Cancer Treatment

Cladribine for lymphomas

Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström’s macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin’s lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions.

Cladribine is in a phase II study for matnle lymphoma as a single agent, NCT00002879. A 2006 preliminary report suggested that caldribine in combination with rituximab regimens were highly effective and well tolerated modalities of treatment in heavily pretreated patients with indolent lymphoproliferative disorders.

http://clinicaltrials.gov/ct2/show/NCT00002879

Darren S Sigal and Alan Saven Cladribine in indolent non-Hodgkin’s lymphomaExpert Review of Anticancer Therapy April 2008, Vol. 8, No. 4, Pages 535-545

Robak T, Smolewski P, Cebula B, Szmigielska-Kaplon A, Chojnowski K, Blonski JZ.
Rituximab combined with cladribine or with cladribine and cyclophosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma.Cancer. 2006 Oct 1;107(7):1542-50.

Velcade for low grade lymphoma

Bortezomib is a drug that belongs to the class of drugs called proteasome inhibitors. The proteasome is a protein complex that breaks down rusty and modified proteins that cells are meant to dispose off. Its housekeeping job is very important for the cells to keep functioning. Research studies have shown that if the proteasome is inhibited (or stopped from functioning) some cancer cells, including some lymphoma cells may find it difficult to carry out normal functions and even die. Bortezomib (Velcade) is a type of drug that inhibits proteasomes. Theoretically it can be efective in a wide spectrum of malignancies.

It has shown great results in the treatment of relapsed multiple myeloma, another type of cancer that affects the bone marrow. Trials that have tried Velcade in relapsed lymphomas over the past few years have resulted in good responses in certain types of lymphoma, especially Mantle Cell Lymphomas. Bortezomib (Velcade) has been granted approval for the treatment of relapsed or refractory Mantle Cell Lymphoma by the FDA in December 2006. It represents an important step in the approach to second-line treatments in Mantle Cell Lymphoma, a potentially difficult to treat lymphoma.

A number of trials in low grade lymhomas are ongoing. For example, Millennium Pharmaceuticals and development partner Johnson & Johnson have initiated a phase III clinical trial of Velcade in non-Hodgkin's lymphoma. The trial will evaluate the drug in combination with rituximab in patients with relapsed or refractory follicular lymphoma, a subtype of non-Hodgkin's lymphoma (NHL). Anoterh study that Millenium is sponsoring is to determine if the combination of VELCADE and rituximab improves progression free survival relative to rituximab alone in patients with relapsed or refractory B-cell non-Hodgkin"s lymphoma (B-NHL) who never received rituximab or who have previously responded to rituximab. This is an international study being conducted in the United States and in many countries around the world.
An Italian study,NCT00509379,  A Phase II Multicenter Non-Randomized Study to Assess Safety, Toxicity and Clinical Activity of the Association of Bortezomib(VELCADE)With Rituximab in Relapsed/Refractory Indolent Non Follicular and Mantle-Cell Non-Hodgkin Lymphoma, is looking at activity in several low grade lymphoma types, including SLL.

Schenkein D. Proteasome inhibitors in the treatment of B-cell malignancies. Clin Lymphoma. 2002;3(1):49-55.

Cheson BD. Hematologic malignancies: New developments and future treatments. Semin Oncol. 2002;29(4 Suppl 13):33-45.

nccn.org, chronic lymphocytic leukemia

Is Waldenstrom's a "cancer"?

Waldenstrom's (WM) should be considered cancer since it is apresentation of a lymphoma. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion.  Waldenström macroglobulinemia is a clonal disorder of B lymphocytes. This condition is considered to be lymphoplasmacytic lymphoma as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies.

Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA.
Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.Semin Oncol. 2003 Apr;30(2):110-5.

Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al: Waldenstrom's macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000 Jan; 18(1): 214-26

Dimopoulos MA, Galani E, Matsouka C: Waldenstrom's macroglobulinemia. Hematol Oncol Clin North Am 1999 Dec; 13(6): 1351-66

Mycoisis fungoides and Sezary (CTCL) and stem cell transplantation

Cutaneous T-cell lymphoma (CTCL) is classified as an indolent hematologic malignancy with distinct clinicopathologic features. Although prognosis varies depending on the stage, patients who have cutaneous tumor, lymph node or visceral involvement, or peripheral blood involvement (Sézary syndrome) generally have a poor outcome.
Evidence for stem cell transplantation, both autologous adn allogeneic is on the level of case reports. Experts agree that more investigtioan is needed.

Y. Oyama, J. Guitart, T. Kuzel, R. Burt, S. RosenHigh-dose therapy and bone marrow transplantation in cutaneous T-cell lymphoma. 
Hematology/Oncology Clinics of North America, Volume 17, Issue 6, Pages 1475-1483, 2003.
Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003 Dec;149(6):1095-107. [67 references

AVN944

Lay Summary: AVN-944 is reviewed.

AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate-limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro.

Pre-clinical studies showed that AVN944 is a highly specific inhibitor of IMPDH, suppresses pools of GTP, and in cultured cells has a selective growth inhibition effect on cancer cells vs. normal cells.

An earlier single-dose, dose-escalation, healthy volunteer clinical trial conducted in the United Kingdom showed that AVN944 was well tolerated at all tested doses with no notable side effects; had good pharmacokinetic properties; and had a significant inhibitory effect on IMPDH enzyme activity.

A recent phase I study is a repeat-dose dose escalation trial in patients with advanced hematologic malignancies. Patients are dosed for 21 days on a 28-day cycle. A minimum of three patients are treated at each dose level. The study is divided into two arms, one for treatment of leukemia patients and the other for treatment of patients with lymphoma and myeloma. For the leukemia arm of the study, patients are currently being treated at the fourth dose level, 100 mg twice daily. For the lymphoma and myeloma arm, patients are currently being treated at the fifth dose level, 125 mg twice daily. There have been no drug-related Serious Adverse Events (SAEs), indicating that AVN944 is being well tolerated thus far at all dose levels. Pharmacokinetics measurements indicate dose proportional plasma levels of AVN944 during treatment and sustained plasma concentrations at the dose levels tested thus far.

Early Activity Indicators: This Phase I study has also been designed to evaluate several pharmacodynamic and efficacy-related endpoints. Upon entering the trial, all patients have refractory, progressive disease and have failed all prior therapies. Thus far, 12 of 24 patients have had stabilized disease after one cycle of treatment with AVN944. These include patients with both leukemia and multiple myeloma. Patients who have achieved stable disease following completion of a one-month treatment cycle with AVN944, as determined by the clinical investigator, may be advanced to a subsequent cycle.

Four multiple myeloma patients in the study have maintained stabilized disease for several months of treatment with AVN944; two of these patients completed five months of treatment and two others completed eight successive cycles. These two patients continue to have stable disease and are in their ninth month of treatment.  it is clearly experimental.

Author(s): R. B. Klisovic, G. Tricot, S. Coutre, T. Kovacsovics, F. Giles, T. Genna, D. K. Bol, J. W. Strovel, J. M. Hamilton, B. Mitchell A phase I trial of AVN944 in patients with advanced hematologic malignancies.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 14026

Gemzar and Navelbine salvage for lypnoma

Gemcitabine, vinorelbine and prednisone or otehr drugs are being investigated to treat refractory or relapsed aggressive non-Hodgkin lymphomas (NHL).
Lay Summary: Gemcitabine and vinorelbine are somewhat effective but toxic when few options remain, but more investigation is needed.

The optimum therapy for patients with relapsed or refractory aggressive NHL not qualifying for platinum-based and/or high-dose chemotherapy is not known. In one  prospective phase II study evaluating a regimen consisting of gemcitabine (1 g/m2, days 1 and 8), vinorelbine (30 mg/m2, days 1 and 8) and prednisone (100 mg/day, days 1-8) (GVP) given every 21 days, there was substantial activity in poor prognosis relapsed or refractory aggressive lymphomas. It was generally well tolerated, but haematological toxicity is dose limiting. Several other studies yilded similar results.

One has to conclude that despite these results the treatment is still experimental as it is being studies in various studies with otehr agents added and a prospective phase III trial is necessary.

Efstathios S. Papageorgiou, Panagiotis Tsirigotis, Meletios Dimopoulos, Nikolaos Pavlidis, George Fountzilas, Sotirios Papageorgiou, Theofanis Economopoulos (2005)  Combination chemotherapy with gemcitabine and vinorelbine in the treatment of relapsed or refractory diffuse large B-cell lymphoma: a phase-II trial by the Hellenic Cooperative Oncology Group European Journal of Haematology 75 (2), 124–129.

A. Spencer, K. Reed and C. Arthur. (2007) Pilot study of an outpatient-based approach for advanced lymphoma using vinorelbine, gemcitabine and filgrastim. Internal Medicine Journal 37:11, 760–766

Fatih M. Uckun, Sanda Morar and Sanjive Qazi. (2006) Vinorelbine-based salvage chemotherapy for therapy-refractory aggressive leukaemias. British Journal of Haematology 135:4, 500–508

Induction regimens in myeloma

Lay Summary: Induction regimens for high dose chemotherapy have not been sufficiently compared but this should not lead us to concluding that they are experimental.

High-dose therapy with autologous stem cell transplantation (ASCT) has been extensively used in the past 15 years in multiple myeloma. Several randomized studies confirm that ASCT yields superior complete remission and event free survival rates. However what the field is missing is trials comapring variosu induction regimens one to anotehr in terms of effectiveness. Several such regimens are being employed without experiemntal confirmation that theya re equivalent or superior to others.

The goal of induction therapy is to reduce the tumor burden prior to high-dose therapy and autologous transplant. Many groups have used administration of 2 to 4 cycles of VAD for this purpose. VAD has the important advantage of sparing hematopoietic stem cells relative to other chemotherapeutic regimens, particularly combinations of alkylating agents. This increases the likelihood that sufficient autologous stem cells can be collected for transplantation. Other induction regimens that may also be useful for reducing the tumor burden and sparing stem cells include administration of 2 or more cycles of dexamethasone either alone or with thalidomide, CDEP VDT-PACE, PACE and others. Currently, the optimal induction regimen and number of cycles of treatment are unclear. Further studies are underway to clarify this issue.

Despite this fact, I do nto consider it sufficient to deny autologous transplantation, whcih is generally agreed by experts to be standard of care and is enshrined in gudielines. It would be paradoxic to allow transplants as standard of care but in practice not approving any transplant because the induction regimens are not comparatively studied.

Jean-Luc Harousseau, Michel Attal The role of stem cell transplantation in multiple myeloma Blood Reviews, Volume 16, Issue 4, Pages 245-253 (December 2002)

nccn.org, myeloma

Sonneveld P, Segeren CM. Changing concepts in multiple myeloma: from conventional chemotherapy high-dose treatment. Eur J Cancer. 2003;39:9-18.

Myelotarg

MYLOTARG is currently FDA indicated for the treatment of patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. CD 33+ is not required by the FDA.

There are  a nubmer of phase II studies showing effectiveness at age various ages.  The overall response rate (OR) for the 277 adult patients with AML (mean age: 58 years) in first relapse treated in phase 2 pivotal studies was 26% with 13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery). However, it is not clear that adding myelotarg to previously effective chemotherapy  in a patient with a long relapse free interval is beneficial. Repeating the intially successful chemo, with a stem cell transplant consolidation is the standard approach to this situation, especially in younger patients. The only controlled studies are a single agent, in older patients, and not in combination with chemotherapy.

NCCN recommends single agent gemtuzumab in patietns over age 60 and chemo with transplant or trials in younger patients.

A-L Taksin et al, High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group
Leukemia (2007) 21, 66–71

http://nccn.org/professionals/physician_gls/PDF/aml.pdf

Maintenance therapy for myeloma

The definition of maintenance therapy for myeloma is extended drug therapy, administered after achieving a remission or a plateau phase, or in this case when disease is at its minimum. Defining the dose, schedule, and the clinical scenario for maintenance therapy is an important starting point. The ideal maintenance therapy is easily delivered (oral) and, if given intravenously, has a schedule that is convenient for patients. The toxicity from the maintenance agent should be modest and its use should improve progression-free survival (PFS). Ideally, the use of the maintenance treatment should not only improve PFS but also improve OS compared with re-treatment at the time of relapse. Such goals for maintenance therapy allow clinicians to target populations, agents, and schedules that are patient friendly and demonstrate efficacy.

Current evidence does not support the use of IFN as maintenance therapy owing to its lack of improvement in OS and unacceptable toxicity. The scant data that are available do not justify the recommendation of corticosteroids as maintenance therapy for all patients. Conflicting evidence exists for the use of thalidomide as maintenance treatment. Current data are promising, but further randomized trials are needed to verify its effectiveness and those who will most likely benefit from maintenance thalidomide. More randomized trials are needed in order to make clear recommendations to patients regarding maintenance therapy. In addition to PFS, OS and quality of life measures are needed. Two published guidelines regarding the treatment of myeloma have recently been published, from The Italian Society of Hematology (SIES) and Italian group for Bone Marrow Transplantation (GITMO) (2004), and the other from the International Myeloma Foundation (2003). Recommendations for maintenance therapy from both these organizations is that these approaches are not yet standard. VDT-PACE,as a part of the Total Therapy III approach is a novel maintenance starategy which is investigational as well at this time

Barosi G, Boccadoro M, Cavo M, Corradini P, Marchetti M, Massaia M et al. Management of multiple myeloma and related-disorders: guidelines from the Italian Society of Hematology (SIE), Italian Society of Experimental Hematology (SIES) and Italian Group for Bone Marrow Transplantation (GITMO). Haematologica 2004; 89: 717–741.

Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003; 4: 379–398.

R Mihelic et al, Maintenance therapy in multiple myelomaLeukemia (2007) 21, 1150–1157

Velcade first line in Multiple Myeloma

There are relatively few effective treatment options for patients with multiple myeloma. Traditional treatment includes combination chemotherapy with melphalan/prednisone and vincristine/doxorubicin/dexamethasone. Myeloablation with high-dose chemotherapy and subsequent rescue with ASCT is a mainstay for patients fit enough to withstand the regimen, usually patients less than 65 years of age. The immunomodulators, thalidomide and lenalidomide, alone or in combination with dexamethasone, have been shown to be effective in multiple myeloma.

Bortezomib is a first-in-class proteasome inhibitor that has shown remarkable efficacy in multiple myeloma. Bortezomib specifically targets the ubiquitin-proteasome pathway; the proteasome plays a key role in the degradation of ubiquinated proteins in general, and specifically proteins that control tumor cell growth and survival. By targeting the proteasome and acting on the multiple myeloma cells as well as the microenvironment, bortezomib has been shown to increase response in patients with multiple myeloma, especially in patients with relapsed and refractory disease. Bortezomib is currently indicated for the treatment of relapsed and refractory multiple myeloma, including use as second-line treatment after first relapse.

Bortezomib has shown activity as first-line treatment in newly diagnosed, untreated multiple myeloma in two phase II studies
. In one study, overall response after more than 2 cycles of therapy (n = 22) was 64%. Peripheral neuropathy occurred in 21% of patients and was mainly grade 2 and managed with dose modification.

In the second study, patients (completed, n = 23) received single-agent bortezomib with added dexamethasone for less than PR after 2 cycles or less than CR after 4 cycles of treatment [33]. Overall major response was 83%. Best response was recorded for 43% of patients after cycle 2, 39% after cycle 4, and 13% after cycle . The addition of dexamethasone (61% of patients) increased response in 9 patients. Peripheral neuropathy (grades 1-3) occurred in 56% of patients; 12% had neuropathic pain, which resolved when treatment was discontinued.

A number of phase I/II clinical trials have investigated the use of bortezomib in combination with chemotherapy, including dexamethasone, for induction treatment prior to ASCTThe conclusion from these studies is that bortezomib is an effective adjunct to standard induction regimens, with excellent response, successful mobilization of peripheral blood stem cells, and good tolerance. Based on this data, NCCN recommends bortezomib/dexamethasone as primary (front-line) therapy for transplant candidates. Newer studies suggest that it is a superior front line treatment adn FDA approval is expected this year.

Rami Manochakian, Kena C. Miller, Asher A. Chanan-Khan Clinical Impact of Bortezomib in Frontline Regimens for Patients with Multiple Myeloma The Oncologist, Vol. 12, No. 8, 978-990, August 2007;

Mario Dicatoa et al, Management of Multiple Myeloma with Bortezomib: Experts Review the Data and Debate the Issues Oncology Vol. 70, No. 6, 2006

http://nccn.org/professionals/physician_gls/PDF/myeloma.pdf

Revised: 3/5/08