Chronic Lymphocytic Leukemia (CLL) treatments have changed greatly over the past 25 years. In order to more completely understand the magnitude of that change a bit of historical perspective is needed. This blog is my attempt to describe the CLL treatment paradigm and how it has changed through the years.
Early Treatments and the Advent of Chemotherapy
Leukemia was formally defined in 1845 as a blood disorder characterized by an over abundance of white blood cells. Early treatment for leukemia was arsenic trioxide. That persisted until about the 1920s when radiation was recognized to reduce tumor size and decrease white blood cell counts. Early radiation therapy was administered both externally using X-rays and internally by intravenous administration of Phosphorus-32, a short half life (14.29 days) beta emitter.
CLL was first defined as a variant of leukemia in 1913. Prior to that date leukemia included all blood diseases characterized by an over abundance of white blood cells. It was not until after world war II that chemotherapy was developed and applied to the treatment of CLL. The early chemotherapy agents were derived from mustard gas after it was discovered that soldiers exposed to mustard gas developed low white blood cell counts. The sulfur mustards in mustard gas were too toxic for clinical use so nitrogen mustards were developed. The early aliphatic nitrogen mustards (i.e., they had straight carbon chains) included drugs like mechlorethamine hydrochloride (mustine hydrochloride). In the 1950s less toxic aromatic mustards (with 6 carbon rings rather than straight carbon chains) including chlorambucil (Leukeran). Chlorambucil was approved for medical use in 1957 and became the primary treatment for CLL. Chlorambucil is an oral therapy administered as pills. Chlorambucil was used as a single agent treatment or combined with cortico-steroids. Now, 60 years later, chlorambucil is still occasionally used in treatment of CLL, particularly of frail elderly patients due to its low toxicity compared to modern chemotherapy agents. Chlorambucil is also frequently used in clinical trials as a reference treatment although that practice is decreasing since it is widely thought that virtually all modern treatments are more effective than chlorambucil. Chlorambucil is in the class of chemotherapy drugs known as alkylating agents.
Cyclophosphamide was developed in the early 1950s and was FDA approved as an anti-cancer drug in the USA in 1959. Like chlorambucil, the drug is a nitrogen mustard derived alkylating agent. Cyclophosphamide was used extensively in CLL treatment as a single agent and combined with cortico-steroids. The drug can be administered both orally and intravenously, but is generally administered intravenously in CLL therapy. Although no longer used as a single agent, the drug is still commonly used in multi-agent chemotherapy regimens.
Bendamustine (Treanda) is was developed in 1963 in East Germany. It was not available outside East Germany until 1990. Bendamustine is also a nitogen mustard based drug and is classed as an alkylating agent. Bendamustine was approved by the US FDA in 2008 for the treatment of all patients with CLL.
Fludarabine (Fludara) is a purine analog chemotherapy agent first synthesized in 1968. Early clinical trials showed that fludarabine was more effective than chlorambucil. Later trials looked at the combination of fludarabine with cyclophosphamide (FC therapy) as well as the chemo-immuno therapy combinations FR and FCR where R refers to the monoclonal antibody rituximab. Fludaranine single agent therapy was approved by the FDA in 1991 for patients who had not responded to or relapsed after previous therapy. FCR therapy was approved for all CLL patients in 2010. Fludarabine is normally administered intravenously although an oral version of the drug (approved in 2008) is available.
There are a number of other chemotherapy agents used in some treatment protocols for CLL As far as I can tell the following drugs are used off label In some protocols pentostatin is substituted for fludarabine in the FCR protocol. Pentostatin is approved for tratment of hariy cell leukemia, but not CLL. Similarly cladribine is sometimes substituted for fludarabine. Like pentostatin, cladribine is approved for hairy cell leukemia. Lenalidomide, a thalidomide derivative, is approved for multiple myeloma and myelodysplastic syndrome, but has shown some efficacy in CLL. Vincristine, which is approved for acute lymphoblastic leukemia, is also sometimes used off label to treat CLL.
Rituximab (Rituxan) is a chimeric monoclonal antibody which targets the CD20 protein expressed on healthy, mature B-cells and to a lesser extent on CLL B-cells but not on immature or developing B-cells. A chimeric monoclonal antibody is a drug that contains murine (mouse) and human components. Rituximab works by binding to the CD20 protein on the surface of B-cells causing cell apoptosis (cell death). Rituximab was developed in the late 1980s/early 1990s and was approved for the treatment of non-Hodgkins Lymphoma in 1997. In the late 1990s clinical trials of rituximab (R) combined with fludarabine (F) and cyclophosphamide (C) began. Those trials showed superior results to F monotherapy and FC combination therapy. However it was not until 2010 that FCR therapy was approved in the USA by the FDA for for treatment of CLL in previously untreated and treated CLL.
Since the development of rituximab there have been two newer C20 monoclonal antibodies developed. They are obinutuzumab and Ofatumumab. Both drugs work by the same mechanism as rituximab, but the newer dugs are fully humanized and do not contain any murine components to reduce allergic reactions.
Obinutuzumab (Gazyva) is a fully humanized CD20 monoclonal antibody. Obinutuzumab was given FDA approval in 2013 for use in combination with chlorambucil for treatment of all CLL patients.
Ofatumumab (Azerra) is a fully human monoclonal antibody that targets CD20 on the surface o B-cells. Ofatumumab was FDA approved for treatment of relapsed, refractory CLL in 2009. It received a further approval for treatment in combination with chlorambucil of previously untreated patients in 2014. In early 2016 the drug was also approved as a maintenance therapy for patients after at least two prior lines of therapy. Later in 2016 Ofatumumab was also approved in combination with fludarabine and cyclophosphamide (FCOf therapy)for treatment of relapsed CLL following prior treatment.
Alemtuzumab (Campath) is an anti CD52 monoclonal antibody that was initially approved in 2001 for CLL patients who had prior alkylating agent therapy and failed fludarabine therapy. The approval was expanded in 2007 to all CLL patients. However, in 2012 the drug was withdrawn from the US and european markets and reintroduced as Lemtrada in 2014, which is only approved for treatment of multiple sclerosis. The drug is still available for clinical studies and, with some difficulty, off label use for CLL.
Chemo-Immuno therapy is the combination of chemotherapy drugs with monoclono antibodies. This combination has been found to provide better responses and progression free survival results than chemotherapy alone.
FCR therapy (Fludaraine+Cyclophosphamide+Rituximab) was approved for treatment of all CLL patients in 2010. The initial clinical trials for FCR therapy began in the late 1990s. The therapy has been found to be particularly effective for patients with mutated IgVH gene and the 13q chromosome deletion. For those patients FCR therapy generally produces long remissions. As many of 30% of that group of patients from the initial clinical trials are still in remission 17 years later. However, FCR therapy was not found to produce durable remissions for many 17p deleted patients with both the response rate and progression free survival of 17p deleted patients being poor compared to other patients. As a consequence, many doctors no longer advise FCR therapy for 17p deleted patients. Of the current chemotherapy based treatments FCR is the most harsh and restricted to younger, fit patients without decreased kidney or liver function. Currently (2017) FCR is the preferred frontline therapy for younger fit CLL patients without the 17p chromosome deletion or mutated p53 gene. In 2016 and additional FC chemoimmuno therapy combination was approved in which ofatumumab replaced rituximab.
BR (Bendamustine-Rituximab) therapy is a chemo-immuno combination therapy that, in the US, is an on-label use of bendamustine combined with an off-label use of rituximab. BR is an approved therapy for CLL in Germany. BR is generally a less intense therapy than FCR. Consequently it is often used for patients without a 17p deletion or mutated p53 gene who would not be considered eligible for FCR therapy.
Two chlorambucil-monoclonal antibody combinations have also been approved which combine chlorambucil with obiutuzumab and with ofatumumab.
As of 2017 there are three targeted therapies. These drugs target specific signalling pathways within CLL B-cells. They are Ibrutinib which targets the BTK pathway, Idelalisib which tarkets the Pi3K pathway and Venetoclax which targets BCL2. All of these drugs are oral therapies rather than intravenous infusion therapies. At present treatment with these drugs is open ended. In other words, treatment continues until disease progression or intolerable side effects occur. The side effect profiles of these drugs are significantly less than chemotherapy or chemoimmuno therapy treatments. In addition all of these drugs produce response rates more or less independent of cytogenetics (chromosome mutations).
Ibrutinib (Imbruvica), which irreversibly binds to the Brutons Tyrosine Kinase pathway and triggers cell death, was the first of these drugs to get FDA approval for treating CLL. Ibrutinib was approved in February 2014 for CLL patients who had received one prior herapy and had a 17p chromosome deletion. In May 2016 the approval was expanded to all CLL patients. Ibrutinib has a very high response rate (~95%) and patients respond more or less independent of their cytogenetics. Consequently ibrutinib therapy has become the front line therapy of choice for those with a 17p deletion.
Idelalisib (Zydelig), which targets the Pi3K communication pathway, was approved in combination with rituximab for relapsed Cll patients in July of 2014. While the idelalisib part of the therapy is open ended, the rituximab treatment only continues for approximately 5 months.
Venetoclax (Venclexta) is a BCL-2 inhibitor. BCL2, which is over expressed on CLL B cells, promotes extended cell life. Bonding of venetoclax to BCL-2 on CLL B cells triggers apoptosis (cell death). Venetoclax was approved in May 2016 for relapsed refractory CLL patients with 17p chromosome deletion.
Timeline of Treatment Approvals
Prior to the 50s there was only radiation therapy and a few drug therapies I didn’t mention. None of those therapies was particularly effective in that they only slowed progression of CLL. In the 50s the development of comparatively effective chemotherapy drugs (chlorambucil and cyclophosphamide) improved the life of CLL patients in that those drugs did generate remissions in some patients. However those remissions were not particularly durable and the lack of alternate therapies meant that while quality of life was improved, overall survival was not. The approval of fludarabine in 1991 for CLL treatment brought with it much higher response rates and deeper and more durable remissions. However, patients with negative prognostic indicators (17p and p53 mutation) still had a very poor prognosis since those patients were often resistant to fludarabine treatment. The real break through in survival came with the development and approval of FCR therapy. That was particularly true for some 13q deleted patients with IgVH mutations where FCR therapy might even be a cure. Again the 17p deleted patients were largely left out of the break through. In 2014, the approval of the targeted therapies marked another break through that this time included the 17p deleted patients. Furthermore, while some patients still fail therapy with one of the targeted therapies, the other therapies still appear to work for them.
2017 Treatment Paradigm
In 2017 the approval of the targeted therapy drugs ibrutinib, idelalaysib and venetoclax has completely changed the CLL treatment paradigm. Prior to the approval of these drugs treatment options were chemotherapy and chemoimmuno therapy. Since people with 17p chromosome deletions tended to respond poorly to those therapies, and also relapsed relatively quickly if they did respond, the prognosis for 17p and to a lesser extent 11q deleted patients was poor. Survival often depended on receiving multiple rounds of treatment. The approval of the small molecule targeted therapies changed that completely because responses were more or less independent of cytogenetics. As a consequence, cytogenetics has become more of a guide to treatment choice than a prognostic factor. Despite that statement having an 11q or 17p chromosome deletion still is worse than any other genetic anomaly, but the difference is considerably less than it was before the targeted therapies were developed.
2017 treatment options.
As of 2017 treatment options fall into two categories – chemoimmuno therapy and targeted therapy. Cytogenetics and other prognostic factors are used more now to guide therapy than they are for prognosis.
Chemoimmuno therapy is still a valid option for some patients, although some doctors are suggesting that chemo is now a thing of the past. The reasons chemo remains viable are two fold. First for the subset of patients with 13q deletion and mutated IgVH genes, FCR therapy holds out the possibility of a very long deep remission that might even be a cure. Unfortunately, only relatively young and medically fit patients are candidates for FCR, so the population it is viable for is small. The other argument for chemo is that it is a relatively short term treatment – 6 months and done. That prospect makes it preferable to some patients particularly given the very high cost of the targeted therapies. Cost is often a significant consideration for older patients on Medicare since the oral targeted therapies can cost as much as $10K per year even with Medicare Part D drug coverage. Many people simply can’t afford that. For those that prefer the shorter term treatments of chemo, but are not as fit, the options are BR therapy, which still requires a reasonable level of fitness, or chlorambucil with either obinutuzumab or ofatumumab. The two chlorambucil regimens are less physically demanding than either FCR or BR, but the responses are not as deep or durable.
Targeted therapies are now available to all patients. For those with the 17p deletion the first line treatment of choice is now ibrutinib. This option is also open to all CLL patients. Should a patient relapse or have to stop ibrutinib therapy, idelalisib and venatoclax are available. Those options appear to work well after failure of one of the other targeted therapies. With the exception of cost, these therapies have significantly lower side effect profiles than the chemo regimens and are thus possible for older, more frail patients. All of these therapies also hold out the prospect of minimal residual disease negativity, which may be a cure for some, although that determination is pretty far away at present.
Finally, there are currently a number of other targeted therapies in the pipeline. They include several newer BTK therapies with apparently even fewer side affects than ibrutinib as well as other drugs targeting different signalling pathways. In addition there is a lot of clinical research on combinations of targeted therapies (i.e. venetoclax and ibrutinib) and combinations of targeted therapies with monoclonal antibodies. Those studies hold out the possibility of even deeper and more durable remissions and the possibility of stopping targeted therapy after achieving minimal residual disease negativity.
There is also work going on with CarT-cell therapy in which the patients own T cells are removed, modified to attack their CLL B cells and reinjected. Finally, there is always the possibility of a stem cell transplant. However, I am of the opinion that transplant is declining in importance because of the success of targeted therapies, not to mention the risks of stem cell transplant.
I hope this discussion has been useful to you. Please comment if you have any questions.