Chronic Lymphocytic Leukemia: Previously Treated

After being first treated for chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma(SLL), a majority of patients have a favorable response. Some have what is called a complete remission (CR) and others have a partial remission (PR). The standards for defining a CR or a PR are not totally clear, and are liable to subjective interpretation. No matter what the level of success of the initial treatment is, it is important for a person to attend routine follow up examinations. These visits enable the treating physician to monitor the level to which the may or may not be progressing. Of course, the length of time or duration of a response to therapy, the remission, can vary widely. In the interim the patient is generally placed back on "active surveillance" (also known as 'watchful waiting') Most hematologists will request follow up approximately every three months; some more, some less. If the disease is indolent (slow-growing) as much as a year can pass between visits. The re-visit will definitely include blood tests, a physical exam for swollen lymph nodes (lymphadenopathy) and enlarged liver and spleen. On occasion a scan may be requested. A computer tomography (CT) scan is most often used, although there is some radiation connected with it. An MRI (magnetic resonance imaging) scan can be used, but physicians claim less information can be obtained with this type of scan. These days the most popular is a combination PET (positron emission)/CT scan, which sometimes carries less radiation than a full CT scan, and is believed to be the most informative in identifying what is happening in the patient's body.

The persistence of obvious CLL/SLL following treatment is known as refractory (a cancer that is resistant to treatment) disease. In other words, the patient has shown to be "refractory" to the particular treatment just completed. A relapse is a more general term, meaning the return of the disease after some time. From a treatment perspective the difference between refractory disease and relapse is that refractory disease prompts the immediate consideration of a more aggressive treatment approach, while detection of relapse does not always mean that treatment is needed immediately. Also, in the event of a relapse, the doctor may try the original treatment a second time. A period of observation is usually advisable when disease has relapsed. Eventually, more of the same, another, or a more aggressive treatment may be required. A patient may wish to consider several factors with their physician such, as the level of relapse, the rate at which sick cells are increasing and the presence of symptoms, before deciding on a second line treatment strategy.

Second-line treatment options may be more aggressive than first line. For example, if chemotherapy alone was used as a first line therapy, a combination chemotherapy and immunotherapy may constitute a more effective approach. The optimal application of monoclonal antibody therapies in previously untreated CLL/SLL is still under investigation. However, the FDA has approved three immunotherapies (rituximab, ofatumumab and alemtuzumab) for relapsed or refractory CLL/SLL.

Also, as described earlier, a procedure called bone marrow (stem cell) transplantation is another treatment option for CLL/SLL, depending on a number of factors, such as a patient's age and condition.

Specific Treatments Options

It is also important to check whether additional genetic or chromosomal transformations have occurred, such as the p17 transformation mentioned earlier. The ever expanding field of knowledge regarding treatment of relapsed CLL/SLL offers much hope. One strong possibility is to become enrolled in a clinical trial. These are ongoing, and can be found by going to www.clinicaltrials.gov where most trials are listed and described. Technology and knowledge are advancing so rapidly that this might be the best approach for a patient in trouble.

Secondly, depending on the cancer center with which you are working, new approaches, beyond clinical trials, may already be available. Sometimes a doctor may favor a particular approach and, although the FDA may not have approved the special drug for treatment of relapsed CLL/SLL, it may be obtainable on the basis of what is called "compassionate use."

For patients whose disease becomes refractory (no longer responds to treatment) or relapses (returns after treatment), secondary therapies may be successful in providing another remission.  Some common agents that are used either alone or in pairs for relapsed/refractory CLL and SLL include:

  • Bendamustine
  • Chlorambucil
  • Fludarbine
  • Ibrutinib
  • Idelasib (Zydelig) + rituximab
  • Obinutuzumab
  • Ofatumumab
  • Rituximab
  • Venetoclax (Venclexta)
  • Alemtuzumab (Campath; provided only through Campaith Distribution Program; no longer commercially available)

Other combination treatment regimens occasionally used in the relapsed/refractory setting include:

  • HDMP (high-dose methylprednisolone) and rituximab
  • OFAR (oxaliplatin [Eloxatin], fludarbine, cytarabine [Cytosar-U], and rituximab)
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin [Adriamcin], vincristine [Oncovin], and prednisone)

Ofatumumab can also be used as maintenance therapy to prevent relapse in paitnts who achieve full or partial remission after at least two other therapies for CLL.  Stem cell transplants are usually done as parto of a clinical trial in patients with high-risk or relapsed/refractory disease.

Treatments Under Investigation

There are many novel therapies currently under clinical trial investigation in the relapsed/refractory setting and include:

  • ABT-263 (an inhibitor of the Bcl-2 protein)
  • Flavopiridol (a cyclin-dependent kinase inhibitor)
  • Oblimersen sodium (Genasense)
  • Lumiliximab (anti-CD23 antibody)
  • Lenalidomide (Revlimid)
  • TRU-016 (anti-CD37 protein)
  • IPI-145
  • Dasatinib ( Sprycel)
  • MOR00208
  • MEDI-551
  • Ublituximab
  • TGR-1202

Therapeutics is another important area of research. Although we use FCR or BR, CLL remains an incurable disease, and the majority of patients fail to achieve a complete remission. Several agents in development appear to have promise. Two of these in particular, CAL-101 and PCI-32765, are oral drugs called kinase inhibitors; these are very active in patients with relapsed and refractory CLL and are now being further developed in combination with other drugs. GA-101 is a monoclonal antibody that, like rituximab, targets a protein on the cell surface called CD20. GA-101 is being directly compared with rituximab in clinical trials. There are other antibodies targeting other proteins on the surface of CLL cells, such as CD19, and drug-antibody conjugates, in which the antibody is bound to a toxin. In addition, immunomodulatory drugs (IMiDs), such as lenalidomide, are active in CLL. Many more drugs are being evaluated.

It is critical to remember that today's scientific research is continuously evolving. Treatment options may change as new treatments are discovered and current treatments are improved. Therefore, it is important that patients check with their physician or with LRF for any treatment updates that may have recently emerged.