Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676).

We report a patient with acute promyelocytic leukaemia (APL) who received two doses of gemtuzumab ozogamicin for advanced disease. Previous treatments included front-line all-trans retinoic acid and anthracyclines, polychemotherapy consolidation, salvage chemotherapy for the first relapse followed by autologous stem cell transplantation (ASCT), arsenic trioxide for the second relapse followed by a second ASCT and then high-dose methotrexate for more advanced systemic disease with central nervous system involvement. The patient achieved prolonged haematological and molecular remission after monotherapy with gemtuzumab ozogamicin given at the time of the third relapse.

Clinical relevance of residual disease monitoring by polymerase chain reaction in patients with ALL-1/AF-4 positive-acute lymphoblastic leukaemia.

In this study we used reverse transcriptase-polymerase chain reaction (RT-PCR) for the longitudinal monitoring of minimal residual disease in 12 patients with All-1/AF-4 positive ALL. Of these, seven also showed at presentation a typical t(4;11) cytogenetic translocation. Seven patients were infants <18 months of age and five were adults. Eleven patients were treated with high-dose intensive induction and consolidation chemotherapy without bone marrow transplantation and one received conservative treatment due to poor performance status. Three had resistant disease, four relapsed within 12 months after achieving complete remission, and five are in continuous complete remission (CCR) at 32, 39, 52, 53 and 61 months from diagnosis, respectively. The sequential analysis of the ALL-1/AF-4 hybrid transcript showed a persistently negative RT-PCR in the five CCR long-term survivors. The PCR analysis resulted persistently positive in the remaining seven cases, including the four cases who relapsed after the achievement of clinical CR. These data emphasize the clinical relevance of PCR monitoring analysis in t(4;11) ALL patients and should be considered in order to better determine variable post-remission treatment according to risk prediction.

Clinical relevance of the PML/RAR-a gene rearrangement in acute promyelocytic leukaemia.

The molecular mechanisms underlying the t(15;17) cytogenetic translocation of acute promyelocytic leukaemia (APL) have been recently elucidated. Together with new insights into the understanding of APL pathogenesis, such investigations also provided the availability of a novel leukemia-specific marker to be used for both diagnostic and monitoring studies. The chromosome breakpoints of the t(15;17) have been shown to involve the retinoic acid receptor alpha (RAR-a) gene and the newly described PML gene on chromosomes 17 and 15, respectively. Rearrangements of these loci are found in virtually 100% of APLs, including the microgranular variant subtype and cases displaying apparently normal karyotypes. In cases with ambiguous morphology, molecular diagnosis may therefore enable the prompt administration of APL-specific therapies, such as all-trans retinoic acid. Significantly, clinical response to this differentiating agent is predictable based on the presence of the specific PML/RAR-a rearrangement. Appropriate oligoprimers complementary to PML and RAR-a sequences nearby the DNA breakpoints may be successfully used in PCR experiments to amplify the PML/RAR-a hybrid gene and sensitively detect minimal residual disease. Preliminary PCR studies indicate that this approach might indeed prove a very important and reliable prognostic indicator in the follow up monitoring of APL patients. Early identification of impending relapse by PCR may suggest the use of additional treatment in patients at risk and significantly increase the probability of cure of the disease.

Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma.

The molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma, is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6, codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL.

Management of chronic myeloid leukemia in chronic phase with autologous stem cell transplantation and alpha-2 interferon: cytogenetic and clinical results.

Forty-eight patients with chronic myeloid leukemia (CML) in chronic phase (CP) were treated by autologous stem cells transplantation (ASCT) and alpha Interferon (IFN) with three approaches: 1) ASCT at diagnosis followed by IFN, 2) ASCT post IFN with cells collected after an interval from IFN discontinuance, followed by IFN, 3) ASCT in patients selected by cytoconversion obtained with IFN, performed soon after IFN discontinuance. Following ASCT, a major karyotype response (more than 65% Ph1 negative cells, MKR) was observed at least once in 40%, 53% and 83% of patients from the three groups, respectively. At last follow-ups (median 39, 40 and 21 months, respectively) 19%, 13% and 67% of patients still present a MKR with 2 patients from group 1 and 4 patients from group 3 being 100% Ph' negative. Projected survival from diagnosis is 77% at 52 months for patients from group 1 and 47% at 75 months for patients from group 2. Present data indicate that 1) IFN can stabilize results obtained with ASCT, 2) ASCT can potentiate responses to IFN, 3) combined ASCT and IFN can improve survival. Longer follow-up of patients and randomized studies are required to define the real impact on disease outcome by these treatment approaches.