Treatment Of Relapsed

Despite the tremendous advances in the treatment of APL discussed above, a small, but significant, percentage of patients will relapse. In the long-term follow up of the APL93 trial,51 which enrolled 576 patients between 1993 and 1998, 134 (23.3%) patients eventually relapsed (out of 533 who achieved CR). Although most of these relapses occurred within 2.5 years of achieving CR, a substantial percentage (29%) occurred after 2.5 years, with one relapse occurring over 8 years from CR. In the North American Intergroup trial,30 late relapses were also seen, although by far the highest risk period was the first 2 years after CR. Patients with APL, particularly those who present with high WBC counts, are at risk for relapse in the CNS and other extramedullary sites, including skin and ear.60-64 Whether this risk has increased in the "ATRA era" is unclear,62 but of the 22 clinical relapses noted in the PETHEMA LPA96 and LPA99 trials,32 6 (27%) occurred in the CNS. Most patients with extramedullary relapse will be found to have occult (i.e., molecular) or overt leukemia in the marrow, and treatment should be directed not only at the site of extramedullary involvement but also at clearance of systemic disease. The high rate of CNS relapse among APL patients with a WBC count of more than 10,000/^L may warrant routine intrathecal prophylaxis in this group of patients, and such a strategy has been adopted by the European APL Group in their APL2000 trial.20

As modern management of APL patients includes serial monitoring for residual disease using RT-PCR, many patients are identified with so-called molecular relapse, generally defined as two successive positive PML-RARA RT-PCR assays performed 2-4 weeks apart. Assuming an assay sensitivity of 1 in 104, such a finding is highly predictive of subsequent clinical relapse. While there is little doubt that molecular relapses are a harbinger of hematologic relapse, and thus require treatment, there is very little agreement about what constitutes appropriate therapy in this increasingly common clinical situation. There is no formal proof that treatment of molecular relapse leads to better outcomes compared to treatment at the time of hemato-logic relapse, but Lo Coco et al.65 have presented compelling evidence in support of "preemptive" therapy, i.e., at the time of molecular relapse. In that study, among 12 patients with molecular relapse who achieved second molecular CR following salvage with ATRA, ara-C, and mitoxantrone, 10 were alive in sustained molecular remission at the time of the report, for a 2-year survival of 92%. This compared to a 2-year survival estimate of 44% in a previous series of 37 patients treated by the same investigators with identical therapy, but at the time of hematologic relapse.

While clinicians may be reluctant to subject patients with positive RT-PCR results to intensive chemotherapy (┬▒stem cell transplant), some type of treatment needs to be offered. Options include (1) gem-tuzumab ozogamicin66, (2) arsenic trioxide, (3) ATRA (in patients who have not received ATRA within 6 months), (4) standard anthracycline- or ara-C-based chemotherapy, or (5) some combination of the above. Most of the listed agents should convert patients to molecular negativity, but there is no consensus regarding which agent is most effective in this setting, nor is there consensus regarding the duration of therapy, or the type of further intensification (e.g., stem cell transplant) to offer (if any) after achievement of second molecular remission.

Treatment of frank hematologic relapse requires a more aggressive approach, generally incorporating autologous or allogeneic stem cell transplant in second CR. The best option for initial salvage therapy is probably arsenic trioxide, which has been shown to lead to CR rates of 85-95% in relapsed APL.67-71 However, the quality of CRs induced by arsenic trioxide is unclear,72 73 and most clinicians view arsenic trioxide as a "bridge" to stem cell transplant. The goal of salvage therapy, whatever the agent, is attainment of second molecular CR, which is a mandatory prerequisite prior to proceeding to stem cell harvest and possible autologous stem cell transplant. The role of autologous and allogeneic stem cell transplant in the treatment of relapsed APL has received considerable recent attention.74-80 Initial data from Meloni et al.,79 and more recent results from the European APL Group,75 suggest that autologous stem cell transplant may cure as many as 75% of patients who are in molecular remission at the time of stem cell harvest and transplant. Investigators from the Cancer and Leukemia Group B, using a high-dose ara-C/etoposide consolidation/mobilization regimen, have reported an EFS of 74% in APL patients transplanted in second CR.77 Given the good results with polymerase-chain-reaction-negative autografts in relapsed APL, allogeneic transplant is generally recommended only for those patients who are persistently molecularly positive, or who may have failed previous autologous transplant.7578 The role of stem cell transplant in the treatment of relapsed APL has recently been challenged by Au et al.,67 who treated 42 patients with relapsed APL with a regimen of arsenic trioxide (intravenous or oral), followed by idarubicin consolidation and, in most patients, maintenance with oral arsenic trioxide. With short follow up, 38 of the 42 patients were in hematologic and molecular remission, some of them after subsequent retreatment with arsenic trioxide plus ATRA. If results such as these hold up, the role of stem cell transplant in APL will need to be reexamined; however, at present, autologous or allogeneic transplant offers the best hope for long-term survival for the majority of patients with relapsed APL.

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