p16 gene homozygous deletions in acute lymphoblastic leukemia

The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied.     

Chronic myelogenous leukemia with t(9;22) and t(8;11): a new chromosome anomaly

A case of chronic myelogenous leukemia in an elderly man with a new translocation, t(8;11)(q24;q13), associated with a Philadelphia t(9;22) translocation is described. The clinical and hematologic aspects of the disease did not seem to differ from those of the usual cases of chronic myelogenous leukemia except for a basophilic blast crisis.     

Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group.

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.     

Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL) by All Transretinoic Acid (ATRA) Combined with Chemotherapy: The European Experience

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbracks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.     

Segmental coecal cytomegalovirus colitis during fludarabine,cytarabine and mitoxantrone induction chemotherapy for myelodysplastic syndrome

We report the case of a 59-year-old woman treated for a refractory anemia with excess blasts (RAEB) who developed cytomegalovirus (CMV) colitis during induction therapy combining fludarabine, cytarabine and mitoxantrone. CMV infection occurred rarely during cytarabine and anthracyclin based induction therapy for acute myelogenous leukemia or RAEB. CMV infection is usually observed in immunocompromised patients but some cases have been recently observed in patients after autologous stem-cell transplantation with or without CD34 + stem-cell selection. We discuss this case and issues arising from it in relation to the use of combination of high-dose cytarabine and fludarabine.     

Is cytarabine required in the treatment of acute promyelocytic leukemia?

Until the late 1980s, chemotherapy with anthracyclines and cytarabine (AraC) was the only treatment approach for acute promyelocytic leukemia (APL), as for other types of acute myeloid leukemia. Many studies have shown that treatment with all-trans retinoic acid (ATRA), followed by anthracycline-AraC chemotherapy, significantly decreases the incidence of relapse and improves survival in newly diagnosed APL, compared with this chemotherapy alone. This approach was associated with consistent morbidity and mortality during consolidation and maintenance treatment, however, mainly resulting from myelosuppression induced by anthracycline-AraC courses. Several groups have reported high rates of complete remission and low rates of relapse with ATRA and chemotherapy using anthracyclines alone, suggesting that AraC could be avoided in the chemotherapy of APL, reducing toxicity. These results were not confirmed in other studies, however, raising the issue of the role of AraC in treatment of patients with newly diagnosed APL.