[Show abstract][Hide abstract] ABSTRACT: We report a case of a young patient with chronic viral hepatitis HBV infection, diagnosed with CML in March 2006 and treated with imatinib 400mg/die as first line therapy with concomitant Lamivudine. Patient obtained a complete hematologic response (CHR) in 2 months, complete cytogenetic response (CCyR) in six months and major molecular response (MMR) at 24 months. After three years of treatment, she became imatinib intolerant and resistant. In November 2009 patient started nilotinib 400mg/BID. Patient tolerated well the new molecule never experiencing hepatic impairment. After switching to nilotinib, she reached in 12 months transcript reduction more than 3 log (MMR). Even if patient had been informed of the need of continuous therapy and to use effective methods of contraception during tyrosine kinase inhibitor (TKI) treatment, in 2012 she decided to plan a pregnancy. In August 2012 a MR4 was documented, and treatment discontinued before starting pregnancy. She was placed on interferon and observed throughout her pregnancy. The disease remained stable achieving an undetectable transcript level; she delivered a healthy boy in September 2013. Treatment with nilotinib was re-started three months after delivery, and she is still in molecular remission (MR5). A complete discussion of the case and the available literature is presented.
Preview · Article · Dec 2015 · Mediterranean Journal of Hematology and Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Dasatinib was approved for the treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients in first line therapy based on the demonstration of efficacy and safety reported in patients enrolled in clinical trials. We describe a multicentric Italian "real-life" experience of dasatinib used as frontline treatment outside clinical trials. One hundred and nine patients (median age 54 years) were treated from January 2012 to December 2013. Increased incidence of high risk patients were detected according to stratification (26% according to Sokal score, 19% according to Euro score and 16% according to EUTOS) when compared to company sponsored studies. Median time from diagnosis to start of dasatinib was 18 days. Ten patients received unscheduled starting dose (6 patients 50mg and 4 patients 80mg QD), whereas 99 patients started with 100mg QD. At 3 months, 92% of patients achieved a BCR-ABL ratio less than 10%. At 6 months, the rate of CCyR was 91% and the rate of MR3 was 40%, with 8% of the patients reaching MR4.5. Ninety-three patients were evaluable at 12 months: the rate of MR3 was 62%, with MR4.5 being achieved by 19% of the patients. At a median follow-up of 12 months, 27 patients (24.7%) were receiving the drug at reduced dose. Two patients (1.8%) experienced a lymphoid blast crisis and the overall incidence of resistance was 8%. As regards safety, the major side effects recorded were thrombocytopenia, neutropenia and pleural effusions, which occurred in 22%, 10% and 8% of patients, respectively. Present results, achieved in a large cohort of patients treated outside clinical trials, further confirm the efficacy and safety of dasatinib as firstline treatment in CML.
No preview · Article · Nov 2015 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: Nilotinib (NIL) is approved for the first-line treatment of CML based on the results of the ENESTnd study that demonstrated a higher efficacy compared to imatinib (IM). However, there are concerns on the vascular toxicity of NIL, disclosed by an increased rate of cardiovascular adverse events (CVAEs) with respect to imatinib. For this reason, we investigated the CVAEs in 2 studies of the GIMEMA CML WP that included NIL as first-line treatment of CML: the GIMEMA CML 0307 trial (73 pts; NIL
400 mg BID), and the GIMEMA CML 0408 trial (123 pts; 3-months alternating regime of NIL 400 mg BID and IM 400 mg QD). The median age at CML diagnosis of all 196 pts was 55 (18-84) years; 59 (30%) pts were ≥65 years; 52% were males; cardiovascular risk factors (CVRF: hypertension, dyslipidemia, diabetes, BMI ≥30, and prior ischemic disease) were present in 74 (38%) pts (median 1, range 1-4). There were no significant differences between the pts characteristics in the 2 studies. The
median f-up was 61 months. Nineteen CVAEs occurred in 17 (8.6%) pts: 7 acute myocardial infarctions (MI); 5 PAODs; 2 carotid stenosis, 2 aortic atherosclerosis, 1 stroke, 1 unstable angina, and 1 stable angina (1 patient had 1 PAOD, 1 stroke, and 1 MI). In pts with CVAEs, the median age at CML diagnosis was 67 (43-84 years), and the median interval from CML
diagnosis to CVAE was 38(1-76) months. Out of the 17 pts with CVAEs, 53% were males; 70% were ≥65 years at CML diagnosis; 76% had at least 1 CVRF, and 65% were treated with NIL alone. All pts but one (who died at 90 years for congestive heart failure post MI) are alive. Treatment of CVAEs included coronary angioplasty in 5 pts, lower limb amputation in 2 pts, and peripheral vascular surgery in 2 pts; all other pts received medical treatment; 12/17 pts permanently discontinued NIL. In univariate analysis, the occurrence of CVAEs was associated with age≥65 years (12/59[20%] vs 5/137[3.6%]; p=0.0004), the presence of at least one CVRF (13/74[18%] vs 4/122[3.3%]; p=0.001), and the monotherapy with NIL (11/73[15%] vs 6/123[4.8%]; p=0.018). CVAEs occurred at a significant rate in pts treated with NIL-based regimes, and in particularly in pts ≥65 years and/or with CVRF. Noteworthy, the alternating schedule of NIL and IM resulted in a lower incidence of CVAEs compared to NIL monotherapy. Thus, considering the morbidity associated to CVAEs, the risk/benefit ratio of NIL monotherapy should be
carefully evaluated in selected groups of patients.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.
Full-text · Article · Sep 2015 · Blood Cancer Journal
[Show abstract][Hide abstract] ABSTRACT: Prolonged survival in patients with chronic myeloid leukemia treated with BCR-ABL1-targeted tyrosine kinase inhibitors allows consideration of parenthood for patients on chronic therapy, but there are limited data regarding the effects of dasatinib on pregnancy. Pregnancy-related outcomes in dasatinib-treated patients or their partners reported to Bristol-Myers Squibb from clinical trials or healthcare providers through December 2013 were reviewed. Outcomes were available in 46/78 dasatinib-treated women (59%) and 33/69 partners of dasatinib-treated men (48%). Fifteen women (33%) delivered a normal infant; 18 (39%) and eight (17%) had an elective or spontaneous abortion; and five (11%) had an abnormal pregnancy. There were seven reports of fetal/infant abnormalities (encephalocele, renal tract abnormalities, and hydrops fetalis). Thirty of 33 (91%) infants fathered by dasatinib-treated men were reported normal at birth. Also, animal studies evaluated the impact of dasatinib on fertility, embryo-fetal toxicity, and development, suggesting that dasatinib may be a selective developmental toxicant. The outcomes of most pregnancies conceived by men treated with dasatinib were normal, but due to the small number of cases, further monitoring is required. Significant effects on pregnancy outcomes in women treated with dasatinib were found, supporting current recommendations that women avoid becoming pregnant during dasatinib treatment and be informed of fetal risks. This article is protected by copyright. All rights reserved.
No preview · Article · Sep 2015 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Several factors are predictive of treatment-free remission (TFR) in chronic myeloid leukemia (CML) but few data exist on the role of natural killer (NK) cells and their killer- immunoglobin-like receptors (KIRs). KIR and HLA genotypes were investigated in 36 CML patients who discontinued tyrosine kinase inhibitor (TKI) treatment after achieving deep molecular response (MR(4.5)). Cumulative TFR was significantly higher in patients homozygous for KIR A haplotype (85.7% vs 45.5%; p=0.029). Younger age, Bx haplotype and the combination KIR3DS1/KIR3DL1present/HLA-Bw4 present were significantly associated with relapse. KIR genotypes could prove useful in identifying patients that are likely to maintain MR(4.5) after discontinuing TKI treatment.
Full-text · Article · Aug 2015 · Experimental hematology
[Show abstract][Hide abstract] ABSTRACT: For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine-kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died, and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (lower than or equal to 10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but since 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also due to second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.Leukemia accepted article preview online, 19 June 2015. doi:10.1038/leu.2015.152.
Full-text · Article · Jun 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage.
Patients and methods:
To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period.
Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011).
The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome.
Clinical trial numbers:
NCT00510926, NCT00514488, NCT00769327, NCT00481052.
Full-text · Article · Oct 2014 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score≥1. Imatinib standard dose was reduced at start of therapy (200-300mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score≥1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score≥1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score≥1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score≥1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score≥1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score≥1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score≥1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.
Full-text · Article · Jul 2014 · Leukemia Research
[Show abstract][Hide abstract] ABSTRACT: Combined-modality treatment is standard treatment for patients with clinical stage I/II Hodgkin lymphoma (HL). We hypothesized that an early positron emission tomography (PET) scan could be used to adapt treatment. Therefore, we started the randomized EORTC/LYSA/FIL Intergroup H10 trial evaluating whether involved-node radiotherapy (IN-RT) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as compared with standard combined-modality treatment.
Patients age 15 to 70 years with untreated clinical stage I/II HL were eligible. Here we report the clinical outcome of the preplanned interim futility analysis scheduled to occur after documentation of 34 events in the early PET-negative group. Because testing for futility in this noninferiority trial corresponds to testing the hypothesis of no difference, a one-sided superiority test was conducted.
The analysis included 1,137 patients. In the favorable subgroup, 85.8% had a negative early PET scan (standard arm, one event v experimental arm, nine events). In the unfavorable subgroup, 74.8% had a negative early PET scan (standard arm, seven events v experimental arm, 16 events). The independent data monitoring committee concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping random assignment for early PET-negative patients.
On the basis of this analysis, combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL, although early outcome was excellent in both arms. The final analysis will reveal whether this finding is maintained over time.
Full-text · Article · Mar 2014 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: The management of patients with chronic myeloid leukemia (CML) during pregnancy has become recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients; in fact, patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy, including the necessity to address issues relating to fertility and pregnancy. Physicians are frequently being asked for advice regarding the need for, and/or the appropriateness of, stopping treatment in order to conceive. In this report, we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for TKI treated CML patients, as well as how to manage a planned and/or unplanned pregnancy.
Full-text · Article · Jan 2014 · Mediterranean Journal of Hematology and Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Background
Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Methods
We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. ResultsAmong 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. Conclusions
Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440.)
Full-text · Article · Nov 2013 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR(3.0) ) in 17%, and less than 0.01% (MR(4.0) ) in 81% of patients. No patient was completely molecular negative (MR(4.5) or MR(5.0) ). The OS at 10 and 20 years is 92% and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR(4.0) . Complete molecular response (MR(4.5) or MR(5.0) ) seems to be unecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.
Full-text · Article · Oct 2013 · American Journal of Hematology