• CLL Drugs ~ Preface

    treatment CLL treatment has come a long way since 2000. Here is an overview of the current batch of treatments. Note that drugs marked with an 'X' are experimental and only available in clinical trials.

    Some like CHOP, FCR, are cocktails often used with steroids or monoclonal antibodies.

  • CHOP (Cocktail of cyclophosphamide, doxorubicin(Adriamycin), Oncovin (vincristine), and prednisone/prednisolone)

    CHOP is an old drug combination dating to the mid 1970s but is still in use today. It is one of the few treatments that works for Richter's Transformations [diffuse large B-cell lymphoma (DLBCL)] in CLL where the leukemia has changed to a lymphoma.

    CHOP is also combined with Rituxan often referred to as R-CHOP.

    In patients with CLL and cardiac problems the doxorubicin is omitted and thus called COP (cyclophosphamide, Oncovin, and presnisone) or sometimes, CVP (cyclophosphamide, vincristine, and presnisone or presdnisolone)



    See more here
    CLL- 80 trial .pdf
    Posted: ~chris October 13th, 2009

  • Chlorambucil (Leukeran) Delivery: Oral, Type: alkylating agent

    Chlorambucil klor-AM-byoo-sil (Leukeran) is a chemotherapy drug that has been used in the treatment of CLL. It is a nitrogen mustard alkylating agent (like Bendamustine) and can be used orally. Like many alkylating agents, chlorambucil has been associated with the development of other forms of cancer and is listed as a carcinogen. (Second Annual Report on Carcinogens (1981))

    Chlorambucil can cause a decrease in the number of white blood cells in the bone marrow. It is often used in combination with Rituxan.

    Chlorambucil - AHFS Bookshelf
    Complete Drug Info .pdf

    Read More Here

    Compared with Fludara

    Canadian Use - .pdf file More Info .pdf

    Posted: ~chris October 27th, 2009

  • Revlamid (X) (Lenalidomide - from the drug thalidomide)

    Revlimid contains the medicinal ingredient lenalidomide which is an antineoplastic agent and an immunomodulatory agent. It is a tweaked version of the 1950s drug Thalidomide See Here , that was given to pregnant women in Canada and cause devastating birth defects into the 1960s, when it was removed from the market.

    Revlimid is only available through a controlled distribution program called RevAid. It is highly controlled due to its past history. Lenalidomide has multiple mechanisms of action that affect cancer cells and their environment. Lenalidomide increases hemoglobin expression; inhibits proliferation of certain hematopoietic tumour cells; enhances T cell, Natural Killer (NK), and NK T cell number and activity; and inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of micro-vessels.

    Revlimid has been used in clinical trials for CLL with mixed results. The worst side effects is called 'Tumour Flare' where the lymph nodes all enlarge with extreme pain to the patient. This can now be controlled to some extent with dosage and Ibuprofen. Another side effect is 'Tumour Lysis' which can be fatal. Revlimid should generally not be considered by patients with previous heart conditions.
    Clinical Trial: NCT00963105 Note: There may be an arm of this trial in Hamilton soon.


    DRUG INFO PORTAL
    Lenalidomide - AHFS Bookshelf
    Health Canada Approval .pdf file

    Posted: ~chris October 27th, 2009

  • Cladribine (Leustatin) Type:denosine analog
    (Not used much for CLL anymore)

    Cladribine (2-chloro - deoxyadenosine, 2-CdA) is a nucleoside analog with substituted halogen atom at position 2 in its purine ring that makes it resistant to deamination by adenosine deaminase (ADA).

    Cladribine is generally used as second line treatment rather than the first line therapy. There are indications that it works for FC refractory patients, because of its unique signal pathways.

    Cladribine - AHFS Bookshelf
    Complete Drug Info .pdf file

    Learn More Here

    Cladribine with prednisone versus chlorambucil with prednisone Complete Drug Info .pdf file

    Posted: ~chris October 13th, 2009

  • HDMP (High dose methylprednisolone)

    High dose methylprednisolone (HDMP) either alone or in combination with cytotoxic agents (Rituxan) has been evaluated in advanced refractory CLL. Steroids induce apoptosis by a number of mechanisms 7-10 while rituximab sensitizes leukemia cells to apoptosis by down modulating expression of the anti-apoptotic protein bcl-2. Therefore, it is possible that rituximab sensitizes CLL B cells to steroid induced apoptosis enhancing the effectiveness of HDMP in refractory CLL.

    Methylprednisolone - AHFS Book shelf

    HDMP Info .pdf file



    Posted: ~chris October 28th, 2009

  • Bendamustine (X) (Ribomustin - Europe and Treanda USA) Delivery: IV Type: alkylating agent with some purine analogue activity

    Bendamustine is a nitrogen mustard used in the treatment of CLL and NHL. It belongs to the family of drugs called alkylating agents.

    Bendamustine was first synthesized in 1963 in East Germany. Until 1990 it was available only in East Germany. It works similar to FC but the actual science is poorly understood.

    It is often used as a single agent or in combinations with others like etoposide, fludarabine, mitoxantrone, methotrexate, prednisone, rituximab, vincristine, and more.

    The huge advantage of Bendamustine is that it still will work on FC refractory patients.

    Bendamustine - AFHS Bookshelf

    Learn More Here ~ and Here ~ and Here

    Treanda Fact Sheet ~ Company Link

    Posted: ~chris October 13th, 2009

  • Campath (Alemtuzumab, MabCampath or Campath-1H) Delivery: Sub-Q IV CD53 Type: Monoclonal Antibody

    Campath (alemtuzumab uh-lem-TOOZ-uh-mab) is a single agent for the treatment of B-CLL, and in the E.U., where it is marketed as MabCampath, for the treatment of patients with B-CLL for whom fludarabine combination chemotherapy is not appropriate. The product was originally launched in its oncology indication in 2001.

    Alemtuzumab is a humanized monoclonal antibody that binds to a specific target, CD52, on cell surfaces and directs the body's immune system to destroy those cells. It is the first and only monoclonal antibody approved by the FDA for the treatment of patients with B-CLL.

    Campath for B-CLL has a boxed warning that includes information on cytopenias, infusion reactions, and infections. The most commonly reported adverse reactions in patients with B-CLL were infusion reactions (fever, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), and infections (CMV viremia, CMV infection, other infections). Campath has in the past been used primarily to treat patients with 17p deletion, but is now in wider use and is being used in conjunction with Fludarabine in clinical trials (see FluCAM - Trial CAM314)
    LINK TO CAMPATH STUDY
    Alemtuzumab AHFS Bookshelf"
    Alemtuzumab IV - Campath 1H .pdf file

    Comments: Unfortunately for some CLL patients with 17p deletions, Campath is not paid for in Ontario and many other provinces in Canada for use with CLL.
    Posted: ~chris October 13th, 2009

  • Ofatumumab (Arzerra, Humax-CD20) Delivery:IV Type: Monoclonal Antibody CD20

    Pronounced: ofa-too-moo-mab Ofatumumab (Arzerra). The drug formerly known as 'HuMax-CD20' is a human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is under development for treating chronic lymphocytic leukemia where it works like Rituxan. It was approved by the FDA as a fast track product only for people suffering from chronic lymphocytic leukemia (CLL) who do not respond to current available treatments.

    Ofatumumab works by targeting the membrane proximal small loop epitope of the CD20 molecule on B cells. The CD20 molecule is highly expressed in both normal and malignant B cells and, when bound by an antibody, sends a signal across the membrane to control growth and trigger death of certain tumour cells.

    Clinical Trials of Ofatumumab used in combinations with FC are available at these centres:

    Grand River Regional Cancer Centre Kitchener Ontario

    Janet MacEachern, MD 519-749-4380 Ext. 835 King St. W Kitchener, Ontario N2G 1G3

    Southlake Regional Health Centre Newmarket, Ontario

    Janet MacKinnon, MD 905-895-4521 Ext. 2297 596 Davis Drive Newmarket, Ontario L3Y 2P9

    Posted: ~chris October 13th, 2009

  • Fludarabine (Fludara)

    Delivery Oral or IV Type: antimetabolites (Purine analogue) Fludara, a purine nucleotide analog, inhibits the synthesis of new DNA, thus preventing leukemia cells from multiplying. The intravenous (IV) formulation of Fludara was first approved in 1991 and is available in 98 countries worldwide as a second-line therapy for B-CLL patients who have failed previous treatment with alkylating agents.

    In addition, Fludara IV has been approved as a first-line therapy of B-CLL in 62 countries. The oral formulation has the same effect as the IV formulation and was approved in Europe in 2001.

    Fludarabine is often coupled with cyclophosphomide. (FC)
    Cyclophosphamide also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group.

    Currently FC+R (Rituxan) is the treatment du jour. Rituxan is a CD20 monoclonal antibody. A fairly rare complication of FCR is rapid drops in neutrophil levels. Why this happens is still unknown.
    Some patients become Fludarabine refractory, which means that this drug no longer works. The reason is still not understood, however Fludarabine refractory patients have a poor prognosis. (Jan 2010)
    Fludarabine -AFHS Bookshelf

    Canadian Drug Bank Project - Fludarabine
    Complete Drug Info .pdf file

    Info Sheet - Fludabine
    Posted: ~chris October 13th, 2009

  • Cyclophosphamide (Endoxan, Cytoxan, Neosar, Procytox, Revimmune) Delivery: Oral

    Cyclophosphamide is an alkylating agent of the nitrogen mustard type.3 An activated form of cyclophosphamide, phosphoramide mustard, alkylates, or binds, to DNA. Its cytotoxic effect is mainly due to cross-linking of strands of DNA and RNA, and to inhibition of protein synthesis.4 These actions do not appear to be cell-cycle specific.

    It is usually not used for treatment of CLL patients over 80 years of age. Currently Cyclophosphamide is used in combination with Fludarabine and Rituxan (FCR) The Rituxan portion is not paid for by provincial drug plans as of November 2009. It may be under review.

    Complete Drug Info .pdf file

    Cyclophosphomide - AHFS
    Info Sheet - Carcinogens
    Posted: ~chris Nov 3rd, 2009

  • Lumiliximab (X) Delivery: IV)

    Lumiliximab is a monoclonal antibody like Rituxan, however it targets CD23 not CD20. The union of lumiliximab and CD23 is ultimately thought to lead to a reaction in the cell that destroys the leukaemic cells bearing the CD23 molecule.
    Lumilliximab (IDEC-152) is a CD23 targeted monoclonal antibody attaching to a low-affinity IgE receptor. It acts as an immunomodulator Generally well tolerated however 15% of patients have reported grade 3 and 4 toxicity.

    It has an advantage over CD20 in that it does not effect T-cells or Natural Killer (NK) cells. However as a single treatment in early studies no complete or partial responses were observe by NCI criteria. 50% of patients saw a reduction in their lymphocyte counts.

    It is currently in clinical trial for relapsed CLL patients in Edmonton, Hamilton, London, and McGill (Montreal)

    Lumiliximab with Fludarabine, Cyclophosphamide, and Rituximab (FC+R) Versus FC+R alone

    More Here
    CLINICAL TRIAL

    Posted: ~chris October 13th, 2009

  • Rituxan (Rituxanmab) Delivery: IV, Type: antineoplastic monoclonal,

    In 1998 it was thought that Rituxan could be the 'silver bullet' for CLL, but although it has been very beneficial and works well for NHL, the CLL silver bullet still alludes researchers. Rituxan is not a drug but rather a chimeric monoclonal antibody taken from hamsters and 'humanized' to recognize CD20 surface proteins on B-cells. Generally it has been rather disappointing in regards to treatment as a first line therapy in CLL. The reason for this is that CD20 markers are not very prolific on CLL B-cells.

    Further, each time Rituxan is used the amount of CD20 is further reduced on the B-cells until after about 3 rounds Rituxan fails to work.
    However, Rituxan does seem to have a very positive effect when combined with Fludara (FR) and Fludara, Cylophosophomide (FCR). It seems to have multiplier effect, which makes the chemo actually work better and longer remissions have been realized. (See the CLL4 and CLL8 trials)
    Rituxan will shortly be eclipsed by 'second generation' monoclonal antibodies which are fully human and may have different targets than CD20, CD23 for example.(See Ofatumumab and RO5072759)
    In October 2009 the FDA announced a warning about Rituxan related to progressive multifocal leukoencephalopathy (PML) PML is a rare, progressive, demyelinating disease of the central nervous system that usually leads to death or severe disability. PML is caused by activation of the JC virus. JC virus resides in latent form in 40-80% of healthy adults.
    Rituxan is being marketed more for use with rheumatoid arthritis than leukemia/lymphoma. Currently it is not paid for by any provincial healthcare system for CLL as a first line treatment. It is available in Clinical Trials usually with Fludara or another drug combo.
    Prescribing Information
    Rituxan - AHFS Bookshelf
    Posted: ~chris Nov 16th, 2009
    Note: FDA Approved Feb 20th, 2010

  • Flavopiridol(X) Delivery: IV, Type: flavone

    Flavopiridol, semi-synthetic flavonoid, has been previously shown to induce apoptosis in B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. The apoptosis was associated with a concomitant activation of caspase-3 without evidence of dependence on functional p53 or Bcl-2 family modulation. In 2007 to 2008 most of the work on this has been done by a team at Ohio State University under the leadership of Drs Grever/Byrd. Currently in small clinical trials.

    View a recent study

    More information
    Posted: ~chris Nov 16th, 2009

  • CAL 101 (X) Delivery: Oral, Type: selective PI3 kinase inhibitor

    A small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K) with potential immunomodulating and antineoplastic activities. PI3K-delta inhibitor CAL-101 inhibits the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), preventing the activation of the PI3K signaling pathway and thus inhibiting tumor cell proliferation, motility, and survival. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. The targeted inhibition of PI3K-delta is designed to preserve PI3K signaling in normal, non-neoplastic cells.

    Currently in Clinical Trials - NCT00710528. No Complete Responses to date.

    Phase 1 - Clinical Trial Info

    More information
    Posted: ~chris Nov 16th, 2009

  • TRU-016 Delivery: IV, Type: CD37 inhibitor

    TRU-016, under development by Trubion Pharmaceuticals Inc and Facet Biotech Corp, is an intravenously administered anti-CD37 IgG fusion protein for the potential treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), as well as for autoimmune and inflammatory diseases. TRU-016 was created by humanizing SMIP-016, a mouse/human chimeric protein that demonstrated antitumor activity against lymphoid malignancies in preclinical studies, including in human B-cell tumour mouse xenograft models.

    In addition, TRU-016 demonstrated synergistic or additive activity in NHL cells in combination with rituximab, rapamycin, doxorubicin and bendamustine. In a phase I/II clinical trial in refractory or relapsed patients with CLL or small lymphocytic lymphoma, TRU-016 was well tolerated, with clinical benefit and a reduced absolute lymphocyte count observed in all cohorts dosed at > 0.1 mg/kg. TRU-016 is a promising therapeutic agent for patients with B-cell lymphoid malignancies, especially patients refractory to standard treatment.

    Currently in Phase 1 dosage clinical trials.


    Posted: ~chris Nov 30th, 2009

  • SF1126 Delivery: IV, Type: mTOTR and PI3K inhibitor

    Semafore Pharmaceuticals' lead product candidate, SF1126, inhibits both the phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR), two key members of the PI3K signaling pathway that is vital to several essential biological processes, such as cell proliferation and survival. PI3K is commonly altered in human cancers, making inhibition of the target attractive for cancer therapy. In view of the fact that mTOR can be activated in a PI3K-independent manner, dual PI3K-mTOR inhibitors, such as SF1126, are expected to offer a therapeutic advantage. As a prodrug that is administered in an inactive form, SF1126 is also unique among clinical stage, dual PI3K-mTOR inhibitors. Once administered, SF1126 targets specific transmembrane cell adhesion proteins known as integrins that are expressed in new tumour vasculature and within the tumour compartment. Because of the targeted design of SF1126, there is a markedly lower chance of inhibiting PI3K and mTOR in healthy, non-cancerous cells which reduces the potential for side-effects. In preclinical studies, SF1126 has shown attractive pharmacokinetic and pharmacodynamic properties and compelling efficacy in xenograft models, both as a single agent and in combination with other therapies. Data from an ongoing Phase I clinical trial of SF1126 in patients with solid tumours recently presented at the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated selective inhibition of the PI3K pathway in tumour tissue but not in normal skin tissue. Notably, there were no clinically significant changes in glucose or insulin levels reported at biologically active doses. Upon completion of single agent Phase I trials, Semafore Pharmaceuticals expects to initiate combination trials in the near future.

    Currently in Phase 1 dosage clinical trials.


    Posted: ~chris Nov 30th, 2009

  • Forodesine --- Delivery: Oral, Type: urine nucleoside phosphorylase (PNP)

    Forodesine is an orally-available transition-state analog inhibitor of purine nucleoside phosphorylase (PNP), a purine salvage pathway enzyme that is essential for the proliferation of T-cells and B-cells.

    Typically, T-cells and B-cells are an essential part of the body's immune system, but when they multiply uncontrollably they can cause various forms of cancer. Inhibiting PNP produces selective suppression of T-cells and B-cells, inducing apoptosis in both types of cells.

    Currently in Phase II clinical trials.

    Clinical Trial Link
    Posted: ~chris Nov 30th, 2009

  • Bafetinib --- Delivery: Oral, Type: dual Bcr-Abl and Lyn-kinase inhibitor

    Bafetinib is a potent, orally available, rationally designed, dual Bcr-Abl and Lyn-kinase inhibitor, which is currently being planned as a third-line treatment for patients with chronic myeloid leukemia (CML) or certain forms of acute myeloid leukemia (AML) that are refractory or intolerant of other approved treatments. CytRx plans in the first half of 2010 to initiate a Phase 2 proof-of-concept clinical trial to evaluate the efficacy and safety of bafetinib (formerly known as INNO-406) in patients with high-risk B-cell chronic lymphocytic leukemia (B-CLL). Based on trial results, CytRx hopes to conduct a larger comparative trial to further determine efficacy of this agent.

    Currently entering Phase II clinical trials.


    Posted: ~chris December20th, 2010

  • Pentostatin (Nipent) aka deoxycoformycin --- Delivery: IV, Type: antimetabolite

    Pentostatin is often used like fludarabine (FCR) in combination with Cyclophosphomide and Rituxan (PCR) PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen (PC), researchers found that rituxan did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Dr. Neil Kay stated in a recent study "Pentostatin has also been shown to have clinical activity in CLL and appears to be less toxic than its fludarabine counterpart, which may offer some important advantages."

    Currently entering Phase II clinical trials.

    Dr. Kay's Mayo Study

    Addition Information in .pdf

    PCR - CLL study
    Posted: ~chris December20th, 2010