Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RAR␣ isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD−ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (−ve/−ve, +ve/+ve, +ve/−ve, −ve/+ve) and D835 (−ve/−ve, +ve/−ve, −ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.

Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARα fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARα+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARα, as assessed by serial dilution experiments, was 10−4. All patients were in hematologic remission and tested PCR− at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR− in ≥2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARα during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up. © 1998 by The American Society of Hematology.

In all, 17 consecutive patients in hematological complete remission (HCR) of acute promyelocytic leukemia (APL) received allogeneic stem cell transplantation (SCT) from an HLA-identical sibling and were monitored by reverse transcriptase polymerase chain reaction of PML/RARa prior and after transplant. Median age was 31 years (range 3-50 years). At 10 years, the actuarial probabilities of nonrelapse mortality, relapse and disease-free survival were 32% (95% CI: 8-56%), 33% (95% CI: 6-60%) and 46% (95% CI: 22-70%). Six patients tested PCR þ ve (1st HCR n ¼ 2; 2nd HCR n ¼ 3; 3rd HCR n ¼ 1) and 11 PCR Àve (2nd HCR n ¼ 11) pre-SCT. Of the six patients PCR þ ve, two showed early persistence of PCR positivity and converted to sustained PCR negativity after CSA withdrawal (one died of secondary tumor in molecular remission and one is alive in relapse), while four converted to PCR Àve rapidly (one died of the underlying disease and three are in molecular remission). Of the 11 patients PCR Àve pre-SCT, six died (four of transplant-related mortality, one of relapse and one after heart transplantation) and five are alive, four in molecular remission and one is in relapse. Allogeneic SCT seems a valid option for advanced APL, particularly for the poor prognostic group of patients with pre-SCT molecularly persistent disease.