Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1794-1794

Abstract: BACKGROUND: The INTERIM study (ClinicalTrials.gov NCT 00858806) showed that in elderly ( 〉 65 years) Ph+ CML patients selected for a stable complete cytogenetic response (CCgR) lasting 〉 2 years, the policy of intermittent imatinib treatment (one month on/one month off) may affect the markers of residual disease (CCgR and major molecular response, MMR or MR3.0), but not the clinical outcomes (overall survival and progression-free survival) (Russo D et al, Blood 2013; 121(26):5138-44). AIMS: To update the results of the INTERIM Study, with a follow up ≥ 5 years. METHODS: After 4 years of follow up, patients continouing INTERIM treatment were monitored with peripheral blood RT-Q-PCR every 3 months according to the ELN-2013 guidelines. RESULTS: At 48thmonth, out of 76 patients enrolled in the INTERIM study, 13 (17%) had lost CCgR and MMR, 14 (18%) had lost MMR only and 50 patients (75%) continued INTERIM. The patients who had lost CCgR and/or MMR resumed imatinib continuously and all of them regained the CCgR and the MMR, within 3 to 12 months. No patient progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. No patient complained of new or more severe side effects during the months “on”. After a follow up ≥ 5 years, 45/76 (59%) enrolled patients are on INTERIM, with a probability of maintaining intermittent administration of 59% (95% CI: 46-69). No patient lost the CCgR and only 9 additional patients lost the MMR while on intermittent treatment. All these patients resumed continuous imatinib treatment and regained the MMR. Thus, at ≥ 5 years, the probability of maintaing CCgR is 80% (95% CI 68-87) and the probability of maintaining the MMR is 61% (95% CI: 48-71). From start of INTERIM, 6 patients died but no deaths were related to CML progression (3 cases of other non haematological neoplasms, 1 stroke, 1 myocardial infarction, 1 chronic obstructive pulmonary disease).The PFS at ≥ 5 years is 94% (95% CI: 89-100) CONCLUSIONS: In summary, with a follow up ≥ 5 years, intermittent imatinib administration (INTERIM) confirmed to be safe, to produce a reversible increase of residual molecular disease in about one third of patients, but not to affect the long-term outcome. Aknowledgments: This work was supported in part by EuropeanLeukemiaNet (contract LSHC-CT-2004-503216) through the European Treatment and Outcome Study (EUTOS), supported by Novartis Oncology Europe, and COFIN 2009 Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol-Meyers and Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Rosti:Consultant: Consultancy, Speakers Bureau; Bristol-Meiers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1794.1794

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2790-2790

Abstract: Abstract 2790 The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated a need for early molecular parameters associated with inadequate responses to Imatinib Mesylate (IM). Recent evidence suggests that CML patients presenting BCR-ABL/ABLIS levels 〉 10% after 3 months of IM or 〉 1% after 6 months of treatment have inferior outcomes in terms of both overall survival (OS) and progression-free survival. We wanted to establish if high BCR-ABL transcripts at diagnosis would also be associated with unfavorable responses to IM. To this end, we correlated quantitative determinations of BCR-ABL measured at diagnosis with the outcome of 230 newly diagnosed CML patients receiving IM 400 mg/die. BCR-ABL transcripts were measured from peripheral blood samples drawn at diagnosis using Real-Time Quantitative PCR (RQ-PCR). All molecular determinations were performed twice (in triplicates) on the same sample using either ABL or glucuronidase-beta (GUS) as reference genes. Median follow-up of the study population was 42 months. Estimated 5-year cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR) and major molecular response were 97.9%, 89.5% and 64.7%. Five-year probabilities of OS, transformation-free survival (TFS: survival without disease transformation to the accelerated phase or blast crisis) and failure-free survival (FFS: survival without IM failure as defined by the 2009 European Leukemia Net recommendations) were 93.8%, 97.8% and 76%. Correlations between high BCR-ABL transcripts at diagnosis and unsatisfactory IM responses were much stronger using GUS in place of ABL as a reference gene. Indeed, while elevated BCR-ABL/GUSIS (p 〈 0.0001) and elevated BCR-ABL/ABLIS (p 〈 0.0001) both correlated with inferior probabilities of optimal response, high BCR-ABL/GUSIS (p 〈 0.0001) but not high BCR-ABL/ABLIS (p=0.18) was associated with lower rates of CCyR after 12 months of IM. Neither BCR-ABL/GUSIS nor BCR-ABL/ABLIS at diagnosis were predictive of OS. However, high BCR-ABL/GUSIS was more accurately associated with lower probabilities of FFS (p 〈 0.0001) and TFS (p=0.01) as compared to BCR-ABL/ABLIS (p=0.02 for FFS; p=0.36 for TFS). When we employed the 2009 European Leukemia Net criteria to subdivide our patient cohort in optimal responders, suboptimal responders and individuals failing IM, we found that elevated BCR-ABL/GUSIS (p 〈 0.0001) was superior to elevated BCR-ABL/ABLIS (p 〈 0.004) in distinguishing patient outcome. Furthermore, while BCR-ABL/ABLIS at diagnosis only discriminated optimal from resistant subjects (p=0.005), BCR-ABL/GUSIS transcripts were significantly different between the three patient groups (optimal vs suboptimal p=0.0002; optimal vs resistant p 〈 0.0001; suboptimal vs resistant p 〈 0.0001). Using receiver operating characteristic curves and the achievement of an optimal response as a specific endpoint, we found that 16.46% BCR-ABL/GUSISat diagnosis defined a threshold distinguishing low risk from high risk patients. High BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from IM that should receive alternative forms of treatment. Disclosures: Turri: Novartis: Consultancy, Novartis Other; Bristol Myers Squibb: Bristol Myers Squibb, Bristol Myers Squibb Other, Consultancy. Morabito:Celgene: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2790.2790

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4046-4046

Abstract: Background. Nilotinib 300 mg BID was approved as frontline treatment in chronic phase chronic myeloid leukemia (CP-CML) patients and allowed to reach deep molecular responses in a shorter median time with reduction of progression rate. Nilotinib is associated to a specific safety profile, with metabolic side effect as the most common events and increased probability of cardiovascular disorders. Aim. Aim of our study is to prospectively assess metabolic changes and cardiovascular safety during treatment with nilotinib, in a single arm multicentric Italian GIMEMA trial (0811), testing the drug as frontline treatment with the primary endpoint to obtain MR4 at 24 months. All metabolic changes were classified according to CTC grade. Lipidic changes were assessed according to American Association of Clinical endocrinologist criteria of 2012 and glucose abnormalities according to American diabetologist association (ADA). Results. One hundred and thirty patients were enrolled in 33 different centers: median age 50.5 years (range 18-85), 64.6% male. Mean body mass index (BMI) was 25.3, with 40% of patients being overweight/obese according to WHO classification. At last contact, 100 patients were still in treatment, the majority with full dose (86%). According to ADA criteria 47%, 10%, 4.6% and 6% of patients experienced grade 1 (101-125 mg/dl), grade 2 (126-150 mg/dl), grade 3 (151-200 mg/dl) and grade 4 ( 〉 200 mg/dl), increased fasting glucose, respectively. As compared to baseline, a significant variation was observed after 1 year (p 〈 0.001). Glycosylated haemoglobin increased in 47% as grade 1 (5.7-6.49%), 10% as grade 2 (6.5-6.99%), 3% as grade 3 (7-7.99) and 4.6% as grade 4 ( 〉 8), respectively according to ADA criteria. AACE criteria identified a significant reduction of triglycerides (p 〈 0.001) and a significant increase of cholesterol both in LDL and HDL fractions (p 〈 0.001). Five patients (3.8%) experienced a peripheral arterial disorders (2 patients with claudication, 2 stenosis and 1 patient with arterial optic ischaemic): one patient required temporary reduction and 1 patient permanent discontinuation. Four patients experienced a venous thrombosis. Six patients (4.6%) had an ischemic cardiac disease and 7 patients (5.3%) an arrhythmia: five patients, based on physician judgment discontinued the treatment. Conclusions. Prospective monitoring of metabolic safety during frontline treatment with nilotinib 300 mg BID showed consistent and specific profile with increased glycaemia and cholesterol level, mostly of grade 1-2. Possible occurrences of cardiovascular side effects impose identification of patients at risk at baseline and a correct monitoring during follow-up. Disclosures Castagnetti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Gugliotta:BMS: Honoraria; Novartis: Honoraria. Tiribelli:Novartis Farma: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau. Saglio:Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria. Baccarani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4046.4046

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3426-3426

Abstract: Abstract 3426 Imatinib mesylate (IM) has shown remarkable efficacy for the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, while most individuals achieve an optimal response to conventional IM therapy, approximately 30% either fail IM or develop intolerance to the drug. Thus, there is a growing need for biological parameters predictive of IM response (at diagnosis or during the first months of therapy) in order to recognize pts with a more aggressive disease that should receive alternative treatments. We examined the outcomes of the first 193 CML pts accrued to the observational SCREEN (Sicily and Calabria CML REgional ENterprise) multicenter non-sponsored study, and analyzed the responses of this unselected population. Pts characteristics were as shown in Table 1. All subjects received IM 400 mg daily. Median follow-up was 26 months (range 3–60). Complete hematological (CHR), cytogenetic (CCyR) and major molecular responses (MMR) were rated according to the European Leukemia Net 2006 guidelines. Peripheral blood samples were used for BCR-ABL determination by quantitative real-time polymerase chain reaction according to the International standardized Scale (IS). To identify parameters predictive of IM response, pts were stratified according to clinical and molecular responses or BCR-ABL transcript levels at diagnosis and analyzed for their outcome on an intention to treat basis. At 12 months, cumulative incidences of CHRs, CCyRs and MMRs were 100%, 82% and 43%, respectively. At 24 months, incidences of CCyR and MMR increased to 87% and 67%. According to the ELN criteria, 121 pts (62%) achieved an optimal response; 36 pts (19%) had a suboptimal response; 32 pts (17%) failed IM because of either primary (20 pts) or secondary (12 pts) resistance. Only 4 pts (2%) were intolerant to IM. Kaplan-Meyer estimates for overall, progression-free, event-free and failure-free survival at 60 months were 99%, 96% 80% and 72%. When we clustered all subjects in optimal responders (ORs) and suboptimal/resistant (S/R) pts and correlated response to therapy with various molecular characteristics we found that the amount of BCR-ABLIS transcripts at diagnosis predicted response to IM. Indeed, the median amount of BCR-ABLIS at diagnosis displayed by patients that failed IM or achieved a suboptimal response was significantly higher (104.154IS) than that of patients obtaining an optimal response (53.478IS; p=0.000611). As WBC counts were not significantly different between ORs and S/R pts (p=0.2065), increased amounts of BCR-ABLIS transcripts were probably representative of the aggressiveness of the leukemic clone. We also observed that pts displaying 〉 10% BCR-ABLIS after 3 or 6 months of IM had a significantly lower chance of achieving a CCyR compared to pts with BCR-ABLIS levels lower than 10% (p 〈 0.001). IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR, CCyR and MMR. However, 35–40% of newly diagnosed CML pts will either fail IM or obtain a suboptimal response. High levels of BCR-ABLIS transcripts at diagnosis may allow the rapid identification of CML pts that are likely to fail IM or to achieve a suboptimal response. Furthermore, failing to achieve BCR-ABLIS transcript levels 〈 10% after 3 or 6 months of IM treatment significantly reduces the probability of subsequently obtaining a CCyR. Table 1. Characterisitics of CML pts included in the SREEN study Age (median yrs) 54 (range 24–90) Sex (M/F) 108/85 WBC × 109/L (median) 64.8 (range 3.4–718.0) Hb (g/dL) 12.1 (range 7.5–17.0) PLT × 109/L (median) 330.0 (range 67.0–1690.0) Organomegaly % 58 Sokal risk stratification % 49 Low/36 Intermediate/15 High Ph+ % (diagnosis) 96 ACA % (diagnosis) 7 BCR-ABL transcript variants % 38 e13a2/53 e14a2/9 other BCR-ABLIS % (median at diagnosis) 58.641 Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3426.3426

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2294-2294

Abstract: Abstract 2294 Background. The TKIs Nilotinib and Dasatinib offer additional therapeutic options for patients with CML who are resistant or intolerant to Imatinib. These agents, active against the majority of Imatinib resistant BCR-ABL mutated clones, have a different pattern of kinase target selectivity, pharmacokinetics parameters, cell uptake, efflux properties and adverse events profiles. Preliminary results suggest that some patients may respond to a second TKI used as third line therapy, but little is known about the long term benefit of such an approach.Aim of this collaborative Italian study was to verify the response (rate and duration) and the clinical outcome in patients with CML treated with a third TKI after sequential failure of the previous ones. Methods. We evaluated 66 patients with CML, resistant/intolerant to Imatinib and treated with Dasatinib or Nilotinib, then switched to a third- line TKI after treatment failure. Of these, 29 patients were treated with dasatinib after imatinib/nilotinib failure and 37 with nilotinib after imatinib/dasatinib failure. Patients were monitored with complete blood counts, cytogenetic analysis, bone marrow aspiration RT-PCR and mutational analysis. Results. A total of 66 patients (median age 63 years, range, 33–85 years) were treated with sequential TKIs; 40 (61%) patients had received interferon-a before starting Imatinib; 26 (39%) patients received imatinib as first line therapy. The median time on imatinib therapy was 47.5 months (range 4–101 months). At the start of nilotinib as second line, 27/29 (93%) patients were in CP, 1 (3.5%) in AP, and 1 (3.5%) in BP. 9 patients (31%) had developed mutations before starting treatment. The median time on second line TKI was 8 months (range 2–36 months). In the resistant patients 4 new mutations were identified (F359V in two patients, T315I, Y253H+F359V). At the start of dasatinib as second line, 33/37 (89.2%) patients were in CP, 4 (10.8%) in AP. 7 patients (18.9%) had developed mutations before starting treatment. The median time on second line TKI was 14 months (range 4–59 months).In the resistant patients 5 new mutations were identified (F137L in three pts, M318T, M244V+F317L). At the start of the third TKI, 60/66 (90.9%) patients were in CP, 5 (7.6%) in AP, and 1 (1.5%) in BP. Of these, 7 patients (18.9%) on dasatinib and 7 (24.1%) on nilotinib had mutations before starting treatment. The best response to the third line treatment with TKI was 10 (15.2%) MMR, 10 (15.2%) CCyR, 8 PcyR (12.1%), 5 (7.5%) mCyR, 24 (36.4%) CHR and 9 (13.6%) No Response (NR). In the dasatinib group, 9 (31%) patients discontinued treatment because of toxicity versus 17 (45.9%) patients in the nilotinib group.Two new mutations (F317L, E255V) emerged with dasatinib as third line therapy.After a median follow up of 13 months (range 2–37 months) 50 patients (48 CP, 2 AP) are continuing therapy (33 on nilotinib, 17 on dasatinib).Since the start of the third TKI, 61 patients (92.4%) are still alive for a median overall survival of 110 months (range 15–300) (52 CP, 7 AP, 2 NA); the 5 deaths (7.6%) were caused by disease progression and spread of the gene mutation T315I. Discussion. In our study, about one third of patients derived benefit from the use of three sequential TKIs; patients with better, longer response (28.7%) to third TKI were the same patients with a better response to the Imatinib and 2TKIs therapy. All these patients had taken interferon therapy before the Imatinib. In this subset of patients (good responders: CCyR and MMR) 5 patients developed mutations that were sensitive to the sequential treatment.The lack of a durable cytogenetic remission could be explained by the emergence of new kinase domain mutations as patients are exposed to sequential TKI; a change of therapy resulted in an adequate response. In our series, patients with poor prognosis showed mutations not sensitive to the TKIs treatment. Conclusions. Although allogeneic SCT is the treatment of choice in all patients failing 2 TKIs who are suitable candidates for this approach, alternative strategies are required for ineligible patients. The use of a third TKI after failure of two previous TKIs induces response in some patients. Longer follow up of a larger series of patients is needed to determine the long term impact of the response. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2294.2294

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5039-5039

Abstract: Relapsed/refractory AML patients  have a poor prognosis; allogeneic hematopoietic stem cell transplantation (HSCT) is the only chance in this setting to achieve long-term disease-free survival (1). It was previously established the activity of clofarabine plus cytarabine in AML relapse (clofarabine dosed once daily for 5 days with 40 mg/m2  followed 4 hours later by ara-C at 1 g/m2 per day)(2).However, modifications of this combination in AML therapy of relapsed/refractory patients warrant further evaluation. Therefore, our goal was to determine the efficacy and safety of clofarabine at lower dosage followed by  cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and to evaluate the capacity of this regimen as a bridge for HSCT. Methods Patients aged 18-65 years with refractory/relapsed AML were treated at the dose of clofarabine 30 mg/mq on days 1-5 and cytarabine 1000 mg/mq gg on days 1-5. We evaluated the complete remission rate (CRR), duration of remission (DOR) and overall survival (OS). Minimal residual disease (MRD) by molecular targeting was considered in all patients. Results Twenty-five (25) patients aged 29-64 years (median 47), who were fit for allogenetic HCT,  received one cycle of 30 minutes infusion of  clofarabine 30 mg/mq, followed 4 hours later by 3 hours infusion of  intermediate dose cytarabine 1000 mg/mq  days 1-5. Only in the first three patients this schedule was followed by gentuzumab. Nine (36%) patients had refractory disease (seven after one induction regimen, one after two previous regimes, one after a prior hematopoietic stem cell transplant (HSCT);  16 (64%) patients  were in their first (12 patients) or second relapse (4 patients); among the 12 patients in first relapse, 5 were from an allogeneic stem cell transplant.  Fourteen patients (56%)  achieved a complete remission (CR), seven (28%) was refractory and 4 (16%) died of treatment related mortality. Eleven (44%) patients  underwent (9 in CR) to allogeneic transplants or DLI infusion (3 patients refractory, and 8 patients relapsed), only one  patient underwent to autologous transplant. One patient, who was relapsed after prior HSCT, obtained a CR but he developed acute  graft vs host disease after therapy  and died in molecular CR*.  Among all patients underwent HSCT after Clofa/Ara-c salvage, six patients (50%) are still alive and in complete remission, six patients (50%) died because of  HSCT complications or AML relapse. The complete remission rate (CRR) was  (56,00 %), the median  Overall Survival  was 5 months for all patients (range 1-38 M), 11 Months for those underwent to tranplantation and 1,5 Months for non transplanted group. Treatment was complicated by neutropenic fever (n=17), grade III-IV mucositis (n=2) , skin rush  (n=4) grade II- III, hepatic transaminase elevations (n=2).  Two (n=5) patient died before their disease status could be evaluated. Conclusions These preliminary results suggest that combination treatment with clofarabine 30 mg/mq and ARA-C 1000 mg/mq is effective in this particularly poor prognosis category of patients, resulting in an ORR very favorably,  representing a potential “bridge” toward bone marrow transplant procedures (among the 14 patients who achieved a CR, twelve (85%) proceeded to HSCT, and six are still alive). The safety profile is acceptable in this relapsed/refractory population, and our results are very similar to previous regimes using higher clofarabine dosages.  More studies with this combination in adults are warranted. References 1 Estey E. Treatment of relapsed and refractory acute myeloid leukemia. Leukemia. 2000;14:476-479. 2. Faderl S et al, “Results of a pase 1-2 study of clofarabine in combination with cytarabine (ara-C)”Blood 2005 Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.5039.5039

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4532-4532

Abstract: Background: In the ENESTnd trial, nilotinib (NIL) showed a superior efficacy to imatinib (IM) with higher response rates and less frequent progression to advanced phases (ABP). Based on these results, NIL has been approved for frontline treatment of chronic myeloid leukemia (CML). The treatment-free remission (TFR) is actually considered one of the most important treatment goals in CML and a sustained deep molecular response (DMR, MR4 or better) is a pre-requisite to achieve TFR. The 5-year update from the ENESTnd trial showed a superiority of NIL over IM in terms of both MR4 and MR4.5, but differences concerning the stability of DMR have not been reported. Moreover, a significant improvement in the long-term outcome has not been demonstrated yet. Despite the efficacy, cost and safety concerns may limit the NIL use as first line treatment in CML. Independent studies are extremely relevant to confirm or to extend the results of company-sponsored trials. Aims and Methods: To assess the efficacy of NIL frontline in terms of DMR, a phase 3b study was conducted by the GIMEMA CML WP (CML0811; NCT01535391). The primary endpoint was the rate of MR4 at 24 months. Key secondary objectives: evaluation of the kinetics of molecular response, assessment of the safety profile, analysis of the outcome. The starting NIL dose was 300 mg BID, with dose escalation to 400 mg BID in case of suboptimal response or failure according to ELN 2009 criteria, with the exception of progression to ABP and in absence of safety issues or BCR-ABL mutations insensitive to NIL. The molecular response was assessed in GIMEMA standardized molecular laboratories (LabNet network) and the results were expressed according to the International Scale. The MR4 was defined as either detectable disease ≤ 0.01% BCR-ABL or undetectable disease with ≥ 10.000 ABL copies; the MR4.5 was defined as either detectable disease ≤ 0.0032% BCR-ABL or undetectable disease with ≥ 32.000 ABL copies. Sustained MR4 or MR4.5: MR4 or MR4.5 for at least 1 year a, with at least 3 evaluable analysis. Adverse events were recorded continuously. A prospective evaluation of glucose metabolism and serum lipids was planned. All the analysis were performed according to the ITT principle. Results: 130 CML patients in early chronic phase have been enrolled in 32 italian hematologic centers; median age, 50 years (range 18-85); high risk patients, 22%, 6% and 8% according to Sokal, Euro and EUTOS scores, respectively; clonal chromosomal abnormalities in Ph+ cells at baseline, 5%; e13a2 BCR-ABL transcript, 34%. The median follow-up is actually 21 months (all patients had at least 18 months observation; a minimum observation of 24 months will be reached by October 2014). Data with at least 24 months follow-up will be presented on site. At the last contact, the patients still on treatment with NIL were 110/130, 85% (74% with 600 mg, 7% with 300 mg or less, 4% with 800 mg daily), while 20/130 patients, 15%, permanently interrupted the study drug for the following reasons: 3% progression to ABP, 2% failure or suboptimal response (dose escalation not feasible), 1% allogeneic stem cell transplantation, 5% toxicity, 4% other reasons (including consent withdrawal and pregnancy). The complete cytogenetic response rate and the major molecular response rate at 12 months were 76% and 53%, respectively. The rates of MR4 at 3, 6, 12 and 18 months were 2%, 12%, 27% and 29%, respectively. Fifty-four patients achieved a MR4 at least once; the patients with a sustained MR4 were 18/54 (33%, or 14% of the total). The rates of MR4.5 at 3, 6, 12 and 18 months were 0, 3%, 10% and 13%, respectively. Only 3 patients achieved a sustained MR4.5. A significant increase of glycosylated hemoglobin was not observed. The total cholesterol, and both LDL and HDL cholesterol fractions significantly increased during treatment. Triglyceride concentrations had not significant variations. Six patients (5%) had a cardiovascular event, including myocardial infarction and arterial thrombosis. All the patients are still alive. Conclusions: The molecular response rates seem to be superior to the historical data of IM. NIL 300 mg BID as frontline treatment of BCR-ABL+ CML, with dose optimization in case of non optimal response, may improve the proportion of patients able to discontinue TKI treatment. Due to the metabolic effects, a baseline selection is crucial to maximize the therapeutic benefit and to minimize the cardiovascular risks. Disclosures Castagnetti: Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Novartis Farma: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rossi:NOVARTIS: Consultancy, Speakers Bureau; BRISTOL MYERS-SQUIBB: Consultancy, Speakers Bureau; ARIAD: Consultancy; ROCHE: Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Soverini:NOVARTIS: Consultancy; BRISTOL MYERS: Consultancy; ARIAD: Consultancy. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Millenium Pharm: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Onyx: Honoraria. Martinelli:Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:ARIAD: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Rosti:ROCHE: Speakers Bureau; ARIAD: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4532.4532

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2273-2273

Abstract: Abstract 2273 Background: While Imatinib (IM) has revolutionized treatment for chronic myeloid leukemia (CML), demonstrating outstanding survival figures, currently no data exist on mid to long term impact of disease burden and therapy from the patients’ perspective. Aim: The main objective of this study is to identify specific limitations of quality of life (QoL) in CML survivors who are undergoing first line treatment with IM in comparison with controls from the general population. Patient-reported symptom prevalence was also investigated. Patients and methods: Patients were recruited in 26 centers, randomly selected to geographically represent the whole study country. Patients selection criteria included: being in treatment with IM for at least three years and being in complete cytogenetic response at the time of study entry. All patients were invited by their treating physicians in the hospital to participate and all consenting patients were requested to complete a Health Survey Packet at home. Pre-paid reply envelopes were also provided with the request to send back completed Surveys to an independent National coordinating Data Center. Generic QoL was assessed with the SF-36 that consists of 36 items covering eight generic health status/QoL domains: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). All scales ranging between 0 and 100 with higher scores representing better outcomes. A previously devised patient-reported CML Symptom Checklist was used to investigate 9 symptoms of possible major concern in these patients. Mean SF-36 scores were compared to available national general population reference values and all analyses were adjusted for age and gender. Statistical comparisons were all adjusted for multiple testing. Differences in mean scores were expressed in Cohen effect sizes (ES; with 0.2, 0.5, and 0.8 indicating small, medium, and large ES, respectively) and clinical significance. Results: Between March and December 2009, 448 patients were recruited in a large national-based survivorship project. Patients’ compliance was optimal with 94% of patients (N=421) returning a valid Health Survey Packet to the National coordinating Data center. At study participation, mean age of patients was 56 years (59% male and 41% female) and median time of IM therapy was 5 years. Seventy-seven percent of patients were receiving standard dose of 400 mg and 43% had at least one comorbidity. Age and gender adjusted comparisons with general population norms revealed worse outcomes for the following scales: RP (P 〈 .001; ES=0.3), GH (P 〈 .001; ES=0.4) and RE (P=.01; ES=0.2). The largest clinically meaningful difference (Δ=12.3 points) was found for the RP domain with mean scores of 61.4 vs. 73.7 respectively for the CML and the general population. Age specific comparisons, adjusted by gender, (55-64; 65–74 and 〉 75 years) suggested an almost uniform pattern in all scales with worse outcomes between CML patients and population controls among the youngest groups. GH was significantly worse in younger patients (55-64) (P=.03; ES=0.4) and no differences were found in the older age groups compared with population norms. Prevalence of reported symptoms (with any level of concern) was: fatigue (82%); problems with muscular cramps (78%); problems with musculoskeletal pain (72%); problems with edema (70%); skin problems (47%); diarrhea (43%); headache (39%); abdominal discomfort and nausea (28%). Conclusion: This study suggests that while still being on treatment with IM for years, CML patients might expect to have a QoL profile broadly similar to that of general population in many areas. However, role limitations (i.e., in work or other regular daily activities) due to physical health seem the major constraint faced by these patients; there is also an indication that younger patients might be those experiencing major limitations. Additional analyses will be undertaken to ascertain the impact of symptoms and other laboratory and clinical data on specific QoL domains. Such unique patient-reported data supplements conventional information on clinical efficacy of IM and may support both clinicians and patients in making more informed treatment decisions in this area. Disclosures: Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol M. Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2273.2273

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3412-3412

Abstract: 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). Figure 1 Distribution of patients according to I-FISH Figure 1. Distribution of patients according to I-FISH 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. Figure 2 Cytogenetic and molecular response in 11 cases who showed I-FISH 〉 1% + nuclei and who were checked by CBA on bone marrow. Black boxes shows the 3 cases who lost the CCgR Figure 2. Cytogenetic and molecular response in 11 cases who showed I-FISH 〉 1% + nuclei and who were checked by CBA on bone marrow. Black boxes shows the 3 cases who lost the CCgR 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. Acknowledgments: This work was supported in part by CML-Leukemia Net and Progetto Regione Lombardia. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3412.3412

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4627-4627

Abstract: Patients with relapsed and refractory AML have a bad prognosis. In this setting it is often difficult to obtain a complete remission. In the last few years fludarabine and high dose Citarabine with or without Idarubicine and G-CSF have been frequently used (FLAG and FLAG-IDA schedules). The immunotoxin gemtuzumab ozogamicin (Mylotarg)(GO) Wyeth is a humanized IgG4 monoclonal antibody directed against the CD33 epitope, which is chemically linked to calicheamicin, a highly potent antitumor antibiotic. As a single agent it has been shown to be an effective agent in the treatment of relapsed AML with a tolerable toxicity profile. Recently the United Kingdom Medical Research Council (MRC) published the preliminary results of AML15 trial, which was designed to evaluate the effect of adding GO to each course of intensive induction or consolidation chemotherapy in patients younger than 60 years as first-line treatment. These results are encouraging. We are using this association in the treatment of relapsed and refractory adult AML. Until now 10 patients have been enrolled in this trial and we show our preliminary results. Patients and methods. 3 patients were resistant to induction; 3 patients were in the first relapse and 1 in the third after conventional chemotherapy, 1 was relapsed after autologous transplant and 2 were relapsed after allogeneic transplantation. The demography and characteristics are shown in the table. 8 Pts were treated with Fludarabine 30 mg/sqm dd 1–5, Citarabine 2,0 gr/sqm dd 1–5, Idarubicine 10 mg/sqm dd 3–5, Mylotarg 3 mg/sqm d −1, G-CSF 375 mg dd 1–6. 2 patients with the same schedule without Idarubicine. Results: 6 patients obtained Complete Remission, 2 died after therapy and 2 were resistant to this schedule.Out of the 6 patients in CR 4 are in continuous complete remission at 3, 3, 8 and 11 months Three of these underwent allogeneic BMT with no significant toxicity and are actually in CR.. Two relapsed at 3 and 7 months. In our experience the toxicity of FLAG-(IDA)-GO schedule is acceptable and the results are promising in refractory and relapsed AML. pts age years disease status treat.response further therapies outcome 1 46 resistant CR BMT CR +11 M 2 52 resistant resistant -- died 3 69 1 th relapse CR -- relapse 7 M 4 65 3th relapse died -- 5 57 relapse after auBMT died -- 6 58 relapse after BMT resistant -- died 7 28 relapse after BMT CR 2nd BMT CR +6 M 8 42 1th relapse CR BMT CR +3 M 9 74 1th relapse CR -- CR +4 M 10 64 resistant CR __ relapse 3 M

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.4627.4627

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7