Treatment

Although there is considerable optimism that the new drug ima-tinib (Glivec, imatinib mesylate) may be as good as, if not better than, IFN in extending chronic phase, the only established "curative" therapy (by which is implied disease-free survival for at least 5 years) in 2003 is allogeneic transplantation. However, despite the extended availability of allografting to older individuals through the development of attenuated conditioning regimens—so-called mini-transplant—the majority of CML patients do not have a transplant option, as shown in Figure 5-1. One has to remember that CML is predominantly a disease of older people, the median age at presentation being 60 years,32 and therefore it is likely that allografting will never be an option for all patients. The development of innovative drug treatments is clearly the way forward to help the majority of patients.

Immediate Management of Newly Diagnosed Patient

The immediate management of a newly presenting patient with possible CML involves the initial history taking and investigation described in the previous sections. The next stage is to control any immediate life-threatening complications such as leukostasis, hemorrhage, or infection, before appropriate antileukemic chemotherapy once the diagnosis is secure. Tumor lysis syndrome is a relatively rare but nonetheless recognized complication and it is prudent to commence allopurinol 300 mg daily by mouth and encourage plentiful oral fluid intake. Once the leukocyte count has fallen below 30 X 109/L allopurinol should no longer be required unless the patient has a history of gout or continues to be hyperuricemic. On some occasions it may be necessary to reduce the leukocyte load more urgently, especially if there is evidence of leukostasis causing the clinical manifestations previously described. This may be achieved by the introduction of large doses of hydroxyurea, in the order of 3.0 to 6.0 g daily, and/or by leukapheresis. Leukapheresis may also considered as the treatment of choice during pregnancy.33,34 If any form of transplant procedure (autograft or allograft) is a possible future option then leukapheresis with cryopreservation of peripheral blood stem cells is preferable prior to initiating any form of treatment. In centers where the facility of leukapheresis is not immediately available it is possible to perform the procedure at a later date having discontinued the hydroxyurea treatment allowing the leukocytes to climb above 30 X 109/L.

Prior to the initiation of antileukemic therapy it is important to discuss frankly, and document, the implications for future fertility with the patient and possibly his or her partner. It is possible to arrange cryopreservation of spermatocytes and possibly oocytes/ovarian slices and this is preferably done in liason with a center specializing in fertility medicine.

Hydroxyurea, in doses of 2.0 to 3.0 g/day, is usually the agent of first choice.35,36 This dose is reduced once the white cell count is reduced below 30 X 109/L. Alternative chemotherapeu-tic agents such as busulfan are no longer routinely used as first line due to their potential for mutagenicity and the number of studies showing benefit of hydroxyurea in patient survival.37-40 For details of mechanisms of actions see the following section on established drug treatments.

At this stage it is important to establish the CMV status of the patient, if there is the potential for a future allograft.

Figure 5—1. An estimate of donor availability and probability of cure as a percentage of all patients with CML assuming that the median age is 50 years and the average number of siblings in a family is two.

<55years but no donor (25%)

Figure 5—1. An estimate of donor availability and probability of cure as a percentage of all patients with CML assuming that the median age is 50 years and the average number of siblings in a family is two.

Although unusual, if blood products are required in the meantime CMV-negative products should be administered until the CMV status is available. HLA typing of patient and sibling(s), and later unrelated donor panels if appropriate, should be performed if transplant is being considered.

Once these steps have been taken one should move on to strategy. Occasionally CML patients with a modestly elevated white cell count that was discovered incidentally may not require intervention with chemotherapy at presentation but can be closely monitored. The diagnosis of CML represents a time of stress and anguish for the patients and their family. Written and Web-based counseling materials and self-help groups can be of great help (see Appendix).

Management Strategy

It is easy for patients with CML to "drift" in their management, as they are often not unwell when they present, and therefore there may be no immediate impetus to discuss management strategy. There are a number of key issues to address soon after diagnosis in order to plan effectively and in a logical manner. A number of individual therapeutic options are described below but a crucial initial consideration is whether a given patient is suitable for a clinical trial—most are. We have attempted to define a strategy to adopt with newly presenting CML patients; however, the scheme shown in Figure 5-2 is not applicable under all circumstances and is only a guide to decision making.

The first consideration is to determine whether allogeneic transplantation is a viable option and this predominantly depends on the patient's age, general health, and the availability of a donor. Within the first 2 to 3 months of diagnosis it should become clear if a sibling donor is identified. If no potential HLA-identical sibling donors are available, the next step involves searching national and international bone marrow panels. Cord bank panels are also worth considering although the cell dose available may be limited. If the searches prove fruitful the patient must be very carefully and repeatedly counseled about the potential risks and benefits.

If allografting is not immediately appropriate the next key decision is whether to use imatinib or IFN-alpha. Whether to

Figure 5-2. Algorithm for therapy in a newly diagnosed CML patient.

perform an "up front" allograft is the key decision and due to the lack of long-term data with imatinib it is difficult to know how best to advise patients. However, many patients are now voting with their feet and choosing a trial of imatinib before considering allografting. Defining "response" to these nontransplant agents is important and a strategy for the evaluation of the degree and duration of cytogenetic and molecular responses must be devised. We propose a scheme in Table 5-5 for the rational use of these relatively expensive techniques. When monitoring CML interphase fluorescent in situ hybridization (FISH) techniques using DNA probes homologous to BCR and ABL are arguably the most representative investigations, but conventional G-banding on at least 30 metaphases will suffice if FISH is unavailable. Quantitative (including real time) RT-PCR should generally be undertaken if FISH positivity is at or below the false-positive level, which is around 6 percent FISH-positive interphase cells unless dual-probe, dual-fusion technology is used. RT-PCR has an established role following allogeneic bone marrow transplantation41 and peripheral blood is as good as marrow. There may be protocol requirements and local preferences or differences in availability, which may dictate techniques and frequency of testing and it is important to recognize that the complexity of these tests dictates that stringent validation criteria must be established.

Because some studies have suggested a survival advantage due to IFN regardless of cytogenetic response, it could be argued that regular marrow cytogenetics are unnecessary. However, this contention remains somewhat controversial and monitoring every 6 months seems to be a reasonable policy. Analysis at 3, 6, 9, 12, 18, and 24 months is recommended post-transplant and yearly thereafter until 5 years. Thus, intervention with donor lymphocyte infusions (DLI) can be considered at the earliest recurrence of BCR-ABL positivity by RT-PCR. After 5 years monitoring should be at the patient's and clinician's discretion. For other patients, especially older individuals and those on hydroxyurea alone, it would seem reasonable to examine the bone marrow only on clinical suspicion of transforming disease.

Established Drug Treatments in Common Use Hydroxyurea

Since its introduction in 197242 this agent has been the "workhorse" therapy for CML.35-39 It is highly effective in controlling the hematological aspects of this disorder43 but does not pro duce any meaningful cytogenetic responses, even at high dose. It has the advantage of relatively few side effects.

The recently published report by the CML Trialists' Collaborative Group44 based on meta-analysis of 812 patients shows no statistical significance between hydroxyurea and busulfan but survival is better with hydroxyurea than with busulfan (53.6 percent vs. 45.1 percent) at 4 years.

IFN-alpha

Since the first reports of its activity in CML in 19 8 3,45,46 IFN-alpha has been widely investigated both as a single agent and in combination. There are no convincing data that there are significant differences between Roferon (Roche) and Intron A (Schering Plough). Both products now come in a pen device similar to those used for delivering insulin. The precise mechanism of action is unclear although many possible mechanisms have been proposed.47-51

Most, but not all, prospective randomized trials comparing interferon with conventional maintenance chemotherapy (usually hydroxyurea or busulfan) have shown a survival advantage of interferon,52-60 leading to the recommendation that IFN-based regimens should be considered in all newly presenting CML patients.61 A meta-analysis of seven randomized trials by the CML Trialists' Collaborative Group62 demonstrated a statistically significant survival advantage of IFN over either hydroxyurea or busulfan. Table 5-6 details the 11 trials identified, with data available from 7 of those (Figure 5-3). The 5-year survival rates were 57 percent with IFN compared to 42 percent with either chemotherapy drug. IFN may be expected to increase life expectancy by a median of 20 months.

Hematological and cytogenetic response to IFN was defined by the Houston group.64,65 A complete hematological response requires the normalization of the leukocyte count to less than 10 X 109/L with the disappearance of immature myeloid cells, normalization of the platelet count to less than 450 X 109/L, along with the disappearance of all signs and symptoms of disease. Cytogenetic response is usually classified according to the proportion of Ph-positive cells. No response is when all metaphases remain Ph-positive; minor response is when 35 to 95 percent of metaphases are Ph-positive; partial response when Ph positivity persists in 1 to 34 percent of metaphases; and complete cytoge-netic response occurs when 100 percent of metaphases are negative for the Ph chromosome on at least one karyotypic examina-

Table 5-5. The Role and Relevance of Cytogenetic G-banding, Interphase FISH and BCR-ABL RT-PCR in the Diagnosis and

Management of CML in Different Phases

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