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The National Oncology Pharmacy Symposium 2006/Canadian Association of Pharmacy in Oncology

Montreal, Quebec / October 13-15, 2006

Chronic lymphocytic leukemia (CLL) is now the most common form of adult leukemia in North America, accounting for one in four new cases of leukemia and some 40 new patients per million individuals (Diehl LF. Cancer 1999;86(12):2584-92). It is most frequently seen in patients aged over 60 (median age at diagnosis is 70), but CLL incidence rises steeply beginning around age 45; and cases in patients aged less than 55 years have increased in recent years. Its cause remains unknown, although genetic predisposition appears to play a role in 5-10% of patients as offspring of affected patients are at increased risk of CLL and other primary cancers.

The diagnosis of CLL is typically made incidentally, when isolated peripheral lymphocytosis is detected on routine blood screening or on laboratory tests ordered for another reason, noted Wally Watral, DPharm, Clinical Pharmacist and Clinical Pharmacy Practice Leader, CancerCare Manitoba, and Assistant Professor, Faculty of Pharmacy, University of Manitoba, Winnipeg. “What happens is you get the accumulation of B cells that lack the ability to undergo the normal process of cell death or apoptosis,” he explained. As such, lymphocytes and occasionally malformed “smudge” cells predominate in blood smears in CLL, and as the disease progresses few or no platelets or neutrophils are seen. Similarly, the marrow of patients with CLL is overpopulated with B lymphocytes that progressively supplant other cell types.

Because CLL is recognized at an early stage in some 80% of cases, about half of affected individuals exhibit no symptoms at the time of diagnosis. About 15% will complain of B symptoms such as fever, weight loss or fatigue. Initial findings on physical examination may include lymphadenopathy (observed in about 90% of patients), splenomegaly (50%), hepatomegaly (15%) or, more rarely, anemia.

Although diagnostic laboratory criteria for CLL were established in the 1990s by the National Cancer Institute sponsored working group, confirming the diagnosis “now primarily hinges on immunophenotyping,” explained Dr. Watral. Characteristic cell types include CD5+, CD19+, CD20+ and CD23+ cells. T-cell markers are absent; however, most cells express monoclonal immunoglobulins with kappa or lambda light chains. Atypical cells should make up <55% of the total or <15 x 109/L (in contrast with other types of leukemia). According to the working group criteria, peripheral blood lymphocyte counts should be >5 x 109/L and bone marrow infiltration >30%; however, these levels do not specifically need to be met if the immunophenotype matches the typical pattern, Dr. Watral stated.

As the disease progresses, bone marrow function is impaired and normal production of neutrophils and immune globulins falls, in turn weakening defence against infection. Autoimmune disorders may also occur. Autoimmune hemolytic anemia is observed in about 10% of new cases of CLL but in more than 30% of individuals with more advanced disease, noted Dr. Watral. Pure red cell aplasia (the absence of red cell precursors) occurs in up to 6% of patients and immune-mediated thrombocytopenia in 2-4%. While these complications can be treated and do not affect overall survival (OS), others have graver implications. Richter’s syndrome involves transformation of the disease to an aggressive form with a median survival of less than six months. A broad range of other malignancies, including solid tumours, may occur.

New Predictive Factors

The course of CLL is highly variable. “A significant portion of patients will live for 20 to 30 years before they die of another cause,” indicated Dr. Watral. Nearly 75% of individuals with CLL will survive for five years; median survival is 10 years. On the other hand, a substantial proportion of patients experience rapid progression despite therapy and die within two years. “Given this variability, we want some means of predicting how patients will do,” he observed. The Rai and Binet clinical staging systems (Figure 1) constituted a first step in determining prognosis. Studies of both systems indicate that more severe disease is associated with lower rates of survival. However, prognosis for individual patients does vary within the Rai and Binet categories. Several newly recognized markers can help make this assessment, affirmed Dr. Watral.

Figure 1. Disease Staging

Doubling of lymphocyte counts within 12 months has been established as a marker of aggressive CLL and poor prognosis; however, this link is retrospective rather than prospective, Dr. Watral noted. A hemoglobin level of <110 g/L also suggests aggressive or advanced disease, as does diffuse as opposed to “patchy” bone marrow involvement. More than 20% expression of CD38+ cells points to an unfavourable course and resistance to treatment with fludarabine. A ß2 microglobulin level >2.0 g/L has also been suggested as a poor prognostic factor, although its predictive power has not been proven in all prospective studies. Resistance to standard drug therapies is an “intuitive” prognostic variable, he remarked. “This is especially true when patients are fludarabine-resistant; the worst survival is seen in these patients.”

Cytogenetic studies now play a key role in determining prognosis and can be used to improve therapeutic decision-making. “It’s known now that 80 to 90% of CLL cells have genetic abnormalities,” explained Dr. Watral. Among these are p53 mutations, which connote a poor response to traditional therapies such as alkylating agents and purine analogues. Deletion of the 17p chromosome is associated with loss of a known tumour suppressor gene and suggests disease progression will be rapid (i.e. within one to two years). Deletion of 11q is also a marker of aggressive disease, often associated with bulky lymph nodes. Trisomy 12 has been correlated with shortened treatment-free survival.

Markers suggesting a relatively better outcome for a patient with CLL include deletion of the 13q chromosome and mutation of B-cell heavy-chain immunoglobulins (IgVH), seen in about half of patients with the disease. “There are almost two different populations of CLL cells and this makes a dramatic difference [in survival],” Dr. Watral stated. One study showed, for example, that patients with IgVH mutation had a median survival of 293 months, as compared with 117 months for those with unmutated cells. The difference was even more marked in patients whose disease was diagnosed at an early stage (Hamblin et al. Blood 1999;94(6):1848-54). “The problem is that determining mutation status is a very involved process and is restricted to certain labs, so people have been looking for a marker that can be correlated with the mutation status,” he observed. An apparent surrogate is zeta-associated protein (ZAP)-70, an internal protein kinase that is not expressed by normal B cells. (ZAP-70 can be measured by any laboratory that can perform flow cytometry, although there is as yet no standardized measurement protocol.) Published research (Rassenti et al. N Engl J Med 2004;351:893-901) showed that patients with CLL who had less than 10% to 20% ZAP-70 positive cells did not require treatment until some nine years after diagnosis, while those with >20% ZAP-70 cells required treatment within about three years.

When to Initiate Therapy

Criteria for initiation of therapy for CLL are listed in Table 1. Traditional treatment options include alkylating agents (chlorambucil or cyclophosphamide) with or without corticosteroids. Several trials have shown that the nucleoside analogue fludarabine produces higher overall, complete and partial response (PR) rates and longer duration of response than alkylating agents or regimens combining chemotherapy with corticosteroids, noted Marc Geirnaert, clinical oncology pharmacist, CancerCare Manitoba. In one large trial, fludarabine and a combination of cyclophosphamide, doxorubicin, vincristine and prednisone produced results much superior to those of cyclophosphamide/doxorubicin/prednisone. However, no study showed a significant OS advantage for fludarabine treatment, he added.

T
Initiation of Therapy

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Evolving Treatment

Newer agents for patients whose disease has failed to respond to traditional cytotoxic therapy include the monoclonal antibodies (MAbs) rituximab and alemtuzumab, which react with CD20 and CD52 antigens, respectively, on CLL cells. Rituximab is generally offered in combination with fludarabine, as it has shown synergy with this agent and does not produce high response rates when given as monotherapy. In a recent phase II trial of rituximab in combination with fludarabine and cyclophosphamide in patients with Rai stage III and IV disease, overall and complete response (CR) rates were 95% and 71%, respectively, and 69% of patients were in remission after four years (Keating et al. J Clin Oncol 2005;23:4079-88). “Of course, phase III trials will have to be performed, but this will be a regimen we’ll see more of in future,” predicted Geirnaert.

A second MAb, alemtuzumab, is indicated for CLL upon failure of alkylating agents and fludarabine. Its approval for this purpose was primarily supported by Keating et al. (Blood 2002;99:3554-61), in which 93 patients with advanced CLL (Rai stage III or IV) and who had experienced fludarabine failure were given alemtuzumab for four to 12 weeks. “The study exceeded the target response rate [of 20%]. Thirty-three per cent of patients had a response, 2% were CR and 31% PR. Median survival in all patients was 20 months and for responders, it
aert summarized (Figure 2).

Figure 2. CAM 211: Overall Survival

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“If you look at historical controls in patients who are fludarabine-refractory, the prognosis is very dim and their median OS is 10 months,” he pointed out. For the patients who responded to alemtuzumab, OS was nearly tripled, a response Geirnaert characterized as “dramatic.” Whether their disease responded or not, patients who received alemtuzumab experienced improvement
anemia, splenomegaly and performance status, he added (Table 2).

Table 2. Keating Summary of Clinical Benefit

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Assessment of alemtuzumab is continuing. Preliminary data from the CAM 307 trial (Hillmen et al. ASCO 2006) indicate that in comparison with chlorambucil (the agent typically used for first-line therapy), the MAb led to an OR rate of 82.6% vs. 54.7% in 297 patients with untreated progressive CLL. CR occurred in 22.1% vs. 2% and PR in 60.4% vs. 52.7%. The combination of alemtuzumab and fludarabine is being compared with fludarabine alone as second-line therapy for CLL. According to preliminary results, rates of OS and CR with the combination were 83% and 30%, respectively. Response duration was 13 months for all patients and 22 months for those who had achieved a CR to the combination (Elter et al. J Clin Oncol 2005;23: 7024-31). Allogeneic stem cell transplant may be offered to patients with very aggressive CLL (for example, those with 17p deletion). Its use is largely limited to younger individuals or those with good performance status. Nonmyeloablative stem cell transplant, which involves reduced-intensity conditioning regimens, can sometimes be offered to older patients with CLL, Geirnaert remarked.

General Considerations

Pharmacists and nurses have key roles in the administration of therapy for CLL, patient monitoring and management of adverse events. Geirnaert and Dr. Watral reviewed several practical aspects of alemtuzumab use garnered from both current management guidelines (Keating et al. Clin Lymphoma 2004;4:220-7) and their centre’s experience.

The MAb is currently indicated for intravenous (i.v.) infusion; however, as discussed below, subcutaneous (s.c.) administration is equally effective and better tolerated. A dose-escalation strategy is recommended to achieve the target dose of 30 mg three times weekly. If a first dose of 3 mg is well tolerated (usually measured by an infusion-related reaction no more severe than grade 2) the second dose is 10 mg; if the 10-mg dose is well tolerated, the third dose is 30 mg. Lower doses may be repeated on subsequent treatment days until they are well tolerated, Geirnaert emphasized. Lymphocytosis in peripheral blood responds rapidly to alemtuzumab, but as clearance from the marrow takes at least eight weeks, a 12-week treatment course is recommended.

During each alemtuzumab infusion, “Nurses should be monitoring the patients for two things, adverse effects and vital signs: blood pressure, heart rate, temperature and oxygen saturation every 15 mi
our, every 30 minutes for the second hour and then for the remainder of the observation period, each hour,” he stated (Table 3).

Table 3. Patient Monitoring

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Management of Adverse Events

Infusion-related reactions: The three most common infusion-related events related to i.v. infusion of alemtuzumab are fever, rash or urticaria, and rigors. “If infusion-related events occur, they are usually grade 1 or 2 severity. Patients should be told that if they do occur, they’re more common during the first week of therapy and get better with time,” Geirnaert told the audience.

Premedication aimed at preventing these reactions include 650 mg oral acetaminophen and 25 to 50 mg diphenhydramine or another antihistamine (i.v. or oral) every four to six hours. “Some centres use corticosteroids just for the dose escalation phase, as this is when we note the greatest release of cytokines,” Geirnaert noted. Because fever tends to occur five to six hours after the infusion, a second dose of acetaminophen may be taken four hours after the first. Patients may be told that infusion-related fever tends to subside after the first week of treatment. Those who experience a rash may take additional diphenhydramine or hydrocortisone. If rash is severe, premedication with an H2 receptor antagonist such as ranitidine may be considered for subsequent infusions.

If rigors develop during the alemtuzumab infusion the treatment is stopped and the patient is given i.v. meperidine 25 mg. The patient is typically reassessed by a physician after 30 minutes. If the rigors have subsided the infusion is reinitiated, Geirnaert indicated. Similar steps are followed if hypotension or dyspnea occur during infusion: a physician is generally asked to assess the patient. Hypotension usually resolves with hydration with normal saline. Ongoing dyspnea may require the administration of a ß2 agonist or, in severe cases, corticosteroids.

As shown in Figure 3, s.c. injection of alemtuzumab produces fewer adverse events. “Rigors, rash, hypotension and fatigue are much less [frequent]...and that’s the main reason why our centre is using the s.c. administration,” Geirnaert indicated. The abdomen is the optimal site for s.c. administration. Patients may apply an ice pack to the injection site for 30 minutes
injection, and as needed at home, to minimize inflammatory reactions. They may be advised that these reactions typically disappear after a week or two.

Figure 3. Comparison of i.v. and s.c. Formulations

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Hematologic adverse events: Cytopenia is a common side effect of alemtuzumab treatment but is generally predictable and manageable, stated Dr. Watral. Thrombocytopenia usually occurs within the first two weeks, but a large majority of patients experience cell recovery above baseline two months after treatment. Neutropenia tends to appear after five to six weeks of treatment and also resolves approximately two months after treatment. Hematologic toxicity does not always require withdrawal of alemtuzumab, “depending on what happens with the patient,” said Dr. Watral. “If the platelet count drops significantly [i.e. <25 x 109/L], it can [sometimes] be managed with platelet transfusion.” Similarly, if neutropenia occurs, the MAb may be withheld until cell counts recover, or if treatment delays are undesirable, the patient may be given granulocyte colony-stimulating factor (G-CSF). “Our approach is that if the absolute neutrophil count gets to <0.25 x 109/L, rather than withholding the alemtuzumab, we look at giving G-CSF, which is known to produce a quick turnaround in the neutrophil count,” he reported.

“Pre-existing neutropenia, thrombocytopenia or anemia are not contraindications to using alemtuzumab. In fact, in the Keating study, between 30 and 40% of patients had some of these symptoms, all of which improved after alemtuzumab therapy,” observed Dr. Watral.

Immunosuppression: Because of the immuno-suppressive effect of CLL as well as agents used to treat it, about 80% of patients will experience infectious complications and approximately half will die of infection. The immunosuppressive impact of alemtuzumab is still being defined. According to one report, when given to previously untreated patients, the MAb led to a profound drop in CD4 and CD8 cells (nadir at week 12); at nine months’ post-treatment, cell counts had increased to only 25% of baseline. Interestingly, however, in the fludarabine-refractory patients treated in the 2002 study led by Keating, the immunosuppressive nadir occurred at week 4 and CD4 and CD8 counts resolved much more rapidly. Also of interest, Dr. Watral remarked, is that approximately 10% of individuals who responded to treatment experienced an infection, while the rate in those who did not respond was 36%. The rate of infection in patients with fludarabine-resistant disease who do not receive alemtuzumab is approximately 60%. “So it doesn’t prove the point, but suggests that if fludarabine-resistant patients receive alemtuzumab, even if they don’t respond, the treatment may moderate the degree of infection they get down the line. It’s something that needs to be studied further,” he commented.

The immunosuppressive effect of alemtuzumab necessitates prophylaxis against Pneumocystis jirovecii (previously known as P. carinii), herpes simplex and varicella zoster virus. The agents typically employed for prophylaxis are listed in Table 4. Prophy
g treatment and for several months after therapy or until CD4 counts recover to >250/µL. If a serious infection does occur, treatment may be postponed and restarted (repeating the dose escalation) after the illness resolves.

Table 4. Prophylaxis

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Cytomegalovirus (CMV) reactivation occurs in 10% to 25% of patients treated with alemtuzumab, usually between weeks 4 and 8 of therapy. CMV reactivation does not necessarily lead to disease, and there is some difference among expert opinion whether CMV monitoring by polymerase chain reaction (PCR) is required, or whether watchful waiting for symptoms is adequate. “In our institution we monitor patients each week by PCR to monitor CMV levels. If patients become positive, they are put on oral ganciclovir. All our patients who have become positive have had rapid reversal with therapy,” Dr. Watral stated.

Discontinuation of Therapy

As stated earlier, the recommended course of alemtuzumab is 12 weeks; however, treatment may be discontinued if a CR occurs earlier or, conversely, if no additional clinical improvement is observed for four weeks or longer. “Certainly, if there is evidence of disease progression, then there’s no point in continuing. If the patient has significant lymphadenopathy and after a couple of weeks of alemtuzumab treatment there’s no change, there’s no indication for continuing,” Dr. Watral remarked. Similarly, serious toxicity may call for withdrawal of treatment.

Summary

Current data on alemtuzumab indicate a course of treatment produces a CR or PR in at least one-third of patients whose CLL has resisted therapy with fludarabine. Even patients who do not enter remission may experience an improvement in CLL symptoms and require fewer transfusions. Immunosuppression, infection and hematologic toxicity are well known adverse effects but can be managed in most patients with premedication and other support measures. Premedication and s.c. administration also heighten the tolerability of the agent.