen CN, Chen LT et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65:242–249
Wang TE, Kao CR, Lin SC et al. Salvage therapy for hepatocellular carcinoma with thalidomide. World J Gastroenterol 2004;10:649–653.
Lin AY, Brophy N, Fisher GA et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 2005;103:119–125.
Patt YZ, Hassan MM, Lozano RD et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 2005;103:749–755.
Zhu AX, Fuchs CS, Clark JW et al. A phase II study of epirubicin and thalidomide in unresectable or metastatic hepatocellular carcinoma. The Oncologist 2005;10:392–398.
Schwartz JD, Sung M, Schwartz M et al. Thalidomide in advanced hepatocellular carcinoma with optional low-dose interferon-alpha2a upon progression. The Oncologist 2005;10:718–727.

Interleukin 2 for melanoma (high dose and low dose) – pro

M Levin, MD — Fri, 31 Aug 2012 01:33:58 +0000

Cytokines are proteins that activate the immune system in a general way. Two cytokines, interferon alpha and interleukin 2, can help boost immunity in patients with melanoma. Both drugs can help shrink metastatic (stage III and IV) melanoma in about 10% to 20% of patients. There are no studies that compare interleukin-2 (IL-2) to the current standard of care, dacarbazine (DTIC), or to placebo in the treatment of metastatic melanoma. IL2 can be given as low dose, intermediate dose of high dose. HIgh dose is probably the most effective but ti is also toxic.
After weighing and reviewing the evidence that does exist, the opinion of the Melanoma Disease Site Group is that high-dose IL-2 is a reasonable treatment option for a select group of patients with metastatic melanoma:
Patients should have a good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1), and a normal lactate dehydrogenase (LDH) level.
Patients should have less than three organs involved or have cutaneous and/or subcutaneous metastases only and no evidence of central nervous system metastases. In this select group of patients IL-2 treatment can produce durable complete remissions.
The recommended dose and schedule of high-dose IL-2 is 600,000 IU/kg/dose intravenously over 15 minutes, every eight hours, for a maximum of 14 doses.
If high-dose IL-2 is delivered, the recommendation is that it be done in a tertiary care facility with staff trained in the provision of this treatment with appropriate monitoring. Low or intermediate dose IL2 is not recommended by the referenced guideline or by NCCN( MS-16).

However, ESMO mentions interleukin as an option without specifying a dose. On the other hand, a guideline by Petrella in 2007 alos does not recommend low dose interferon. It writes: “ Low-dose il-2 has consistently lower overall response rates (2%–5%) than does high-dose il-2, and hence low-dose treatment was not part of the recommendation.”

T. Petrella, MD et al, Single-agent interleukin-2 in the treatment of metastatic melanoma Curr Oncol. 2007 February; 14(1): 21–26.

Petrella T, Quirt I, Verma S, Haynes A, Charette M, Bak K, Melanoma Disease Site Group. Single-agent interleukin-2 in the treatment of metastatic melanoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Mar 20. 32 p. (Evidence-based series; no. 8-5). [32 references]

NCCN.ORG, melanoma, 2012

R. Dummer et al, Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol (2010) 21 (suppl 5): v194-v197.

Beclomethasone for graft versus host disease – pro

M Levin, MD — Thu, 30 Aug 2012 18:31:01 +0000

The pathological and clinical findings of gastrointestinal (GI) graft-versus-host disease (GVHD) are similar to those of inflammatory bowel disease. Three previous studies had shown the safety and efficacy of the topical BDP for GI GVHD. It is possibe that it would function similarly for GVHD. Several small pahse IIs tudies suggest that it suppresses allogeneic immune responses in the gut without causing significant immunosuppression.

This therapy is under study: Compassionate Use of Beclomethasone in Treating Patients With Graft-Versus-Host Disease of the Gastrointestinal Tract, NCT00055666.

G.McDonald, M.Bouvier, D.Hockenbery, J.Stern, T.Gooley, A.Farrand, C.Murakami, D.Levine
Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: A randomized, controlled trial Gastroenterology, Volume 115, Issue 1, Pages 28-35

Y Miura et al, Oral beclomethasone dipropionate as an initial treatment of gastrointestinal acute graft-versus-host disease after reduced-intensity cord blood transplantation Bone Marrow Transplantation (2006) 38, 577–579.

Daclizumab for Graft Versus Host disease – pro

M Levin, MD — Thu, 30 Aug 2012 18:20:31 +0000

Daclizumab (trade name Zenapax) is a therapeutic humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants.Daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections.
This drug has been used to treat graft vs. Host Disease (GVHD) in stem cell as well as other types of transplants but most evidence is in the form of case reports and series.

It was studied in a clinical study: Methylprednisolone With or Without Daclizumab in Treating Patients With Acute Graft-Versus-Host Disease, NCT00053976 . This was a randomized phase III trial to compare the effectiveness of methylprednisolone with or without daclizumab in treating patients who have acute graft-versus-host disease following donor bone marrow transplantation. The study was halted after a planned interim analysis showed a significantly worse 100-day survival in the group receiving corticosteroids plus daclizumab (77% vs 94%; P = .02). Overall survival at 1 year was also inferior in the combination arm (29% vs 60%; P = .002). Both relapse- and GVHD-related mortality contributed to the increased mortality in the combination group. It concluded: “The combination of corticosteroids and daclizumab should not be used as initial therapy of acute GVHD.”

D T Teachey et al, Daclizumab for children with corticosteroid refractory graft-versus-host disease
Bone Marrow Transplantation (2006) 37, 95–99 2005

C H Hui et al, Daclizumab has poor efficacy in steroid-refractory severe acute graft-versus-host disease: a single centre experience with 12 allograft patientsBone Marrow Transplantation (2008) 41, 409–410;2007

Srinivasan, R, Chakrabarti, S, Walsh, T, et al. Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis. Br J Haematol 2004; 124:777.

Stephanie J. Lee, David Zahrieh, Edward Agura, Margaret L. MacMillan, Richard T. Maziarz, Philip L. McCarthy, Jr, Vincent T. Ho, Corey Cutler, Edwin P. Alyea, Joseph H. Antin, and Robert J. Soiffer
Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial Blood 104: 1559-1564;

Donor Lymphocyte Infusions (DLI) for CLL – pro

M Levin, MD — Fri, 24 Aug 2012 01:30:23 +0000

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. Unfortunately, supporting evidence is limited because treatment with CLL with allogeneic transplantation is fairly rare.

Tomblyn, M., & Lazarus, H. M. (2008). Donor lymphocyte infusions: The long and winding road: How should it be traveled? Bone Marrow Transplantation, 42 (9), 569-579.

Deol, A., & Lum, L. G. (2010). Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treatment Reviews, 36 (7), 528-538.

Photopheresis for graft versus host disease – pro

M Levin, MD — Fri, 24 Aug 2012 01:11:20 +0000

The use of photopheresis or Extra Corporeal Perfusion (ECP) 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.
In acute GVHD, a phase II study by Greinix et al. involving 38 patients reported complete remission in 86%, 55%, and 30% of patients with grades 2, 3, and 4 agvhd respectively. The best results were obtained in 82%, 61%, and 61% of patients with skin, liver, and gut agvhd respectively.
Studies focusing on patients with chronic GVHD unresponsive to other therapies reported resolution or marked improvement of lesions in about 50% of patients. The one phase II study by Flowers et al. reported on a multicentre prospective phase II randomized study in 23 transplant centres in North and South America, Europe, and Australia. The 95 enrolled patients were randomized either to ECP plus standard therapy or to standard therapy alone. The conclusion reached was that ECP had a steroid-sparing effect in the treatment of chronic GVHD.
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. SInce then there ahd been a nubmer of otehr reprots but no studies. A 2008 workshop convcded: “The evidence for the efficacy of ECP has been appraised by a combined British Photodermatology Group and U.K. Skin Lymphoma Group workshop on the basis of evidence published up to the end of 2001 and on the consensus of best practice. There is fair evidence for the use of ECP in erythrodermic CTCL and steroid-refractory GVHD, but randomized controlled studies are needed.” National Institute for Health and Clinical Excellence in the UK endorsed the use of ECP for CTCL and because of the complexity of treatment supported its use in specialized centres and also suggested the need for expansion of this service.

A 2012 guideline(Dinghan et al) recommends it as second line treatment.

Dignan FL, Amrolia P, Clark A, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Shaw BE, Potter MN, on behalf of the Haemato-oncology Task Force of the British Committee [trunc]. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol 2012 Jul;158(1):46-61. [125 references]

Greinix HT, Knobler RM, Worel N. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. 2006;91:405–8.

Scarisbrick JJ, Taylor P, Holtick U, et al. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol. 2008;158:659–678.

J. Klassen, The role of photopheresis in the treatment of graft-versus-host disease Curr Oncol. 2010 April; 17(2): 55–58.

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

Flowers ME, Apperley JF, van Besien K. A multi-center prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008;112:2667–74. [Erratum in: Blood 2009;113:4478]

Clinical Summary:
71 year-old man s/p reduced intensisty allogeneic transplant from sister after AML diagnosed and induced in May 2010. He developed Graft vs Host Disease and was treated with tacrolimus but now received photopheresis.

L.E.I.S.H. – pro

M Levin, MD — Mon, 13 Aug 2012 17:51:30 +0000

The LESIH procedure relies on the use of a proprietary LASER System, of a wavelength not significantly absorbed by human tissue and emitting a low power broad beam. It is a form of fractionated Photo-dynamic Therapy.

Both Photo-dynamic Therapy and Radio-fractionated Hyperthermia are FDA approved; however, due to limitations in the available delivery equipment, they cannot be utilized to treat larger tumors.

The LAILT System I, proprietary of LASE MED, Inc. and utilized in the delivery of the L.I.E.S.H. Therapy, is designed to handle any size of tumor.

LMI’s therapy relies on the use of injectable enchancer which is directly injected into the tumor and spreads thorughout it. This OxyM, which is water soluble and completely innocuous, in other words with the same side-effects of a saline solution.

This is an experimental modality that has become a part of “alternative” medical approach. There are no recent publications to suport it and the proprietry system has not been FDA approved, even as a technology. Afsaneh Bakhshandeh, Volker Bath, Gunter J Wiedemann, Walter Longo, Benjamin M Lerner, Cynthia L Tiggelaar, and H Ian Robins Year 2000 guidelines for clinical practice of whole body hyperthermia combined with cytotoxic drugs Journal of Oncology Pharmacy Practice, Vol. 5, No. 3, 131-134 (1999)from the University of Lübeck and the University of Wisconsin

Lagendijk JJ, Van Rhoon GC, Hornsleth SN, Wust P, De Leeuw AC, Schneider CJ, Van Dijk JD, Van Der Zee J, Van Heek-Romanowski R, Rahman SA, Gromoll C.
University Hospital Utrecht, The Netherlands.
ESHO quality assurance guidelines for regional hyperthermiaInt J Hyperthermia. 1998 Mar-Apr;14(2):125-33.