Eliana Zuffa

Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph(+) ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fifty-three patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10(-3). At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients who showed at day 22 a decrease in BCR-ABL levels to < 10(-3) compared with patients who never reached these levels during induction. In multivariate analysis, BCR-ABL levels of < 10(-3) at day 85 correlated with disease-free survival. No deaths or relapses occurred during induction. Twenty-three patients relapsed after completing induction. A T315I mutation was detected in 12 of 17 relapsed cases. Treatment was well tolerated; only 4 patients discontinued therapy during the last phase of the induction when already in CHR. In adult Ph(+) ALL, induction treatment with dasatinib plus steroids is associated with a CHR in virtually all patients, irrespective of age, good compliance, no deaths, and a very rapid debulking of the neoplastic clone.

Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up

The findings of this study suggest that imatinib mesylate at a daily dose of 600 mg is effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but does not significantly modify longer-term outcome of this condition. See related perspective article on page 1765. Background Imatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. Design and Methods We conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as <15% blasts and <30% blasts plus promyelocytes in blood or bone marrow and <20% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. Results Ninety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50%) returned to chronic phase, and 24 patients (26%) achieved also a complete hematologic response. Sixteen patients (17%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. Conclusions Imatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: NCT00514969).

Cost-Effectiveness of Interferon-α and Conventional Chemotherapy in Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) usually presents in a chronic phase of variable duration, after which a fatal condition similar to acute leukemia (blast crisis) develops. In some patients, a transitional or accelerated phase is evident [1]. The Philadelphia (Ph) balanced chromosomal translocation, t(9:22)(q34; q11), is present in most malignant cells at the time of CML diagnosis [1]. Although allogeneic bone marrow transplantation is the preferred therapy in patients for whom a compatible donor is available, the current front-line options for most patients are hydroxyurea or interferon- [2-5]. Both drugs can engender a complete hematologic response, defined as a reduction in the marrow myeloblast count to less than 1% of the leukocytes and return of the peripheral blood leukocyte count to normal. Conventional chemotherapy with hydroxyurea is inexpensive, is taken orally, and has few long-term side effects [2]. It confers a median survival of 41 to 58 months but is not associated with long-term survival in most patients; it also cannot cure CML [2-4]. In patients with CML, interferon- therapy leads to a median survival that is somewhat longer (61 to 89 months) than that produced by hydroxyurea [3-5]. It also provides some patients with long-term survival, particularly patients who have a major karyotypic response (a substantial reduction in the number of Ph-positive marrow cells) [3, 6]. Interferon- is expensive, must be taken subcutaneously, and is associated with substantial toxicity in some patients. Approximately 20% of patients must discontinue therapy because of adverse side effects [3]. Those who continue to receive interferon- have reactions that range from mild to moderately severe. Interferon- may cure CML in some patients who have prolonged complete karyotypic response (no detectable Ph-positive marrow cells) [7]. Thus, the problem of initial therapy for chronic-phase CML is that conventional therapy offers little chance of long-term survival and no chance of cure, whereas an agent that offers superior survival and a chance of cure is toxic and expensive. We used a decision analysis model to compare the cost-effectiveness of interferon- with that of hydroxyurea as an initial strategy for chronic-phase, Ph-positive CML. Methods Data Review On the basis of data from recent large clinical studies [2, 3, 5, 6], we developed a model of the evolution of CML for which either hydroxyurea or interferon- is used as front-line therapy. With the help of experienced clinical investigators, we thoroughly dissected the data that underlie our decision analytic model. Conventional chemotherapy for CML has historically consisted of either hydroxyurea or busulphan. The German CML Study Group [2] recently reported results of a randomized comparison between hydroxyurea and busulphan as front-line therapy for chronic-phase CML. Hydroxyurea was clearly superior, conferring a median survival of 58 months. In contrast, busulphan was associated with a median survival of 45 months [2]. The Italian Cooperative Study Group on Chronic Myeloid Leukemia [3, 8] compared interferon- therapy (218 patients) with conventional chemotherapy (104 patients) in a randomized study. At 8 months, 64 patients receiving interferon- had complete hematologic remission. Of these 64 patients, 29 achieved a major karyotypic response [8]. Seventeen patients who received conventional therapy had complete hematologic remission; only 1 of these patients had a major karyotypic response. Partial hematologic responses were noted in 102 interferon- recipients and 68 hydroxyurea recipients. Thirteen patients (11 receiving interferon- and 2 receiving conventional chemotherapy) had no response to treatment. Progressive disease developed in 18 patients (12 receiving interferon- and 6 receiving conventional therapy). On the basis of data on evaluable patients obtained in the Italian study during the first 24 months of therapy [8], we estimated that 12 patients could not tolerate interferon- therapy during this period. An additional 28 patients could not be evaluated for hematologic response [8]; further review by the Italian group, however, indicated that about half of these patients subsequently had allogeneic bone marrow transplantation [3]. Karyotypic response occurred in 30% of patients receiving interferon- and in 5% of patients receiving conventional chemotherapy [3]. At 72 months, overall survival was 50% in the interferon- group and 30% in the chemotherapy group [3]. The Cancer and Leukemia Group B [5] reported a median survival of 66 months in 107 previously untreated patients with chronic-phase CML who received interferon- therapy. Twenty-nine percent of these patients (95% CI, 20% to 38%) had a major karyotypic response; the median time to karyotypic response was 9 months. Kantarjian and colleagues [6] recently reported their findings on 274 patients with chronic-phase CML who were treated with interferon- for 10 years. Eighty percent of these patients had complete hematologic remission, and 38% had a major karyotypic response; 5-year survival rates ranged from 70% to 93% depending on the degree of karyotypic response. A recent analysis of 242 patients with CML blast crisis documented a median survival of 18 weeks [9]. Decision Analysis Model We developed a decision analysis model [10] that was based on the probabilities of the clinical events detailed above. The model follows the decision tree structure for the first 8 months of front-line therapy (Figure 1). Our literature review suggested that the transition probabilities for remission and relapse within the first 8 months are different from those in subsequent months [3, 8]. The choice is between initial therapy with interferon- or with hydroxyurea. For each branch of the decision node, the model is divided into the following possible states of health, depending on events that occur in the first 8 months of therapy: Figure 1. Decision tree for first 8 months of therapy. 1. Complete hematologic remission with accompanying karyotypic response (a karyotypic response cannot be achieved with hydroxyurea); 2. Complete hematologic remission without accompanying karyotypic response; 3. Partial hematologic remission; 4. Chronic-phase CML without hematologic remission; 5. Accelerated-phase CML, characterized by increasing peripheral leukocyte counts and marrow blast counts; 6. Blast crisis of CML (>30% blasts in the marrow), which leads to an acute leukemic state; 7. Discontinuation of primary therapy and attempted allogeneic bone marrow transplantation because a donor became available; and 8. Death from CML or other causes. The clinical research panel ratified the choice of states, but some of the reports on which the model is based use other states of health. In particular, the panel believed that partial karyotypic responses were difficult to judge, and they defined complete hematologic remission with karyotypic response as a 66% reduction (from the percentage of Ph-positive cells before treatment) in the proportion of Ph-positive metaphases in the bone marrow. Similarly, the panel judged that the natural history of partial hematologic response is similar (regardless of the changes in bone marrow after interferon- therapy) and therefore did not subdivide partial hematologic response into states with and without karyotypic response. Except for the state of complete remission with karyotypic response, the initial states are duplicated in the computer model to reflect the natural history of CML with interferon- or hydroxyurea treatment. Interferon- is associated with a risk for clinically significant toxicity, which might necessitate a change of therapy in the first 8 months. The model assumes that therapy would be switched to hydroxyurea in month 4 (halfway through the initial treatment period). This simplification does not change the behavior of the model and keeps the tree from becoming computationally intractable. Beginning with the ninth month of therapy, the natural history is modeled as a Markov process. We switched to a Markov model at month 9 because the transitions between states of health are relatively constant after this point. Figure 2 shows a diagram of the state-transition model. Because remissions still occur even after the eighth month of therapy, transitions to partial hematologic remission, complete hematologic remission with karyotypic response, and complete hematologic remission without karyotypic response are allowed. To overcome the limitation imposed by sparse data, patients with remission failure remain in their remission state until they progress to the accelerated phase rather than moving into the transient chronic state. The chronic-phase state and the remission states compete with a risk for progression to the accelerated phase. From any state that does not include karyotypic response or accelerated disease, a patient can discontinue primary therapy and have bone marrow transplantation. However, once disease is in the accelerated phase, the only forward transition is to blast crisis or death. Transition to death can occur from any state. To allow comparative analyses, death was subdivided into death from CML and death from other causes. Figure 2. State-transition diagram of Markov model for chronic myeloid leukemia. Figure 3 shows other aspects of this Markov process for a patient who initially receives interferon-. At any time through month 24, toxicity can force a change to hydroxyurea. On the basis of discussions with the panel, interferon- treatment is discontinued at month 24 if no karyotypic response has been achieved. Therefore, patients who do not have complete hematologic remission at 24 months but do have accompanying karyotypic response are automatically switched to their corresponding hydroxyurea states by a Boolean Markov node [10]. Figure 3. Transitions in the Markov model caused by intolerance of interferon- (IFN) or lack of karyotypic response (KR). As with mo

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients.

Fludarabine plus cytarabine (Ara‐C) and idarubicin (FLAI) is an effective and well‐tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara‐C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty‐seven patients received FLAI, as the first induction–remission course, and 55 patients received ICE. Post‐induction treatment consisted of high‐dose Ara‐C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara‐C) and autologous stem cell transplantation (auto‐SCT) or allogeneic (allo)‐SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0·01), while death during induction was 2% and 9% respectively. Both haematological (P = 0·002) and non‐haematological (P = 0·0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo‐SCT. After a median follow‐up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti‐leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.

Results of a Multicenter, Controlled, Randomized Clinical Trial Evaluating the Combination of Piperacillin/Tazobactam and Tigecycline in High-Risk Hematologic Patients With Cancer With Febrile Neutropenia

PURPOSE Empiric antibiotic monotherapy is considered the standard of treatment for febrile neutropenic patients with cancer, but this approach may be inadequate because of the increasing prevalence of infections caused by multidrug resistant (MDR) bacteria. PATIENTS AND METHODS In this multicenter, open-label, randomized, superiority trial, adult, febrile, high-risk neutropenic patients (FhrNPs) with hematologic malignancies were randomly assigned to receive piperacillin/tazobactam (4.5 g intravenously every 8 hours) with or without tigecycline (50 mg intravenously every 12 hours; loading dose 100 mg). The primary end point was resolution of febrile episode without modifications of the initial allocated treatment. RESULTS Three hundred ninety FhrNPs were enrolled (combination/monotherapy, 187/203) and were included in the intention-to-treat analysis (ITTA). The ITTA revealed a successful outcome in 67.9% v 44.3% of patients who had received combination therapy and monotherapy, respectively (127/187 v 90/203; absolute difference in risk (adr), 23.6%; 95% CI, 14% to 33%; P < .001). The combination regimen proved better than monotherapy in bacteremias (adr, 32.8%; 95% CI, 19% to 46%; P < .001) and in clinically documented infections (adr, 36%; 95% CI, 9% to 64%; P < .01). Mortality and number of adverse effects were limited and similar in the two groups. CONCLUSION The combination of piperacillin/tazobactam and tigecycline is safe, well tolerated, and more effective than piperacillin/tazobactam alone in febrile, high-risk, neutropenic hematologic patients with cancer. In epidemiologic settings characterized by a high prevalence of infections because of MDR microorganisms, this combination could be considered as one of the first-line empiric antibiotic therapies.

Incidence of bacterial and fungal infections in newly diagnosed acute myeloid leukaemia patients younger than 65 yr treated with induction regimens including fludarabine: retrospective analysis of 224 cases

Objectives:  Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non‐conventional drugs such as fludarabine are considered responsible for the increased risk of infections.

Fludarabine, Arabinosyl Cytosine and Idarubicin (FLAI) for Remission Induction in Poor-Risk Acute Myeloid Leukemia

Progress in treatment of acute myeloid leukemia (AML) is slow and treatment intensification alone has limited effects, particularly in poor-risk cases. Poor-risk cases, that are identified mainly by prior history, leukemic cell mass and cytogenetic abnormalities, share multiple mechanisms of drug resistance that are responsible for treatment failure. Since Pgp-mediated resistance to anthracycline can be reduced with Idarubicin (IDA) and resistance to arabinosyl cytosine (AC) can be reduced with Fludarabine (FLUDA), we tested a combination of high dose AC (2000mg/sqm, 5 doses), FLUDA (30 mg/sqm, 5 doses) and IDA (12mg/sqm, 3 doses) for remission induction and consolidation in 45 consecutive cases of poor-risk AML. The complete remission (CR) rate was 71 % after the first course and 82% overall, with a projected 2-year survival and relapse-free survival of 44% and 50% respectively. Non-hematologic toxicity was very mild, that is very important in elderly patients, but hemopoietic toxicity was substantial, with a time to hematologic recovery of 3 to 4 weeks and two cases of death in CR. Peripheral blood stem cells (PBSC) could be mobilized and collected successfully only in 11 cases. This three-drug combination is effective and has a limited non-hematologic toxicity, but FLUDA may increase the difficulty of obtaining PBSC early after remission induction.

Neutralizing anti‐interferon‐α antibodies and response to treatment in patients with Ph+ chronic myeloid leukaemia sequentially treated with recombinant (α2a) and lymphoblastoid interferon‐α

Neutralizing anti‐IFNα antibodies (nIFNα Abs) occur in a significant proportion of patients with hairy cell leukaemia, hepatitis or solid tumours treated with recombinant IFNα (IFNα2a or IFNα2b), but information on their incidence in chronic myeloid leukaemia (CML) is scanty and their clinical relevance is not yet completely defined. By using an IFNα antiviral neutralization bioassay, the frequency of nIFNα2a Abs was evaluated in 67 Ph+ CML patients during IFNα2a therapy at doses ranging from 6 to 9 MU/d. 15 patients (22%) developed nIFNα2a Abs (titre ranging from 1:40 to 1:20480) and 11/15 (73%) were haematologically and/or karyotypically unresponsive to treatment. 52 patients did not develop antibodies and 11 of them (21%) were unresponsive. The negative relationship between the positivity for nIFNα2a Abs and the response to treatment was highly significant (P = 0.0001). In nine nIFNα2a Abs positive patients, treatment was changed from recombinant IFNα2a to lymphoblastoid IFNα (IFNα‐ly), at the same dose and schedule. After 9 months of IFNα‐ly treatment a haematological response was achieved in 4/7 cases who were non‐responsive to prior IFNα2a therapy and was maintained in the other two patients previously responsive to IFNα2a. However, no karyotypic response was observed. This data shows that a significant proportion of Ph+ CML patients receiving treatment with IFNα2a can develop neutralizing antibodies and that these antibodies are associated with a loss of IFNα2a efficacy. Changing the patients to treatment with lymphoblastoid IFNα may restore haematological response but it is not likely to induce a karyotypic response.

The type of BCR/ABL junction does not predict the survival of patients with Ph1-positive chronic myeloid leukaemia

Summary. The prognostic value of the location of the breakpoint on chromosome 22 in patients with Ph 1+ chronic myeloid leukaemia (CML) is still controversial. We analysed both DNA rearrangement and transcript type in a new continuous series of CML patients. By Southern blotting analysis, we found that, out of 72 patients, 43 had a 5’rearrangement and 29 a 3’one, of the 43 5′‐rearranged patients, 35 carried an a2b2 transcript and eight an a2b3 one, while, of the 29 patients rearranged in the 3’part of the M‐BCR area, 26 had an a2b3 transcript, one had an a2b2 transcript and two carried both types of transcript. Thus, mRNA studies allow to detect an a2b3 transcript in 17·7% of 5’rearranged patients. However, no correlation was observed between type of transcript and survival, as after DNA studies.

Case-control study of multidrug resistance phenotype and response to induction treatment including or not fludarabine in newly diagnosed acute myeloid leukaemia patients

One hundred and six patients aged ≤60 years with newly diagnosed acute myeloid leukaemia (AML) treated with fludarabine‐based regimens (cases) were matched with 106 AML patients treated with conventional non‐fludarabine‐based regimens (controls). The cases and controls were matched by expression of the multidrug resistance P‐glycoprotein (MDR‐Pgp), measured by flow cytometry as mean fluorescence index (MFI), cytogenetics, and age. The complete remission (CR) rate of the cases was 61% among the MDR‐Pgp‐positive (posve) patients (MFI ≥ 6) vs. 75% among the MDR‐Pgp‐negative (negve) ones (MFI < 6) (P = 0·16). Conversely, in the controls, the CR rate was 44% among the MDR‐Pgp‐posve patients vs. 67% among the MDR‐Pgp‐negve ones (P = 0·02). The 4‐year disease‐free survival (DFS) and overall survival (OS) of MDR‐Pgp‐posve cases were significantly longer than those of MDR‐Pgp‐posve controls (DFS, 28·1% vs. 6·5%, P = 0·004; OS, 33·5% vs. 9·6%, P = 0·01). This difference was not found among the MDR‐Pgp‐negve patients. By univariate (P = 0·007) and multivariate (P = 0·007) analysis, the MDR‐Pgp‐posve phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine‐based induction treatments as a promising strategy for MDR‐Pgp‐posve AML patients. In this setting of patients, large prospective randomised studies should be planned.