Franca Radaelli

Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia

Purpose: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. Experimental Design: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. Results: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. Conclusions: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.

Second malignancies in essential thrombocythemia (ET): a retrospective analysis of 331 patients with long-term follow-up from a single institution

Abstract Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an indolent clinical course, with a median survival exceeding 20 years. A minority of patients undergo thrombohemorrhagic complications, which might be prevented by cytoreductive treatment in high risk categories. Alkylating agents (ALK) have been demonstrated to increase the risk of acute leukemia and myelodysplastic syndromes in patients with myeloproliferative disorders, whereas the potential oncogenicity of hydroxyurea (HU) remains a matter of debate. In this study, we retrospectively investigated long-term development of hematological and non-hematological second malignancies in 331 patients with ET, analyzing possible associations with chemotherapy treatments. Median follow-up was 108 months. Of the 194 patients who were treated with chemotherapy, 116 (60%) received only HU, 38 (19·5%) only ALK (busulfan or melphalan) and 40 (20·5%) ALK followed by HU. After a median time of 87 months from the diagnosis of ET, 43 patients developed a second malignancy, hematological in 15 and non-hematological in 28, for an overall cumulative incidence of 13%. According to the type of treatment, second malignancies were documented in 11·2% of patients treated with only HU, in 26·3% of patients who received only ALK, and in 25% of those treated with ALK followed by HU. Ten cases (7·3%) were recorded among the 137 patients who did not receive any treatment. Our analysis revealed a significant association between treatment with alkylating agents and an increased risk of developing second hematological malignancies, whereas no such association was detected with regard to treatment with hydroxyurea single agent in our ET population. In addition, different treatment strategies did not affect the risk of developing second solid cancers.

The response to imatinib and interferon-α is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive Chronic Myeloid Leukemia patients in early chronic phase

Before the introduction of imatinib, interferon α-based regimens were the gold standard for treatment of early chronic phase chronic myeloid leukemia patients. The combination of IFN-α with imatinib is currently being investigated in at least two large clinical trials, the German CML Study IV and the French SPIRIT trial. We reviewed the cytogenetic and molecular responses of 76 early chronic phase chronic myeloid leukemia patients who were treated with imatinib and interferon-α and of 419 early chronic phase chronic myeloid leukemia patients treated with imatinib alone front-line. The complete cytogenetic response rate was higher in the IM+IFN-α group than in the imatinib group at six months (60% vs. 42%; P=0.003), but not at 48 months (88% vs. 88%). The durability of the complete cytogenetic response was similar in the two groups with 94% and 91% of complete cytogenetic responders in continuous complete cytogenetic response at 48 months (P=0.56). The major molecular response rate was higher in the IM+IFN-α group at six months (58% vs. 34%; P=0.0001) and 12 months (67% vs. 47%; P=0.001) but not later on (65% vs. 57% at 48 months; P=0.25). Overall and progression free survival were comparable in the two groups; a significant trend to a better event free survival was observed in patients treated with PegIFNα (91% vs. 78%; P=0.02). These data suggest that the response to the combination treatment is more rapid. It is not yet known how much a rapid reduction will influence the longer-term overall and progression free survival, and the cure rate.

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p<0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p=0.620). Acquired Ph-negative cytogenetic abnormalities (p=0.010), lack of complete molecular remission (p=0.016) and age (p=0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p=0.005 for any toxicity, p=0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis.

An unusual febrile nonhemolytic reaction occurred after transfusion in a thalassemia major patient with asymptomatic Plasmodium falciparum infection

BACKGROUND: Febrile nonhemolytic transfusion reactions occur in 0.12% of transfusions, usually during transfusion or within 4 to 6 hours after transfusion and are not medically dangerous.