Recent Advances in the Biology and Treatment of Acute Promyelocytic Leukemia, страница 7

SALVAGE THERAPY

Despite recent advances in the treatment of APL, approximately 20% to 25% of APL patients who enter CR will relapse.¹'² The outlook is reasonably optimistic for these patients, particularly those who are candidates for farther aggressive therapy.

Autologous and Allogeneic Bone Marrow Transplant

The role for both autologous and allogeneic (allo) bone marrow transplantation (BMT) in APL is diminishing. Given the long CR durations and presumed cures of the majority of patients, there is currently no indication for either type of BMT in first CR. However, our practice is to harvest and cryopreserve bone marrow or peripheral stem cells in first CR after completion of 3 months of maintenance ATRA therapy. This product can be tested for the presence of occult leukemia cells (described later) and used, if needed, at the time of relapse. At the time of relapse, the best strategy is to attempt reinduction with ATRA (± chemotherapy), and to proceed directly to either autologous (auto) or allo BMT (in those who have cells available or who have a suitable donor). Most patients, especially those who have not received ATRA for 1 year or more, appear to respond to ATRA again at the time of relapse.⁷⁵ The choice between auto and allo BMT will be dictated by patient age and clinical condition, availability of a human leukocyte antigen (HLA)-matched sibling donor, and, possibly, the presence or absence of detectable leukemia cells in the autologous bone marrow or stem-cell harvest.

Along these lines, Meloni et al⁷⁶ recently reported results in 15 relapsed APL patients who underwent auto BMT in second CR. Bone marrow harvests firom seven of the patients were PCR positive, and all of these patients subsequently relapsed. In contrast, six of eight patients who received PCR-negative autografts remain in long-term CR.⁷⁶ Mandelli et al⁷⁷ have summarized the results of both auto and aUo BMT in APL patients reported to the European BMT registry, before the ATRA era. The leukemia-free survival rate for patients transplanted in second CR ranged from 22 to 31% for patients receiving allo or anto BMT, respectively. In summary, although the best strategy for salvage therapy in APL has not been defined, auto BMT (or peripheral-blood stem-cell transplantation [PBSCT]) in an ATRA-induced second CR, using PCR-negative stem cells, may be the safest, most widely applicable, and most effective approach. If this is not feasible, allo BMT from a matched sibling or alternative donor should be pursued in appropriate patients.

Other Approaches to Salvage Therapy

The curative potential of other choices for salvage therapy remains unknown and, whenever possible, patients should be entered onto clinical trials. Additional options for salvage therapy include the following:

Arsenicals. Preclinical studies in China suggest that arsenic trioxide (AszOg) is an effective cytodifferentiation/cytotoxic agent for APL cells in vitro.⁷⁸ The single published clinical study⁷⁸ suggests a high response rate in ATRA-refractory patients, but the durability of such responses remains unknown. A trial of arsenic trioxide in refractory APL is currently underway in the United States at Memorial SIoan-Kettering Cancer Center, under the direction ofDr Raymond Warrell.

Alternative retinoid compounds. Japanese investigators have reported results with a synthetic retinoid, Am80, that is significantly more active than ATRA in vitro as a differentiation agent.⁸⁰ In that study of 24 relapsed patients, 14 (58%) achieved a CR with Am80. The median time from last receiving ATRA for these patients was 22 months (range, 3 to 58). Thus, it might be expected that most of these patients would have also responded to a rechallenge with ATRA- 9-cts reti-noic acid, a ligand for both RARs and RXRs with a favorable pharmacokinetic profile, was essentially ineffective in relapsed APL patients who had previously received ATRA.⁴¹ Recently, Hsu et al⁸¹ described a novel retinoid with significant in vitro activity against retinoic add-resistant cell lines. Clinical trials of this agent in refractory APL orAML are awaited. FUTURE DIRECTIONS

Although cure is now attainable in a substantial percentage of patients with APL, significant numbers of patients continue to relapse. Large-scale clinical trials (as currently being performed or planned in Europe and North America) are therefore needed to refine the therapy for this rare disease, and to identify those patients who are at highest risk for relapse. The ultimate challenge is to translate the remarkable success achieved inAPL to patients with other subtypes ofAML, who continue to have fairly dismal outcomes. This will only happen with farther research into the basic biology of APL leukemogenesis and into the role of retinoids in myelopoiesis. A complete understanding of the molecular pathogenesis of APL will clarify whether this disease is a fortunate medical curiosity, or whether it will serve as a paradigm for the development of effective differentiation therapies in other types of human cancers.

In summary, RT-PCR is an extremely sensitive and specific technique to detect PML-RARot or RARa-PML, and can serve as a valuable (sometimes critical) adjunct in the diagnosis of APL. In the area of MRD detection, the most important recent finding is the presence of either PML-RARn or RARa-PML transcripts in APL patients in long-term CR. Thus, in the absence of a clear definition and statement of sensitivity level, it cannot now be stated that a positive RT-PCR assay is predictive of certain relapse in APL. The development of standardized, quantitative RT-PCR techniques (as proposed by the United States Intergroup and to be tested in the next APL trial) will hopefully address the issue ofinteriaboratory variation and allow an answer to the basic question of MRD biology in APL: that is, at what time point, and at what sensitivity level, should the