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The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.

Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR4(BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10 000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.

Small cell lung cancer accounts for 13–15% of all lung cancer worldwide. There has been a decrease in the number of cases, with no clear explanation, except probably to changing in smoking habits in the last two decades. In the early 1980s, it became clear that SCLC was an extremely sensitive tumour to radiation as it was to chemotherapeutic agents. With cisplatinum etoposide combinations or cyclophosphamide, anthracycline and vincristine/etyoposide regimens responses were observed in 50–70%, with 20–30% complete remissions in extensive disease. For limited-stage patients chemotherapy associated with thoracic radiation was able to produce a cure rate of 10–20%.The addition of prophylactic brain irradiation to limited stage cases has reduced mortality by a factor of nearly 5%. But despite these early good results no breakthrough came later on, and in the last decade or so, we are still facing this plateau. New agents have recently been included in the therapeutic armamentarium, such as gemcitabine, irinotecan, paclitaxel and more recently pemetrexed. This fact has allowed many patients to receive a relatively active second line therapy, but the overall survival remains unchanged. Targeted therapies are undergoing some evaluations, but the data are too premature and, so far, quite discouraging. At the present time there is an urgent need to improve clinical research in this somehow forgotten disease.

Small cell lung cancer accounts for 13–15% of all lung cancer worldwide. There has been a decrease in the number of cases, with no clear explanation, except probably to changing in smoking habits in the last two decades. In the early eighties, it became clear that SCLC was an extremely sensitive tumor as to radiation as to chemotheraputic agents. With cisplatinum etoposide combinations or cyclophosphamide, anthracycline and vincristine/etyoposide regimens responses were observed in 50–70%, with 20–30% complete remissions in extensive disease. For limited stage patients chemotherapy associated with thoracic radiation was able to produce a cure rate of 10–20%.The addition of prophylactic brain irradiation to limited stage cases has reduced mortality by a factor of nearly 5%. But despite these early good results no breakthrough came later on, and in the last decade or so, we are still facing this plateau. New agents have recently been included in the therapeutic armamentarium, such as gemcitabine, irinotecan, paclitaxel. This fact has allowed many patients to receive a relatively active second line therapy, but the overall survival remains unchanged. Targeted therapies are undergoing some evaluations, but the data are too premature and so far quite discouraging. At the present time there is a urgent need to improve clinical research in this somehow forgotten disease.

Germ cell tumor is the most common malignancy in young men. The cure rate of these patients has tremendously increased in the cisplatin era, and recent results have indicated that the management of patients with GCT is still improving. The use of FDG-PET in the management of patients with GCT has been recently investigated. This report attempts to comprehensively review new advances and delineate the potential applications of FDG-PET in GCT.

SummaryAbout 40% of patients with advanced cancer develop metastases in the central nervous system (CNS), mainly from primary tumors of lung, breast and melanoma. In most of cases there are multiple CNS metastases, making surgery or localized radiosurgery not feasible. The current standard of care for these patients is radiation therapy, which can improve neurologic symptoms but does not have any impact on the patient’s overall survival. Temozolomide, capecitabine and gefitinib are safe and active in the treatment of CNS metastases from melanoma/recurrent gliomas, breast carcinoma and lung cancer, respectively. New, orally administered drugs hold a great potential for patients with CNS metastases.

Two patients with germ cell testicular cancer were submitted to radioimmunotherapy (RIT) by using the monoclonal antibody 131I-radiolabelled (MoAb) H17E2, raised against placental alkaline phosphatase (PLAP).Both patients had been previously treated with repeated chemotherapy regimens assisted by autologous bone marrow transplant (ABMT), that, in the end were unsuccessful, thus necessitating further experimental treatment.RIT was well tolerated and the targeting of multiple neoplastic lesions was satisfactory. Nevertheless, the clinical results of treatment were minimal owing to the extension of the tumour.The data obtained suggest the possibility of applying this form of treatment in patients with minimal residual disease after previous traditional chemotherapy regimens.

Bosutinib (SKI-606), an orally bioavailable dual Src/Abl inhibitor, shows inhibitory activity against Bcr-Abl 200 times more potent than imatinib, but has minimal inhibitory activity against platelet-derived growth factor receptor (PDGFR) or c-kit. In addition, it inhibits a wide variety of Bcr-Abl kinase domain mutants, except T315I. A phase I study in CML identified the phase II dose as 500 mg daily and showed evidence of clinical efficacy. We thus initiated the phase II portion of the study to investigate efficacy and safety of bosutinib in patients (pts) with chronic phase Ph+ CML who had failed imatinib therapy. We report preliminary data for 98 pts, median duration of treatment 5.1 mos (range 0.03–16.7 mos). Median age 56 yrs (range 18–86 yrs), 48% male. Prior therapy included interferon (40 pts), imatinib (98 pts), dasatinib (13 pts), nilotinib (4 pts), stem cell transplant (6 pts). Among pts who failed imatinib (with no other tyrosine kinase inhibitor), 57 were imatinib resistant, 21 pts were intolerant. Of 23 resistant pts evaluable for hematological response, 17 (74%) had complete hematological response (CHR). Of 36 evaluable imatinib-resistant pts, 15 (42%) achieved major cytogenetic response (MCyR) including 12 (33%) with complete cytogenetic response (CCyR). Among imatinib intolerant pts, 4 (57%) achieved MCyR and 3 (43%) CCyR; 5/6 (83%) pts evaluable for hematologic response achieved CHR. Among 8 pts who had previously received nilotinib or dasatinib, 3 (38%) achieved CHR, 2 (25%) MCyR. Among imatinib-resistant pts, median time to MCyR was 47.3 wks. Of 40 imatinib-resistant pts evaluable for molecular response, 13 (33%) achieved major molecular response, 6 (15%) of which were complete. Of 72 pts with samples tested for mutations, 19 different mutations were found in 27 pts (38%). CHR occurred in 4/5 pts with P-loop mutations and 14/17 with non-P-loop mutations; MCyR occurred in 1/4 pts and 8/19 pts, respectively. Treatment was generally well tolerated. Gr 3–4 hematologic laboratory abnormalities included thrombocytopenia in 9 pts (9%), neutropenia in 8 pts (8%), anemia in 1 pt (1%). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea) but these were usually gr 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 wks of therapy. Gr 3–4 non-hematologic toxicity occurring in >5% of pts were diarrhea (n=6, 6%), increased ALT (n=6, 6%), rash (n=9, 9%). In most instances these events resolved with medical management and dose reduction allowing for continuation of therapy. 10 pts reported grade 1/2 edema. 1 pt had both pleural and pericardial effusions and 1 had pleural effusion, all gr 1/2 and considered unrelated to treatment. A single pt had gr 3 possibly related pleural effusion with concomitant pneumonia and pre-treatment history of recurrent pleural effusions. We conclude that bosutinib is effective in imatinib-resistant pts with chronic CML across a range of mutations and after the failure of other TKIs. The relative specificity without significant c-kit or PDGFR inhibition distinguishes bosutinib from other TKIs and may be responsible for the relatively favorable toxicity profile with only a small numbers of pts experiencing hematologic toxicity or pleural effusions/edema.

Bosutinib (SKI-606), an orally bioavailable dual Src/Abl inhibitor, shows inhibitory activity against Bcr-Abl 200 times more potent than imatinib, but has minimal inhibitory activity against platelet-derived growth factor receptor (PDGFR) or c-kit. In addition, it inhibits a wide variety of Bcr-Abl kinase domain mutants, except T315I. A phase I study in CML identified the phase II dose as 500 mg daily and showed evidence of clinical efficacy. We thus initiated the phase II portion of the study to investigate efficacy and safety of bosutinib in patients (pts) with chronic phase Ph+ CML who had failed imatinib therapy. We report preliminary data for 98 pts, median duration of treatment 5.1 mos (range 0.03–16.7 mos). Median age 56 yrs (range 18–86 yrs), 48% male. Prior therapy included interferon (40 pts), imatinib (98 pts), dasatinib (13 pts), nilotinib (4 pts), stem cell transplant (6 pts). Among pts who failed imatinib (with no other tyrosine kinase inhibitor), 57 were imatinib resistant, 21 pts were intolerant. Of 23 resistant pts evaluable for hematological response, 17 (74%) had complete hematological response (CHR). Of 36 evaluable imatinib-resistant pts, 15 (42%) achieved major cytogenetic response (MCyR) including 12 (33%) with complete cytogenetic response (CCyR). Among imatinib intolerant pts, 4 (57%) achieved MCyR and 3 (43%) CCyR; 5/6 (83%) pts evaluable for hematologic response achieved CHR. Among 8 pts who had previously received nilotinib or dasatinib, 3 (38%) achieved CHR, 2 (25%) MCyR. Among imatinib-resistant pts, median time to MCyR was 47.3 wks. Of 40 imatinib-resistant pts evaluable for molecular response, 13 (33%) achieved major molecular response, 6 (15%) of which were complete. Of 72 pts with samples tested for mutations, 19 different mutations were found in 27 pts (38%). CHR occurred in 4/5 pts with P-loop mutations and 14/17 with non-P-loop mutations; MCyR occurred in 1/4 pts and 8/19 pts, respectively. Treatment was generally well tolerated. Gr 3–4 hematologic laboratory abnormalities included thrombocytopenia in 9 pts (9%), neutropenia in 8 pts (8%), anemia in 1 pt (1%). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea) but these were usually gr 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 wks of therapy. Gr 3–4 non-hematologic toxicity occurring in >5% of pts were diarrhea (n=6, 6%), increased ALT (n=6, 6%), rash (n=9, 9%). In most instances these events resolved with medical management and dose reduction allowing for continuation of therapy. 10 pts reported grade 1/2 edema. 1 pt had both pleural and pericardial effusions and 1 had pleural effusion, all gr 1/2 and considered unrelated to treatment. A single pt had gr 3 possibly related pleural effusion with concomitant pneumonia and pre-treatment history of recurrent pleural effusions. We conclude that bosutinib is effective in imatinib-resistant pts with chronic CML across a range of mutations and after the failure of other TKIs. The relative specificity without significant c-kit or PDGFR inhibition distinguishes bosutinib from other TKIs and may be responsible for the relatively favorable toxicity profile with only a small numbers of pts experiencing hematologic toxicity or pleural effusions/edema.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Animal studies with imatinib have shown it to be teratogenic, embryotoxic and to result in increased rates of post-implantation loss. As a consequence there are justifiable physician/patient concerns regarding the safety of tyrosine kinase inhibitors during pregnancy. We can now report on 180 mothers (the majority with chronic myeloid leukemia but some treated for other indications) exposed to the drug during pregnancy. Timing of exposure to imatinib by trimester is available for 146 (81%). 71% of these were exposed in the 1st trimester (includes 4 exposed in both 1st and 2nd trimesters), 38 (26%) were exposed in all trimesters and 4 only after the 1st trimester. Outcome data are known for 125/180 (69%). 63 pregnancies resulted in the birth of normal live infants (50% of those with known outcome (KO), 35% of all pregnancies). 35 women (28% of KO or 19.5% of all pregnancies) underwent elective terminations, 3 following identification of fetal defects. The remainder either had no defects or were of unknown status. There were 12 pregnancies with fetal abnormalities (9.6% KO), resulting in 8 live and 1 still birth. 18 pregnancies (14.4% KO) ended in spontaneous abortion. Although within expected limits for the general population (spontaneous abortion rates of 10–15%) these data may be skewed by absent data from 55 cases. In 51 patients whose pregnancies were reported after a known outcome (as opposed to reporting at the time of confirmation of pregnancy) 11 (22%) resulted in spontaneous abortion- a higher rate than expected in the general population which may suggest an abortifacient effect. Abnormalities included one infant with premature closure of the skull sutures (craniosynostosis), one with hypoplastic lungs, exomphalos, left duplex kidney, right absent kidney, hemivertebrae and a right shoulder anomaly, another child with exomphalos, right renal agenesis and hemivertebrae and a fourth with a small exomphalos and scoliosis. These 4 cases are pertinent as in animal models imatinib causes similar bony defects including exencephaly, encephaloceles and deformities of the skull bones. Other severe defects included a child with communicative hydrocephalus, cerebellar hypoplasia, atrial septal defect, over-riding aorta, ascites and pericardial effusion - this infant was born live but later died. A baby with a meningocoele was still born. The remaining cases include cleft palate and polydactyly, 2 cases of hypospadias, 1 case of pyloric stenosis, 1 abnormal ultrasound with raised AFP and 1 case of warfarin embryopathy. Despite this information, balancing the risk to the foetus of continuing imatinib vs. the risk to the mother of stopping it remains difficult. In a recent report of 10 women who interrupted treatment with imatinib due to pregnancy, 6 had an increase in Ph positive metaphases. At a median of 18 months since restarting imatinib only 3/10 have achieved a complete cytogenetic response. Given the above findings the current recommendation to avoid imatinib during pregnancy remains unchanged. In cases of accidental or desired pregnancy, risk/benefit evaluations must be carried out on an individual basis with careful counselling of both parents. As experience with imatinib continues to grow, further information will become available which should clarify the situation. To facilitate this a global pregnancy registry will be established in the near future.

We planned a prospective analysis involving 3 multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche Adulto) CML Working Party (WP) to evaluate the correlation between conventional cytogenetics (CC) and FISH response in CML pts in chronic phase (CP) treated with Imatinib. Karyotype and FISH analyses were performed on bone marrow (BM) cells in 26 local laboratories and in 12 WP reference labs. Peripheral blood samples for quantitative RT-PCR were centralized in Bologna. The data are reported in Figure 1 and in Table 1. Fig 1 shows the relationship between CC and FISH (r=0.91;p=0.008). Tab 1 shows the demonstration of FISH data according to CC data and the number of metaphases available for CC. Of 217 pts in CCgR by CC and > 20 metaphases studied, 81.6% were FISH negative, 15.2% showed a low rate of FISH positive cells (1–5%) and 3.2% an higher rate. Of 94 pts in CCgR by CC but with < 20 metaphases studied, 71.3% were FISH negative, 21.3% showed a low rate of FISH positive cells (1–5%) and 7.4% an higher rate. Of 43 pts in PCgR by CC and FISH positive, 48.8% showed 1– 5% positive cells. Moreover, 358 samples were performed simultaneously by CC, FISH and quantitative RT-PCR: 179 (50%) samples in CCgR showed major molecular response (MMolR, defined as a BCR-ABL × 100 ratio < 0.1%): 164 (91.6%) were FISH negative and 15 (8.4%) were FISH positive (1.3–10% positive cells). We conclude that interphase FISH is a very releable method of monitoring the CCgR once it has been achieved. The relationship of FISH on BM cells with molecular response is at least as good as the relationship of CC with molecular response. It remains to be shown if the same results can be obtained on peripheral blood cells, that are already widely used for molecular monitoring.

Background: Imatinib (IM) is the drug of choice for the treatment of Ph+ CML, where a complete cytogenetic response (CCgR) is achieved in more than 80% of early chronic phase (ECP) patients, with a 5-year survival of 90% (Simonsson B, Blood 2005). In the patients who initiated the treatment in late chronic phase (LCP) the response rate is lower and the long-term effect on survival is not yet determined. Aim: We monitored the hematologic, cytogenetic and molecular response to IM in a cohort of 291 patients who were treated with IM in LCP, with focus on progression-free survival and overall survival of complete cytogenetic responders. Methods: Two hundred and ninety-one patients with Ph+ CML in LCP were enrolled in a national prospective study of the GIMEMA CML Working Party in 2001, and were monitored for cytogenetic response and for molecular response every 6 months. Cytogenetics was performed on bone marrow cells with conventional methods. Molecular response was assessed on bone marrow or peripheral blood samples by quantitative PCR (RQ-PCR) using TaqMan methodology and expressing the results as a ratio of BCR-ABL to ABL x100. Patient age ranged from 19 to 82 years (median 52 years). The duration of chronic phase prior to IM treatment ranged from 1 to 202 months (median 38 months). Treatment was IM 400 mg daily through all the study period, with a few exceptions of dose increase to 600 or 800 mg. The median follow-up time after the first IM dose is 62 months. Results: One hundred and sixty patients (55%) achieved a CCgR in 3 to 62 months (median 6 months) after the first IM dose and 126 of them (79%) are still in continuous CCgR after 5 years. For the 160 patients the 5-year survival free from progression to accelerated or blastic phase is 95% and overall survival is 91%. These data are very similar to those reported for the ECP patients in the IRIS study (Simonsson B, Blood 2005). At 5 years, 107 patients were evaluated for molecular response; 62% of them were in major molecular response with a BCR-ABL/ABL ratio lower than 0.10. The BCR-ABL transcript was undetectable in 7 cases by RQ-PCR and in 2 cases by nested PCR. No patient developed heart failure. Conclusions: We confirm that in LCP the CCgR rate to IM is lower than in ECP, but we show that for the complete cytogenetic responders progression-free and overall survival are likely to be as good as for ECP patients, suggesting that the quality of the CCgR is prognostically more important than the duration of leukemia prior to IM treatment. Figure Figure

We planned a prospective analysis involving 3 multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche Adulto) CML Working Party (WP) to evaluate the correlation between conventional cytogenetics (CC) and FISH response in CML pts in chronic phase (CP) treated with Imatinib. Karyotype and FISH analyses were performed on bone marrow (BM) cells in 26 local laboratories and in 12 WP reference labs. Peripheral blood samples for quantitative RT-PCR were centralized in Bologna. The data are reported in Figure 1 and in Table 1. Fig 1 shows the relationship between CC and FISH (r=0.91;p=0.008). Tab 1 shows the demonstration of FISH data according to CC data and the number of metaphases available for CC. Of 217 pts in CCgR by CC and > 20 metaphases studied, 81.6% were FISH negative, 15.2% showed a low rate of FISH positive cells (1–5%) and 3.2% an higher rate. Of 94 pts in CCgR by CC but with < 20 metaphases studied, 71.3% were FISH negative, 21.3% showed a low rate of FISH positive cells (1–5%) and 7.4% an higher rate. Of 43 pts in PCgR by CC and FISH positive, 48.8% showed 1– 5% positive cells. Moreover, 358 samples were performed simultaneously by CC, FISH and quantitative RT-PCR: 179 (50%) samples in CCgR showed major molecular response (MMolR, defined as a BCR-ABL × 100 ratio < 0.1%): 164 (91.6%) were FISH negative and 15 (8.4%) were FISH positive (1.3–10% positive cells). We conclude that interphase FISH is a very releable method of monitoring the CCgR once it has been achieved. The relationship of FISH on BM cells with molecular response is at least as good as the relationship of CC with molecular response. It remains to be shown if the same results can be obtained on peripheral blood cells, that are already widely used for molecular monitoring. No FISH negative FISH 1–5% FISH > 5% CCgR = 20 met 217 177 (81.6%) 33 (15.2%) 7 (3.2%) CCgR < 20 met 94 67 (71.3%) 20 (21.3%) 7 (7.4%) PCgR = 20 met 43 0 21 (48.8%) 22 (51.2%) CCgR and MMolR 179 164 (91.6%) 12 (6.7%) 3 (1.7%) Figure Figure

Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity.

Background: Imatinib (IM) is the drug of choice for the treatment of Ph+ CML, where a complete cytogenetic response (CCgR) is achieved in more than 80% of early chronic phase (ECP) patients, with a 5-year survival of 90% (Simonsson B, Blood 2005). In the patients who initiated the treatment in late chronic phase (LCP) the response rate is lower and the long-term effect on survival is not yet determined.

Animal studies with imatinib have shown it to be teratogenic, embryotoxic and to result in increased rates of post-implantation loss. As a consequence there are justifiable physician/patient concerns regarding the safety of tyrosine kinase inhibitors during pregnancy. We can now report on 180 mothers (the majority with chronic myeloid leukemia but some treated for other indications) exposed to the drug during pregnancy. Timing of exposure to imatinib by trimester is available for 146 (81%). 71% of these were exposed in the 1sttrimester (includes 4 exposed in both 1stand 2ndtrimesters), 38 (26%) were exposed in all trimesters and 4 only after the 1sttrimester. Outcome data are known for 125/180 (69%). 63 pregnancies resulted in the birth of normal live infants (50% of those with known outcome (KO), 35% of all pregnancies). 35 women (28% of KO or 19.5% of all pregnancies) underwent elective terminations, 3 following identification of fetal defects. The remainder either had no defects or were of unknown status. There were 12 pregnancies with fetal abnormalities (9.6% KO), resulting in 8 live and 1 still birth. 18 pregnancies (14.4% KO) ended in spontaneous abortion. Although within expected limits for the general population (spontaneous abortion rates of 10–15%) these data may be skewed by absent data from 55 cases. In 51 patients whose pregnancies were reported after a known outcome (as opposed to reporting at the time of confirmation of pregnancy) 11 (22%) resulted in spontaneous abortion- a higher rate than expected in the general population which may suggest an abortifacient effect. Abnormalities included one infant with premature closure of the skull sutures (craniosynostosis), one with hypoplastic lungs, exomphalos, left duplex kidney, right absent kidney, hemivertebrae and a right shoulder anomaly, another child with exomphalos, right renal agenesis and hemivertebrae and a fourth with a small exomphalos and scoliosis. These 4 cases are pertinent as in animal models imatinib causes similar bony defects including exencephaly, encephaloceles and deformities of the skull bones. Other severe defects included a child with communicative hydrocephalus, cerebellar hypoplasia, atrial septal defect, over-riding aorta, ascites and pericardial effusion - this infant was born live but later died. A baby with a meningocoele was still born. The remaining cases include cleft palate and polydactyly, 2 cases of hypospadias, 1 case of pyloric stenosis, 1 abnormal ultrasound with raised AFP and 1 case of warfarin embryopathy. Despite this information, balancing the risk to the foetus of continuing imatinib vs. the risk to the mother of stopping it remains difficult. In a recent report of 10 women who interrupted treatment with imatinib due to pregnancy, 6 had an increase in Ph positive metaphases. At a median of 18 months since restarting imatinib only 3/10 have achieved a complete cytogenetic response. Given the above findings the current recommendation to avoid imatinib during pregnancy remains unchanged. In cases of accidental or desired pregnancy, risk/benefit evaluations must be carried out on an individual basis with careful counselling of both parents. As experience with imatinib continues to grow, further information will become available which should clarify the situation. To facilitate this a global pregnancy registry will be established in the near future.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity. Evaluation included weekly blood counts and monthly bone marrow including cytogenetics. Molecular evaluation of BCR-ABL transcript levels by real-time qPCR was performed at baseline and upon documentation of complete cytogenetic response. A total of 174 pts (161 im-r and 13 im-i) were enrolled between December 2004 and July 2005 in 39 centers worldwide. There were 96 (55%) males; median age was 57 years (range 22–86); median time from original diagnosis of CML was 82 months. Prior therapy included im in all pts (>600 mg/day in 91 (52%), im for >3 years in 103 (59%) pts, interferon in 126 (72%) pts, stem cell transplantation in 23 (13%) pts. Major cytogenetic response (MCyR) to prior im had been seen in 57 (33%) pts. The average daily dose (median across all pts) was 130 mg/day (range 44–199). Major hematologic response (MaHR) was documented in 110 (63%) pts with complete hematologic response in 75 (43%) and no evidence of leukemia in 35 (20%). At 9 months, 85% of pts have maintained their MaHR. MCyR was documented in 65 (37%) pts, complete in 49 (28%), partial in 16 (9%). Median progression-free survival (PFS) has not been reached; estimated PFS at 9 months is 70%. In the 94 pts with BCR-ABL mutations at baseline the MaHR rate was 69%. Generally, response rates were similar in the im-i and im-r groups. Cytopenias were significant with grade 3–4 thrombocytopenia and neutropenia in 82% and 76% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent (% any grade, % grade 3–4) were diarrhea (51%, 8%), headache (29%, 1%), fatigue (26%, 4%), fever (25%, 3%) and pleural effusion (25%, 3%). Pleural effusions were optimally managed with dose interruption and diuretics and/or pulse steroids. Dasatinib is highly effective in pts with im-r or im-i AP-CML with high rates of durable MaHR and MCyR. An updated analysis with at least 12 months of follow-up, including molecular response data and mutational analysis at time of progression, will be presented.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Data from a phase I study suggest that dasatinib exhibits potent activity with high hematologic and cytogenetic response rates in CML patients with myeloid blast crisis (MBC) who were imatinib (IM)-resistant (IM-R) or -intolerant (IM-I). Here we report the preliminary results from one Phase II trial (Study CA180006 or ‘START-B’) in MBC, which was initiated in December 2004. This open-label study was carried out in 37 centers worldwide between December 2004 and May 2005. A total of 74 IM-R or IM-I MBC pts were accrued (41 male, median age 56 years [range 21–71]). Preliminary data are currently available on the first 34 pts (29 IM-R and 5 IM-I). Dasatinib was administered orally, at a dose of 70 mg twice daily (BID) in a continuous daily dosing schedule; dose escalation to 100 mg BID was permitted for patients who did not achieve hematologic response and dose reduction to 50 mg and 40 mg BID was allowed in the presence of persistent toxicity. Complete blood counts were performed weekly and bone marrow assessment, including cytogenetic analysis, was performed monthly. Mutations in the BCR-ABL domain were assessed in all pts. Pretreatment characteristics of these 34 pts included: 71% male, median age 54 years (range 21 – 71). Median duration of CML from first diagnosis was 49.3 months (range 5.6 – 215.5). Prior therapy included bone marrow transplant (5 pts, 15%) and interferon (18 pts, 53%). In 44% of pts, the highest IM dose was >600 mg/day and 41% of pts received IM for >3 years. Best responses to IM were complete hematologic response (CHR) in 82% of pts and major cytogenetic response in 39% of pts (complete in 27%, and partial in 12%). At baseline, 35% of pts had a WBC count ≥20 x 103/mm3, 71% had a platelet count <100 103/mm3 and 24% had ≥50% bone marrow blasts. BCR-ABL mutations were documented in 4/10 pts with data currently available. Dasatinib doses were increased in 32% of pts while dose reductions were required in 21% of pts, mostly due to persistent thrombocytopenia. Major hematologic responses were documented in 16/29 (55%) pts with 7 CHR and 9 no evidence of leukemia (CHR without complete recovery of PMN or platelets). There were 13 (45%) cytogenetic responses, including 6 (21%) complete (0% Ph+) and 5 (17%) partial (1 – 35% Ph+). Molecular response data are not yet available. Dasatinib therapy was associated with rapid and profound myelosuppression. PMN <500/mm3 occurred in 59% of pts and platelets <25 x 103 /mm3 in 56% of pts. Non-hematologic toxicities were uncommon and usually grade 1 or 2, with diarrhea in 8 pts, rash in 4 pts, nausea in 3 pts (1 grade 3) and peripheral edema in 3 pts. 4 pts had pleural effusion. In conclusion, preliminary data from this Phase II study provide further evidence of the activity of dasatinib in CML patients with MBC and of its acceptable safety profile. Data on all 74 pts, with a minimum of 6 months follow-up, will be presented at the meeting.

Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Data from a phase I study suggest that dasatinib exhibits potent activity with high hematologic and cytogenetic response rates in CML patients with myeloid blast crisis (MBC) who were imatinib (IM)-resistant (IM-R) or -intolerant (IM-I). Here we report the preliminary results from one Phase II trial (Study CA180006 or ‘START-B') in MBC, which was initiated in December 2004. This open-label study was carried out in 37 centers worldwide between December 2004 and May 2005. A total of 74 IM-R or IM-I MBC pts were accrued (41 male, median age 56 years [range 21–71]). Preliminary data are currently available on the first 34 pts (29 IM-R and 5 IM-I). Dasatinib was administered orally, at a dose of 70 mg twice daily (BID) in a continuous daily dosing schedule; dose escalation to 100 mg BID was permitted for patients who did not achieve hematologic response and dose reduction to 50 mg and 40 mg BID was allowed in the presence of persistent toxicity. Complete blood counts were performed weekly and bone marrow assessment, including cytogenetic analysis, was performed monthly. Mutations in the BCR-ABL domain were assessed in all pts. Pretreatment characteristics of these 34 pts included: 71% male, median age 54 years (range 21 – 71). Median duration of CML from first diagnosis was 49.3 months (range 5.6 – 215.5). Prior therapy included bone marrow transplant (5 pts, 15%) and interferon (18 pts, 53%). In 44% of pts, the highest IM dose was >600 mg/day and 41% of pts received IM for >3 years. Best responses to IM were complete hematologic response (CHR) in 82% of pts and major cytogenetic response in 39% of pts (complete in 27%, and partial in 12%). At baseline, 35% of pts had a WBC count ≥20 x 103/mm3, 71% had a platelet count <100 103/mm3and 24% had ≥50% bone marrow blasts. BCR-ABL mutations were documented in 4/10 pts with data currently available. Dasatinib doses were increased in 32% of pts while dose reductions were required in 21% of pts, mostly due to persistent thrombocytopenia. Major hematologic responses were documented in 16/29 (55%) pts with 7 CHR and 9 no evidence of leukemia (CHR without complete recovery of PMN or platelets). There were 13 (45%) cytogenetic responses, including 6 (21%) complete (0% Ph+) and 5 (17%) partial (1 – 35% Ph+). Molecular response data are not yet available. Dasatinib therapy was associated with rapid and profound myelosuppression. PMN <500/mm3occurred in 59% of pts and platelets <25 x 103/mm3in 56% of pts. Non-hematologic toxicities were uncommon and usually grade 1 or 2, with diarrhea in 8 pts, rash in 4 pts, nausea in 3 pts (1 grade 3) and peripheral edema in 3 pts. 4 pts had pleural effusion. In conclusion, preliminary data from this Phase II study provide further evidence of the activity of dasatinib in CML patients with MBC and of its acceptable safety profile. Data on all 74 pts, with a minimum of 6 months follow-up, will be presented at the meeting.

Starting in February 1994, 20 patients (pt) with a median age of 50 years (range 41−63) from 7 European centers have been included. Complete data were obtained in 16 patients so far. CPC were mobilized with chemo (Epirubicine 75mg/m2/d, D1+D2) followed by G-CSF 5μg/kg/d for 14 days. HD chemo consisted in 3 sequential courses of ICE regimen (Ifos. 10g/m2, Carbo. 1200mg/m2and Etop. 1200mg/m2) under CPC protection and G-CSF 5μg/kg/d. Out of the 16 pt, 12 completed full program (3 cycles). One pt died of septic shock before receiving any ICE course. One pt died during the first ICE of renal insufficiency. Two pt had only 2 courses because of toxicity. Among the 16 pt, response rate (RR) was: 7 CR, 6 PR, 1 PD; 3 pt are not evaluable due to early withdrawal (overall RR: 13/16=81%). Thirty-nine cycles of HD chemo were given with a median hematological recovery of 9 days (range 7−12) until neutro. counts 1.0×109/I and 9 days (range 7−17) until thrombo. 20×109/I. No cumulative, hematological toxicity was seen. Accrual of patients is still ongoing and updated results will be presented.