Summary
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.
Abstract 3412
The phase II explorative study of intermittent Imatinib (IM) treatment (InterIM) in elderly patients with Ph + chronic myeloid Leukemia (CML) who achieved a stable complete cytogenetic ...response (CCgR) after at least 2-years standard IM therapy (any dose between 300 and 800 mg/day) was started in April 2008 and closed for the enrollment in August 2009, since more than 78 patients required by statistics were included into the study. The main objective of the study was to investigate if after 12 months (trial time) the CCgR achieved with standard (daily administration) IM therapy could be maintained with InterIM. For this purpose, the CgR status was assessed by Interphase Fluorescence In Situ Hybridization (I-FISH) on peripheral blood (≥ 200 cells counted) every 3 months. When I-FISH (% Ph + nuclei) increased more then 1%, chromosome banding analysis (CBA) on bone marrow was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities (ACA). At the present time, out of the 95 patients who were enrolled, 82 patients were evaluable and out of them 77 (94%), 73 (89%), 71 (87%) and 70 (85%) completed 3, 6, 9 and 12 months of the treatment program, respectively. Therefore, the great majority of patients completed the study core and at the end of 2010 all the patients are expected to complete the trial time (12 mo). During the first 12 months of InterIM, 1% to 11% of the evaluable patients at 3, 6, 9 and 12 months showed an I-FISH >1% Ph+ nuclei (Figure 1).
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Totally, eleven (13%) out of 82 patients treated with InterIM showed an I-FISH >1% and they were checked by CBA on bone marrow (Figure 2). Out of them only 3 cases, that means 4% of the 82 evaluable patients, lost the CCgR and resumed standard IM therapy (daily administration), but none completed 3 months of therapy. All the patients lost the MMR and increased several folds the BCR-ABL transcript levels. Two pts had a low risk Sokal and one a high risk; age was 66, 69, 77 years; time from diagnosis was 29, 91 and 100 months; duration of IM therapy was 29, 83 and 84 months; the IM dose was 400mg in all cases.
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As concern as molecular response, 99% of the patients had a major molecular response (MMR=<0.001-0.1 BCR-ABL/ABLISX 100) at the baseline. The proportion of the patients who maintained the MMR after 3, 6, 9 and 12 months of InterIM was 95%, 92%, 91%, 84%, respectively. Interestingly, we found a weak but significant correlation between the % of BCR-ABL + nuclei and the BCR-ABL transcript levels in the patients who completed the trial time (12 mo) (r=0.27; p=0.001).
In conclusion, the results of the InterIM study core (12 months), clearly show that Intermittent Imatinib (IM) treatment (InterIM) is sufficient to maintain the complete cytogenetic response (CCgR) previously achieved with standard IM therapy in elderly (≥ 65 years) Ph+ CML patients. The risk to loose the CCgR has been very low (4%), while the benefit either in terms of reduction of IM dose and of costs of therapy or in terms of compliance (data not shown) was very high.
This work was supported in part by CML-Leukemia Net and Progetto Regione Lombardia.
No relevant conflicts of interest to declare.
Abstract 860
Elderly CML patients treated with Imatinib (IM) in early chronic phase (CP) have similar cytogenetic response and survival compared with younger patients, but they show a lower ...compliance to standard IM therapy (400 mg/day).
The aim of the study is to investigate if CCgR that has been achieved with standard (daily administration) IM therapy can be maintained with the same dose of IM given intermittently (INTERIM).
The study population is represented by elderly patients (≥ 65 years old) with Ph+ CML and with stable CCgR after at least 2 years of standard IM therapy (daily administration). IM is given at the same dose that was given at the time of enrollment by the following intermittent schedule: 1 week on / 1 week off for the 1st month; 2 weeks on / 2 weeks off for the 2nd and 3rd month; 1 month on / 1 month off from the 4th month thereafter. In cases of loss of CCgR INTERIM was stopped and standard therapy (daily administration) was resumed. After 12 months, the patients who are in continuous CCgR are advised to continue the intermittent study schedule and to be followed indefinitely. The CgR status was evaluated at baseline (by conventional cytogenetics on bone marrow and FISH on peripheral-blood) and every 3 months during the study (only by FISH on peripheral-blood). If FISH (% of Ph+ cells) increased more than 1% in two consecutive examinations, evaluation of marrow cells metaphases was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities. Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral blood was due at baseline and every 3 months during the study and mutational analysis of ABL was performed in case of loss of CCgR.
One-hundred and fourteen patients have been considered eligible, but 17 (15%) refused to enter into the protocol. Out of 97 enrolled patients, 87 started INTERIM, 5 patients (5%) went off the study for major protocol violation before the 3rd month and, at present, 82 patients are ongoing. Of these 82 patients, 52, 30 and 11 completed the 3rd, 6th and 9th month, respectively. The preliminary results of the first 6 months are here reported. The distribution of patients according to FISH results is shown in Fig. 1. Only 1/68 pts (at 6th month) showed an increased >1% in Ph+ cells by FISH but he maintained a CCgR when checked by conventional cytogenetic. As showed in Fig. 2, 96 to 87% of patients maintained a major molecular response MMR (≤0,1) according to International Scale (IS).
This study is trying to test the minimum effective dose of Imatinib to maintain the CCgR in elderly CML patients with stable CCgR. The preliminary results at 6 months do not show negative trends both for cytogenetic and molecular response. Therefore, the study is ongoing and all patients are expected to complete the trial time (12 months).
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No relevant conflicts of interest to declare.
Hairy cell leukemia (HCL) is a rare B-cell neoplasm generally responsive to Cladribine. Cladribine is generally administered intravenously either as a continuous weekly infusion or as a 2-hour daily ...or weekly infusion for 7 days. Subcutaneous Cladribine is an alternative route with 100% bioavailability and with efficacy similar to intravenous 2CdA at the dose of 0.7 mg/kg/cycle. In indolent non-Hodgkin lymphomas other than HCL, reduction to 0.5 mg/kg/cycle determined equivalent efficacy and lower toxicity. In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we have evaluated efficacy and toxicity of subcutaneous Cladribine given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 days (total dose 0.7 mg/kg, arm B) as a single course in newly diagnosed HCL requiring treatment. Responses to treatment were assessed on day 60 and day 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were considered as beneficial responses, while minor Responses (mR) and No Responses (NR) were rated as treatment failures. Toxicity was assessed from day 0 to day 60 after treatment, according to the 2003 NCI/CTCAE v3 criteria. In this interim analysis, 92 of the 132 patients currently recruited (45 patients in arm A and 47 in arm B) were evaluated for toxicity and response to treatment. 2CdA was administered at the proposed regimen with no modifications in all patients. Eighty-five of 92 patients (92%) had a beneficial response to treatment (57/92 CR, 62%; 28/92 PR, 30%). The 7/92 treatment failures scored as 3/92 mR (3%) and 4/92 (5%) NR. Responses were equivalent in the two arms (p=0.7), with 41/45 (91%) beneficial responses (27/45 CR, 60%; 14/45 PR, 31%; 2/45 mR, 4% and 2/45 NR, 4%) in arm A versus 44/47 (94%) beneficial responses in arm B (30/47 CR, 64%; 14/47 PR, 30%; 1/47 mR, 2%; 2/47 NR, 4%). Overall grade 3–4 toxicity was recorded in 16/92 (17%) patients (8/92 FUO, 9%; 4/92 documented infections, 6%, 3/92 skin rashes, 3%; 1/92 hepatic toxicity, 1%) and appeared less frequent in arm A (4/45, 9%) than in arm B (12/47, 25%) (p=0.05). Analysis of distribution of toxicities in the two arms (arm A: 2/45 FUO, 4%; 0/45 documented infections; 1/45 skin rash, 1%; 1/45 hepatic toxicity, 1%; arm B: 6/47 FUO, 13%; 4/47 documented infections, 9%; 2/47 skin rashes, 4%) revealed a significantly lower frequency of FUO and infections in arm A (2/45, 4%) than in arm B (10/47, 22%) (p=0.02), to suggest a higher risk of infection in the 7 day regimen. The present data indicate that overall activity of subcutaneous 2CdA is similar to the intravenous formulation (Cheson, 1998). Furthermore, the current interim analysis suggests that subcutaneous 2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and lower toxicity than subcutaneous 2CdA at standard doses (0.7 mg/kg) and is easy to give in an outpatient setting.
We conducted a long-term follow-up retrospective study on 91 consecutive newly diagnosed acute promyelocytic leukaemia (APL) patients. Induction and consolidation therapy were well-tolerated by most ...patients. Of the 79 patients who were initially treated with the all-trans retinoic acid (ATRA)-containing regimens, there were 3 haemorrhagic deaths during the first period of therapy (4%) and one in consolidation which was due to infection. Following consolidation, molecular assessment of response was performed on 67 patients, and 66 were found to have achieved cytogenetic and molecular remission (98%). After a median follow-up of 100 months (12-192), 10 of the 75 patients who achieved complete remission (13%) relapsed. Seventy-eight percent of the patients were expected to be alive at 14 years from diagnosis, i.e., 90 and 48% of patients of intermediate-low risk and high risk at presentation, respectively (p=0.0009). Sixty-nine patients were in molecular remission after first-line and/or salvage therapy (74%). To date, 4 patients out of the 91 have undergone salvage allogeneic transplant (4%).
Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen 3 days of treatment with fludarabine 30 mg/m(2), cytarabine (AraC) 2 g/m(2), and liposomal daunorubicin 80 mg/m(2). ...The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment 21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2-18) and 8 months (range: 2-26), respectively. Median survival among these patients was 8 (range: 1-40) and 12 (range: 1-30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.
Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness ...(WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies.
Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers.
Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1).
Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p<0.05), being the patients below 40 years 14% and those over 70 years 33% of cases; PLT count (109/L) 846 ± 309 with lower values in males than in females (813 ± 261 vs. 866 ± 334, p<0.002), and with values 1001–1500 and over 1500 in 16% and 4% of cases, respectively; WBC count (109/L) 9.1 ± 2.9, without difference by sex, and with values 12–15 in 10% and over 15 in 3% of cases; Hgb (g/dL) 14.2 ± 1.6 with higher values in males than in females (14.8 ± 1.5 vs. 13.8 ± 1.5, p<0.001), and with values over 16.5 in 8.5% of males and 2.7% of females, respectively; splenomegaly in 488 (27%), echo-documented in 324 cases (18%); history of hemorrhage and thrombosis in 90 (5%) and 325 (19%) of cases, respectively; disease-related symptoms in 41% and general thrombotic risk factors in 93% of cases, respectively. The WHO 2001 diagnostic criteria were reported for 33% of cases observed before the year 2004 and for 53 % of cases observed since the year 2004. Detailed data at diagnosis were reported as follows: bone marrow biopsy in 1087 cases (61%) with a frequency of 51% and 68% before and since the year 2004, respectively; bcr-abl study in 1045 cases (59%); cytogenetics in 828 cases (46%) with karyotype abnormalities in 27 patients (3%). The JAK2 V617F mutation, searched in 574 cases (32%), was observed in 320 of them (56%). The patient follow-up was 4.5 ± 4.5 years with a total of 5245 pt-yrs. During the follow-up the hemorrhagic events were 5.7% (1.3/100 pt-yrs), being the major events 1.9% (0.4/100 pt-yrs); the thrombotic complications were 14.9 % (3.3/100 pt-yrs), resulting the major arterial 9.4% (2.1/100 pt-yrs), the major venous 3.5% (0.8/100 pt-yrs) and the minor thrombosis 2% (0.4/100 pt-yrs). An antiplatelet treatment, almost always with low dose aspirin, was performed in 75% of the patients, without significant difference in the cases diagnosed before and since the 2004. A cytoreductive treatment was done with use of Hydroxyurea (HU, 64%), Interferon alpha (IFN, 16%), Anagrelide (ANA, 15%), Busulfan (BUS, 4%), and Pipobroman (PIPO, 2 %). In the ET patients diagnosed since the year 2004 respect those diagnosed before, it was observed a decrease in the use of all the cytoreductive drugs, particularly BUS (−62%), IFN ((−62%), and ANA ((−68%). The use of the cytoreductive drugs was related to the patient mean age (years): BUS (76), PIPO (72), HU (67), ANA (53), IFN (48). In the patients diagnosed since the 2004 as compared with those before 2004, the mean age of the treated patients increased for BUS (from 69 to 81 yrs, p<0.001) and for HU (from 64 to 69 yrs, p<0.001) while it decreased for IFN (from 49 to 46 yrs, p<0.05).
Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.
Infections are the major cause of morbidity and mortality of acute myeloid leukemia (AML). Invasive Fungal Infections (IFIs) occur in at least 10 to 20% of the patients submitted to induction and ...consolidation treatments, are responsible for death during induction in up to the 5% of the cases and may cause a delay in consolidation and intensification therapy. Among the risk factors for IFIs it has been included the use of Fludarabine (Fluda), which can induce severe and prolonged immunosuppression. In this study we retrospectively analyzed the infections occurred in 224 newly diagnosed AML patients, aged at least 65 years, consecutively treated with an induction regimen including Fluda, Ara-C and idarubicine with or without etoposide (FLAI/FLAIE). During induction phase, 181/224 (81%) patients experienced a fever of undetermined origin (FUO), the incidence of Gram negative and positive sepsis was 16% (37/224) and 29% (65/224) respectively and 7/224 (3%) patients developed a possible/probable IFI. In 6/224 patients (3%) a proven IFI was found (4 aspergillosis and 2 candidiasis). We then collected the data of the incidence of infections during the first consolidation course (FLAI: n=70; high-dose Ara-C HD-AC: n=65; idarubicine and HD-AC: n=89). The overall incidence of FUO was 34% (76/224), the number of Gram negative and positive sepsis was 52/224 (23%) and 49/224 (22%), respectively and 2/224 (1%) patients developed a proven IFI (3 aspergillosis and 1 candidiasis). We subsequently evaluated the incidence of infections in the three different consolidation groups. No significant differences were observed in terms of FUO, Gram positive and negative bacteraemia/sepsis and possible, probable and proven IFIs, during consolidation with Fluda-based regimen and with HD-AC-based regimens. Interestingly, the overall incidence of IFIs during consolidation with FLAI was significantly lower than during consolidation with HD-AC-based treatment program (0% vs 9%; p=0.02). These data, even though retrospectively collected, suggest that Fluda-based chemotherapy is not followed by increased incidence of infections, in particular IFIs, in comparison with conventional non-Fluda based regimens commonly used for AML induction. In our series, Fluda-based consolidation chemotherapy caused a significantly lower incidence of IFIs compared to HD-AC-based consolidation. This may be related to the lower duration of neutropoenia in patients treated with FLAI with respect to those treated with HD-AC/HD-AC + idarubicine.
Treatment of Hodgkin's lymphoma (HL) is perceived to be relatively straightforward. Consequently, patients are not usually referred to hemato-oncologically specialized centres and are treated locally ...instead. Comprehensive findings beyond prospective controlled trials are therefore lacking. Clinical data of 209 patients who had received a HL diagnosis were collected. A total of 7 patients received radiotherapy (RT) alone (3%), 75 (35%) were treated with a combination of chemotherapy (CT) and RT and 127 patients received CT alone mainly doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Complete response (CR) following first-line treatment was achieved in 178 patients (85%) and in 195 (93%) after salvage treatment. Favorable disease (p=0.000359), limited-stage disease (p=0.0003), involvement of lymph nodes above the diaphragm (p=0.05) and absence of mediastinal bulky tumor involvement positively affected the CR rate following first-line treatment. Out of the 195 patients that achieved CR, 31 relapsed. Male gender (p=0.043) and age over 45 years (p=0.047) were significantly associated with an increased incidence of relapse. Age at diagnosis was the key factor affecting long-term outcome. The event-free survival (EFS) projected at 120 months was 80 and 57% for patients younger and older than 45 years, respectively (p=0.022). The overall survival (OS) projected at 120 months was 92 and 38% for patients younger and older than 45 years, respectively (p=0.00561). A second neoplasia was diagnosed in 8 patients. The development of a tumor in 4 cases (breast, lung and thyroid cancer) was likely RT-related. Only 1 patient not receiving RT developed acute myeloid leukemia. The EFS and OS of the 141 early-stage patients treated with CT + RT (n=62) or with CT alone (n=79) were not statistically different.
The aim of this study was to elucidate the relationship between clonal and normal haematopoiesis in chronic myelogenous leukemia (CML). Thirteen female patients who reached complete cytogenetic ...response (CCR) after Imatinib® treatment were studied. Although all the study patients exhibited a polyclonal pattern of X inactivation, p210 BCR ABL transcript remained detectable in all cases by nested RT-PCR. This study also demonstrated the presence of p190 transcript in nine out of 13 study patients. A longer follow-up analysis is needed to clarify the prognostic value of these results. The recent observation that clonal cytogenetic abnormalities may occur in CML patients in polyclonal remission after imatinib suggests that a neoplastic stem cell lacking BCR ABL rearrangement may acquire further cytogenetic alterations other than Philadelphia chromosome.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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