Chronic lymphocytic leukemia medical therapy

Overview
While generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. No chemotherapy has clearly prolonged survival in CLL. Instead, the condition is monitored over time. The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life. CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy with removal of the enlarged spleen) or by radiation therapy.

Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.

Initial Treatment
Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.

CLL (+12) has the capacity for autoimmune cytopenias. Although about 20% of patients have Coombs positivity only about 8% actually develop hemolytic anemia and about 20% have decreased platelets as well. For warm autoimmune hemolytic anemia give steroids initially, using immunoglobulin secondarily. Cyclosporine is used if steroids and IV-IgG fail. One might also consider Alemtuzumab +/- fludarabine or cytoxan with dexamethasone. For refractory AIHA do splenectomy or splenic irradiation.

Corticosteroids are first-line agents for people in whom the immune systems has been altered by CLL. CLL may cause autoimmune syndromes in which the patient's immune system attacks and destroys his or her own blood cells. When the red blood cells are affected, the condition is known as immunohemolytic anemia, characterized by decreased numbers of red blood cells, which may cause fatigue, dizziness, and shortness of breath. When the blood platelets are affected, it is called immune-mediated thrombocytopenia, in which a decreased numbers of platelets may lead to bleeding.

For younger patients who are experiencing symptoms, the physician may consider early chemotherapy, plus allogeneic or autologous bone marrow transplantation (alloBMT; autoBMT).

In general, the indications for treatment are:


 * falling hemoglobin or platelet count
 * progression to a later stage of disease
 * painful, disease-related overgrowth of lymph nodes or spleen
 * lymphocyte doubling time (an indicator of lymphocyte reproduction) of fewer than 12 months

Transformation of CLL to high-grade disease or aggressive non-Hodgkin's lymphoma
If the patient experiences blood flow problems caused by high numbers of leukemia cells in the circulation, the physician may recommend leukapheresis, also known as apheresis, to separate out white blood cells, prior to chemotherapy. Symptoms that are related to enlargement of the lymph nodes in one area or an overgrown spleen may be treated by localized, low-dose radiotherapy, or surgical management by splenectomy (removal of the spleen). But if leukemia has invaded the lymph nodes at many different sites, total body irradiation (TBI) may be needed.

Alkylators
Chlorambucil (CHB) should be considered for older patients (>90 years) with severe comorbidities (eg renal insufficiency) where they're likely to live less than a year regardless of treatment. CHB is associated with a median survival of about 2 years in patients with advanced stage CLL; a higher response rate (RR) may be achieved with more aggressive treatment regimens such as CHOP but without any clear survival advantage. This agent has been replaced by newer agents. Cytoxan, Oncovin, Prednisone (COP) is not superior to CHB alone, either in complete response rate (CR) or prolonged survival. CHOP does improve the RR to stage B patients but, again, with no survival advantage.

Bendamustine (treanda) is used in the treatment of CLL (& indolent NHL) that has progressed within 6 months after treatment with Rituxumab. Administer as 100 mg/m2 / 30" on days 1+2 of a 28 day cycle; up to 6 cycles. Bendamustine is superior to chlorambucil in the treatment of CLL.  Bendamustine is also given with Ritux for relapsed CLL with the overall response rate (ORR) dependent on chromosomal subtype; 11p deletion = 92%, trisomy 12 = 100%, 17p deletion = 44%, umutated IgVH = 74%.

Purine analogues
Although the purine analogue fludarabine was shown to give superior response rates than chlorambucil as primary therapy, there is no evidence that early use of fludarabine improves overall survival. Fludara can actually make CLL-AIHA worse. It is indicated for patients who have refractory and / or relapsed disease refractory to alkylating agents. Adding prednisone to fludarabine does not increase the RR over fludarabine alone. Add prednisone to fludara only in the presence of autoimmune anemia or thrombocytopenia. Note that fludara with steroids increases the likelihood of P. carinii & Listeria infection. Patients who fail to respond to fludarabine after 2-3 courses should not receive additional courses. No further treatment is indicated if a CR has been achieved; otherwise 2 courses are given after the maximal response is achieved, not to exceed one year.

Combination chemotherapy
Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:


 * fludarabine with cyclophosphamide


 * fludarabine with rituximab


 * FCR (fludarabine, cyclophosphamide, and rituximab) FCR are well tolerated in previously treated CLL.  However most of their toxicity is myelosuppression.  FCR had a high CR rate (25%), nodular PR (16%) & PR (32%).  Molecular remissions are obtained in 1/3 of patients.
 * CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)

Refractory CLL
"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including lenalidomide, flavopiridol, and bone marrow (stem cell) transplantation, are considered. Prolymphocytic transformation of CLL requires treatment with CHOP.

Monoclonal antibodies
The monoclonal antibody, alemtuzumab (directed against CD52), may be used in patients with refractory, bone marrow-based disease. Alemtuzumab (Campath) is an anti-CD52 monoclonal antibody; CD52 is on all B & T lymphocytes. Its use carries a RR = 33% with a CR = 2%. Patients with pre-exisiting cytopenias show improvement in bone marrow function due to the lack of stem cell (CD34) toxicity. Its toxicity against T-cells can lead to significant immunosuppression and infectious complications (esp CMV reactivation). Dose modifications are made for drug related cytopenias. Premedications for its administration are necessary and (almost always) the first dose can be characterized by fever, rigors and nausea. It is recommended to give benadryl, tylenol, hydrocortisone as well as Bactrin DS and Famciclovir. If a 17p del is found in a young CLL patient one could consider Alemtuzumab and early transplant. It is otherwise approved for CLL refractory to alkylating agents and fludarabine. Ofatumumab is a novel monoclonal antibody against CD20 but targets a different epitope than Rituximab. It is also different from Ritux in that it is a completely humanized anti-CD20 antibody whereas Ritux is a chimeric. Ofatumumab (HuMax-CD20) appears to work well for patients who have lower CD20 levels on the surface of their lymphocytes. Therefore it should be more effective than Ritux in treating CLL (Ritux may not work as well because of low CD20 levels). It is an active treatment option for CLL patients refractory to both fludarabine and alemtuzumab.