ABSTRACT: Over the past 2 decades, our understanding of the pathobiological events underlying chronic myelogenous leukemia (CML) has grown. At the same time, effective transplant and nontransplant treatment approaches to CML have been developed that increase the options available to newly diagnosed patients, and that can cure or prolong survival in this formerly incurable disease. Newly diagnosed patients presenting with extreme leukocytosis or thrombocytosis may benefit from immediate therapy with hydroxyurea (Hydrea) and pheresis. After stabilization, eligible patients may elect to undergo immediate transplant. The majority, however, should begin therapy with either interferon-alpha and cytarabine, or they should be entered into the STI-571 trials. [ONCOLOGY 15(1):23-35, 2001]
Unrelated donors are an alternative source of hematopoietic stem cells for allogeneic transplantation. Over the past 15 years, an international network of computerized registries has been developed. In the United States, the National Marrow Donor Program has access to approximately 4 million unrelated donors typed by HLA. This program can locate suitably matched donors for more than one-third of potential recipients and, in most cases, can procure marrow donations within 4 months of the initial search request.
Survival rates after HLA-matched unrelated-donor transplant in CML may approach those observed after related-donor transplant. In a recent retrospective analysis, the incidence of long-term survival was over 60% in a highly selected subset of good-risk CML unrelated-donor transplant recipients (Figure 3). However, as in related-donor stem cell transplantation, outcome is highly dependent on patient characteristics. Older recipient age, prolonged interval to transplant, advanced disease, and donor/recipient HLA mismatch adversely affect outcome.
Depletion of T lymphocytes from the donor stem cell inoculum reduces the incidence of GVHD; however, the incidence of relapse may be markedly increased. This observation led to the understanding that the antileukemic effect of allogeneic stem cell transplantation in CML depends less on the high-dose preparative regimen and more on the immune-mediated suppression of residual host malignant progenitors by donor effector cells. One strategy that has evolved from these observations is the use of "donor lymphocyte infusions" to prevent or treat relapse after allogeneic stem cell transplantation.
Donor lymphocyte infusions can induce cytogenetic and hematologic remissions in patients relapsing after allogeneic transplant. Approximately two-thirds of relapsing posttransplant CML patients will have a complete hematologic and cytogenetic response to donor lymphocyte infusions. Treatment with donor lymphocyte infusions is more effective when initiated before hematologic progression has occurred, and may even be useful as prophylaxis against relapse when used in combination with T-lymphocyte-depleted transplants. Unfortunately, approximately one-third of donor lymphocyte infusion recipients will develop GVHD, which may be fatal. Aplasia may also occur.[37-40]
High peritransplant morbidity associated with allogeneic transplant therapy for CML is related to the toxicity of the preparative regimen and to the development of GVHD. A nonmyeloablative preparative regimen (also known as a "mini-transplant" or "transplant-lite") reduces myelosuppression and organ toxicity. Graft-vs-host disease may also be reduced with this strategy, because it is triggered to some extent by tissue inflammation.
Preparative regimens used in nonmyeloablative transplants have included a purine analog (fludarabine [Fludara] or cladribine [Leustatin]) with immunosuppressive properties and, in some centers, low-dose total-body irradiation. Additional peritransplant immunosuppression may be needed to ensure donor engraftment.
Very preliminary reports on this new transplant approach suggest that sustained engraftment, complete cytogenetic and hematologic remission, and low peritransplant morbidity can be achieved.[41-45] Because the nonmyeloablative regimens are less toxic, they may extend the option of allogeneic stem cell transplantation to older or sicker patients who otherwise would not be considered for conventional transplants. This is particularly relevant in CML, for which the median age at presentation is over 50 years.
The long-term efficacy of nonmyeloablative transplants, however, has not been determined. Optimal use of immunosuppressive agents in nonmyeloablative conditioning is not yet understood, and the preparative regimen may need tailoring according to the disease type and HLA matching. Acute and chronic GVHD do occur after nonmyeloablative conditioning and can result in serious or fatal complications.
The marrow and blood of at least some CML patients contain coexistent benign and malignant hematopoietic progenitor populations. Investigators have capitalized on this observation by administering high-dose chemoradiotherapy followed by infusion of autologous marrow or blood cells. In some cases, the inoculum has been "purged" ex vivo with chemotherapeutic agents, interferon, or antisense agents to selected gene targets such as the BCR-ABL oncogene. More recently, in vivo purging has been achieved by "priming" patients with high-dose chemotherapy, followed by the collection of blood cells enriched for benign progenitors.[46,47]
Autologous transplant therapy for CML can effect partial or complete cytogenetic remissions, and may prolong survival. Peritransplant complications and mortality are reduced, compared to allogeneic stem cell transplantation. The role of autologous stem cell transplantation in CML is not yet fully understood. In most cases, autologous stem cell transplantation is not curative and may serve best as a "platform" for subsequent chemotherapy, cytokine therapy, or immunotherapy.
Perhaps one of the most exciting occurrences in the treatment of CML is the development of tyrosine kinase inhibitors such as STI-571. The agent STI-571 "targets" specific tyrosine kinases encoded by the BCR-ABL oncogene and disrupts their intracellular signals. Incubation of normal and CML progenitors with STI-571 in culture results in selective suppression of malignant cells and survival of normal progenitors.
Phase I dose-escalation studies demonstrate little toxicity at oral daily doses of 400 mg, and have not yet determined the maximum tolerated dose. Preliminary results of phase II studies suggest that STI-571 therapy can induce hematologic remissions in the majority of CML patients and cytogenetic responses in some.[49-51] A phase III, prospective, randomized trial has been initiated to compare the efficacy of interferon-alpha plus cytarabine vs STI-571 in newly diagnosed CML patients.
Although the results of STI-571 therapy are exciting, the long-term benefits of this agent are not yet known. Optimal dose and dose schedules and dose-limiting or idiosyncratic toxicities have not been fully determined. The promising strategy of combining STI-571 with other therapeutic agents or with hematopoietic stem cell transplantation awaits exploration.
A patient with newly diagnosed chronic-phase CML now has several therapeutic options. The advent of the promising but not yet fully tested tyrosine kinase inhibitor STI-571 further complicates the decision-making process. One approach to therapy is described in Figure 4.
Newly diagnosed patients presenting with extreme leukocytosis or thrombocytosis may benefit from immediate therapy with hydroxyurea and pheresis. Allopurinol and vigorous hydration should be administered to prevent complications of hyperuricemia. After stabilization, potential hematopoietic stem cell transplant candidates and their siblings should be typed for HLA. Eligible patients may elect to undergo immediate transplant.
The majority of patients, however, will not be eligible for or elect early transplant therapy. These patients should be offered a course of interferon-alpha and cytarabine administered daily as described above, or they should be entered into STI-571 trials, if available.
Patients receiving a trial of interferon-alpha plus cytarabine who develop unacceptable toxicity or who do not achieve a major cytogenetic response within 1 year, as well as those entered into STI-571 trials who experience disease progression, may choose alternative approaches. These approaches include treatment with hydroxyurea, and novel nontransplant therapy such as arsenic trioxide (Trisenox) or homoharringtonine (HHT). Eligible patients may consider allogeneic or autologous hematopoietic stem cell transplantation. Therapy with interferon-alpha should be discontinued for at least 3 months prior to allogeneic stem cell transplantation.
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