Search

There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia-negative myeloproliferative neoplasms (MPN-AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN-AP/BP treated frontline with AZA at the standard dosage (75mg/m2). Median time from diagnosis to AP/BP evolution was 92.3months (IR 29.9-180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI+PR+CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5months (95% CI, 8.2-18.7). There was no difference in median OS among patients with HI, PR, or CR (P=.908). These three subgroups as “responders” having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6months (95% CI, 10.1-25.0) versus 4.1months (95% CI, 0.4-10.0) (P=.001) Only female gender was significant for both achievement of response (.010) and OS duration (P=.002). In conclusion, AZA is useful for the management of MPN-AP/BP, with an overall response rate (HI+PR+CR) of 61.5% and a longer OS in responders.

Background Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. Methods Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735 ), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. Results Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively. Conclusion Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.

Chronic myeloid leukemia (CML) is a triphasic clonal myeloproliferative disorder characterized by the presence of Philadelphi a chromosome (Ph) in over 95% of cases alongside excessive accumulation of clonal myeloid cells in hematopoietic tissues. This occurs as a result of reciprocal translocation between the long arms of chromosome 9 and 22 t (9;22) (q34; q11) creating the fusion oncogene BCR–ABL1 which exhibits constitutive tyrosine kinase activity. It is one of the commonest haematological malignancies in low economies around the world including Nigeria. The clinical features of CML are often described in 3 phases namely the chronic phase (CP), accelerated phase (AP), and blastic phase (BP) while CP is the most common stage with progression to AP and BP occurring later. Despite that, prognosis of CML is dependent on phase of disease, age, and response to therapy, the only curative approach in use currently is hematopoietic stem cell transplantation with other drugs being used for cytogenetic responses. This study focuses on the aetiopathophysiology, cytogenetics, molecular biology, clinical/laboratory features and treatment options of CML. Rigorous review of literature on the study was retrieved from relevant oncology journals and textbooks abstracted and indexed in PubMed, Google Scholar, ProQuest, CINAHL, and Science Direct. The study discovered that, resistance of CML to imatinib has been reported with research having reached the advanced stage on the use of alternative drugs (e.g., Nilotinib and Desatinib). There are also potentials for these new drugs to become the treatment choice and first line drugs for the treatment of CML.

Objectives: The advent of the tyrosine kinase inhibitors has markedly changed the prognostic outlook for patients with Ph⁺ and/or BCR-ABL1⁺ chronic myeloid leukemia (CML). This study was designed to assess the overall survival (OS) of Nigerian patients with CML receiving imatinib therapy and to identify the significant predictors of OS. Methods: All patients with CML receiving imatinib from July 2003 to June 2013 were studied. The clinical and hematological parameters were studied. The Kaplan–Meier technique was used to estimate the OS and median survival. P-value of

Objective: Chronic leukemias are rare in childhood & CML is extremely rare in children. Imunophenotypic studies have a limited role in the diagnosis of CML but are increasingly being used in CML blast transformation. Purpose of the study was determine the clinical and laboratory and Flow immunophenotyping (FIC) features with Mutational analysis of blast transformation of CML in children. Methods: 11 years analysis was done 187 cases of suspected CML were studied in children and adolescents. Patients were evaluated at KMIO between 2004 to 2015. 97 cases had Bone marrow diagnosis of CML. 22 cases peripheral smear was suggestive of blastic phase CML (20 %) were chosen for the study. Bone marrow confirmation was available in all the cases. Cytogenetics and Molecular confirmation was also available in all cases. FIC was done in 8/22(36%) cases. Mutations were studied in 7 cases. Results: The disease predominantly affected older children more than 10 years 16/22(72 %). Male sex predilection was seen. Gender ratio was 1.4: 1. Most predominant clinical sign was splenomegaly. Leucocyte count>100X109/L was seen in all cases. Peripherals smear suggested CML in all 22cases and bone marrow aspiration confirmed the diagnosis.17 Cases were at diagnosis. 5 Cases progressed to blastic phase from chronic phase. Median year of transformation was 4 years. In 22 cases Phildelphia chromosome was noted and 5 cases revealed additional markers PCR revealed p210 transcript in all cases. In 8 cases in the blastic phase Flow cytometry immunophenotype was done. 5 cases were myeloid blastic phase, single case was mixed phenotype, 2 cases were lymphoid blastic phase. Conclusion: Imatinib highly effective in children with advanced phase of CML. This is the largest, exclusive first reported series of blastic phase of CML in children from a single center. Only 5 cases received Imatinib, All 5cases attained remission; Cases are on follow up and continue to be in remission after a mean of 6 months.

Context Two decades ago, the introduction of tyrosine kinase inhibitors (TKIs) has improved the outcome and overall survival of chronic myeloid leukemia (CML) patients and changed the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in this setting. Still, allo-HSCT remains the treatment of choice for patients diagnosed and/ or progressed to advanced phase (accelerated and blastic phase) and who have failed and/or are intolerant to multiple TKIs. Objective The aim of this study was to investigate the clinical outcome in 19 patients who were referred for this procedure to The Hematology and Bone Marrow Transplantation Center, Fundeni Clinical Institute. Design Retrospective single-center case series. Setting The Hematology and Bone Marrow Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania. Patients We analyzed the records of 19 CML patients who underwent allo-HSCT between 2012–2020 in the Hematology and Bone Marrow Transplantation Center of Fundeni Clinical Institute. Results Median time from CML diagnosis to allo-SCT was 34 months. Out of 19 CML patients, 6 patients were in the first chronic phase (CP), and 13 patients were in the second or later CP. TKI resistance was the most common transplant indication. Mutation status was positive in two patients. TKI intolerance was present in six patients. Out of 19 CML patients, 14 patients survived the transplantation procedure and achieved major molecular response (MMR). Conclusions Allo-HSCT still represents an important therapeutic option in CML, especially for patients diagnosed or/and progressed to advanced phase or are resistant or/and intolerant to TKI treatment.

Background Chronic myeloid leukemia (CML) rarely occurs in children and adolescents, which shows more aggressive features like high risk of more advanced disease at the time of diagnosis. Suboptimal response to tyrosine kinase inhibitors (TKIs), adverse events, or advanced disease may impede the treatment. Case Herein we present a nine-year-old chronic phase CML case. He had no major molecular response (MMR) to imatinib, which was switched to dasatinib. MMR was ensured for 24 months, yet he developed a lymphoid blastic phase under dasatinib. He obtained a remarkable response to ponatinib when administered in parallel to multiagent induction chemotherapy. Conclusion Ponatinib therapy is effective and promising as a bridge to hematopoietic stem cell transplantation in children. Although more studies are necessary to determine indications, dose, efficacy, and safety data.

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m 2 , respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.

Aberrant DNA methylation of various genes has been identified to be associated with disease progression in chronic myeloid leukemia (CML). Our study was intended to investigate DLX4 methylation pattern in different clinical stages of CML and further determine its role in regulating DLX4 expression. Real-time quantitative methylation-specific PCR and bisulfite sequencing PCR were applied to detect DLX4 methylation. 5-aza-2'-deoxycytidine (5-aza-dC) was used for demethylation studies. DLX4 was significantly hypermethylated in CML patients (P = 0.002) especially in blastic phase (BC) stage (P

Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)–resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT).

Paget's disease (PD) is a common bone disorder of the aging population where the spine is the second most common involved location after the pelvis. Though imaging findings are well described on CT and radiographs, recognition on MRI can be challenging. We reviewed 16 cases with radiologic or histologic confirmation of uncomplicated PD of the spine. In most cases, MRI showed a mixed pattern of increased/ decreased T1 signal (fine trabecular or coarse) of the vertebral bodies. There was also associated band-like decreased T1 and T2 signal of the endplates. This correlates with the mixed osteolytic and blastic phase of the disease, the most common phase in the spine. Subtle or conspicuous "picture-frame" appearance may also be identified. Present in most cases, but frequently overlooked manifestation on MRI, was the expansion of the vertebral body and/or posterior elements/ spinous process. We identified a subtle diffuse decreased T1 and T2 bone marrow signal, not corresponding to sclerosis on CT or radiographs, in two cases. We proposed this, as an earliest sign on MRI, likely representing early fibro-vascular bone marrow transformation and to our knowledge not previously described. Less commonly, sclerotic PD was also found which is perhaps the most difficult to evaluate given its broad differential. Most cases of PD of the spine were overlooked or confused with other entities by the radiologists. Interpretation of MR images of the spine in the absence of prior imaging is not uncommon. Thus, recognition of MRI manifestations is important to allow appropriate management, to avoid misinterpretations and in most cases to avoid biopsy.

Philadelphia-positive (Ph+), BCR-ABL1, chronic myeloid leukemia (CML) is a model of leukemia driven by a single, specific, chromosome translocation, the t (9;22) (q22;q11). This translocation, leading to a new, hybrid, leukemia-specific gene (BCR-ABL1) encoding for a deregulated tyrosine-kinase protein (p210), drives the leukemic transformation of hematopoietic stem cells [1-6] and induces the progression of the disease from the early chronic phase (CP) to the late blastic phase BP) which close the natural history of the disease. In the 2000s, the introduction of Imatinib, the first tyrosinekinase inhibitor (TKI) able to target the protein p210, significantly changed the fate of CML to fatal disease in real chronic disease.

Telomerase is activated in chronic myeloid leukemia (CML); however, it is not known whether the catalytic telomerase reverse transcriptase subunit (hTERT) is vital in the progression of this disease. This study involved patients with CML in the chronic phase (pretreatment and after treatment), accelerated and blastic phase. Expression of the hTERT gene differed significantly among the four major groups (p0.05). We also compared hTERT expression according to demographic parameter such as age and sex, and found no significant differences (p0.05). Taken together, our findings suggest the importance of hTERT as a valuable molecular marker in the follow-up of patients with CML, which may have clinical implications for the prognosis.

Patients with chronic myeloproliferative leukemia (CML) have frequent haemorrhage and/or thrombosis in their medical history. The mechanisms of these major and life-threatening complications remain unclear. Membrane organization influences many of the unique cellular functions and is strongly correlated, among other factors, to the membrane lipid composition; it may be evaluated by following up the membrane fluidity and aggregation properties of the platelet. In this study, we evaluated the platelet aggregation, the expression of platelet surface receptors, the membrane fluidity (as evaluated by fluorescence anisotropy) and its correlation to reactive oxygen species (ROS) production, in patients with chronic myeloid leukaemia (CML). It was found that the patients in accelerated and blastic phase of CML present an altered platelet aggregation response to all reagents except for ristocetin as compared with chronic phase group, which shows only epinephrine-altered response. We also found that BCR/ABL transcript leads to higher levels of ROS in accelerated and blastic CML phases. Patients without molecular remission have lower platelet membrane fluidity. We obtained a positive correlation between ROS level and membrane fluorescence anisotropy changes. The CD41 expression was decreased in CML patients and P selectin expression was found to be higher in these patients than in healthy volunteers. Platelets of CML patients have altered aggregation parameters in accelerated and blastic phases, in which BCR/ABL transcript level is increased. The increased level of ROS in CML patients without molecular remission is associated with a decrease in fluidity of platelet membrane and expression of CD41/CD61 receptors. These findings may contribute to understanding the mechanism of the altered platelet response reported in CML patients.

The aim of the present study was to examine the expression and significance of CCAAT/enhancer binding protein α (C/EBPα) and SRY‑related high mobility group box containing transcription factor 4 (SOX4) in chronic myeloid leukemia (CML). Bone marrow samples were collected from patients with CML, and peripheral blood mononuclear cells were collected from healthy controls. Protein and mRNA were extracted from the collected samples, and analyzed using western blotting and reverse transcription‑quantitative polymerase chain reaction analyses, respectively. Spearman's method was used to evaluate the correlation between the expression levels of these two genes, with P0.05 considered to indicate a statistically significant difference. A total of 79 patients, including 57 patients with newly diagnosed CML and 22 patients treated with imatinib therapy, and 30 controls were enrolled. The expression of SOX4 was upregulated in the patients with CML, whereas the expression of C/EBPα was downregulated (P0.05). However, no differences were observed among the chronic, accelerated and blastic CML phases, respectively (P0.05). In addition, no associations were found between the changes in expression and age, gender, white blood cells or the expression of breakpoint cluster region/abelson in patients (P0.05). However, the expression of SOX4 was negatively correlated with the expression of C/EBPα (P0.01). Following imatinib treatment, the expression of SOX4 was downregulated in the progression‑free patients, but upregulated in the blastic phase patients, whereas the expression of C/EBPα showed the opposite trend. Therefore, C/EBPα and SOX4 were important and negatively associated with the process of CML, and the C/EBPα‑SOX4 axis may be a novel potential therapeutic target for the treatment of CML.

a b s t r a c t To test the recently developed EUTOS score in predicting optimal response to imatinib and the long-term outcome, 265 patients with early chronic phase chronic myeloid leukaemia treated with standard dose imatinib were analysed. Achievement of optimal response endpoints were higher in low-risk patients, though the difference was not statistically significant: PCyR at 6th month 86% vs 67% (p = 0.06), CCyR at 12th month 80% vs 63% (p = 0.09), MMR at 18th month 61% vs 36% (p = 0.11). However, EUTOS score was predictive for the long-term response. With a median follow-up of 61 months, 53% high-risk patients experienced imatinib failure, compared to 23% in the low-risk group (p = 0.013). Among high-risk patients, 4/17 (23%) progressed to accelerated/blastic phase or died, compared to 11/248 (5%) low-risk patients, with 5-year progression-free survival rates of 84 ± 10% and 96 ± 1%, respectively (p = 0.04). Our data confirm that EUTOS score envisions the long-term outcome of imatinib therapy. © 2013 Elsevier Ltd. All rights reserved.

In the era of new-generation tyrosine kinase inhibitors (TKIs), prognosis of Ph+ leukemia (CML/ALL) has dramatically improved. Furthermore the number of CML patients who have stopped TKI is increasing. Usually TKI is stopped in patients who have sustained a deep molecular response. The MRD monitoring interval and threshold of restarting TKI is mostly established in CML. In Ph+ALL patients, prophylactic/maintenance administrations of TKI are used during post hematopoietic stem cell transplantation (HSCT) as well as post chemotherapy. Unlike CML, currently there are no standard methods of detection BCR-ABL in Ph+ALL and no established selection of patients who can stop TKI. In addition, after TKI stopped, there is no consensus about how often to monitor to detect molecular relapse and threshold of restart for TKI. In the current study, we tried to determine the optimal frequency of MRD monitor after the cessation of TKI in Ph+ALL using a mathematical model. In this model, we determined several agreed items. Mimicking CML, we defined BCR-ABL/ABL ratio of 0.1% as"MR3" and undetectable levels of BCR-ABL transcript as "MR5". We estimate that patients with MR3 and MR5 have 109 and 107 Ph+ cells in the body, respectively. In this perspective, we defined "MR3" and "MR5" as "optimal intervention threshold" and "detection threshold". From the literatures, we determined that growth rate of leukemia is distributed between 1%/day and 100%/day (doubling time of leukemic cells is 1 day). Also, we assumed that single cell have a relapse potency and the growth rate is constant during observation in each patient. The number of Ph+ cells in a MR5 patient is distributed between 1 cell and 1 x 107 (MR5). "Success" is defined as if molecular relapse is detected between MR3 and MR5 and "Failure" is defined as if detected more than MR3. Table shows the interval from single leukemia cell to MR5 leukemia burden (1 x 107 cells) and the interval from MR5 to MR3 (X100) according to growth rate. Figure is a graph of Table. We calculated using most extreme cases. In the highest growing speed (100%/day), if the number of Ph+ cells is just below detection level (MR5) , it will take 6.6 days to reach MR3 (optimal intervention threshold). Also, if the number of Ph+ cells is only 1 cell, it will take 23.3 days to reach MR5. The other ultimate condition is that the number of leukemia cells is only one in the body and has the slowest growth rate (1%/day). In this case it will take 1620 days (4.4 years) to reach MR5. It was reported that the growth rate of Ph+ cells in the blastic phase of CML is approximately 8% (doubling time 9 days) (Branford. Blood. 2012;119:4264). Applying this value to our model, it will take 209 days to reach MR5 (detection threshold) from single Ph+ cell. If the number of leukemia cells is just below the detection level (MR5), it will take 60 days to reach MR3 (optimal intervention threshold). In this patient a 2 months interval can detect MRD before it reaches to MR3 (Success). If 1 Ph+ cell remains when TKI is stopped, it will reach the MRD detection level (MR5) in 269 days. If Ph+ cells does not appear until this time, this patient is supposed to be cured in this model. In the clinical setting, growth rate is unknown. Thus in the beginning, a highest growth rate of 100% is applied. (Figure) Monitoring should be performed every 6.6 days for avoiding MRD is detected over MR3 (Failure). If Ph+ cells does not appear until 23.3 days after stop of TKI, which indicate growth rate of 100% is neglected. Because MRD does not increase from MR5 to MR3 during 23.3 days, the growth rate is less than 21.8% from the Table and Graph. At this point, interval MRD monitoring can be prolonged from 6.6 to 23.3 days until 82 days after stop of TKI. Similarly, if Ph+ cells does not appear at 82 days, growth rate is calculated less than 5.8% and interval can be prolonged from 23.3 to 82 days until 290 days. Again if Ph+ cells does not appear, now growth rate is estimated less than 1.6%. Taken together, soon after stop of TKI, frequent monitoring of MRD is needed. The interval can be prolonged with the passage of time. After allogeneic HSCT, the growth rate of leukemia may be down regulated to some extent according to the GVL effect. At the detection of MRD, interventions such as TKI, donor lymphocyte infusion or chemotherapy are started as soon as possible. Thus the tight monitoring according to the mathematical model is important. The current strategy may be applied to other leukemia in which MRD monitoring by PCR is established. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Background: The introduction of tyrosine kinase inhibitor (TKI) has reduced the indications for allogeneic hematopoietic stem cell transplants (HSCT) in patients with chronic myeloid leukemia (CML). In children and adolescents/young adults (AYA), however, the long-term side effects of TKI and financial burden could become a future issue. Thus, the role of HSCT with reduced intensity conditioning (RIC) as an alternative to TKI especially in the first chronic phase (CP1) should be defined for children and AYA with CML. However, less is well-known about the efficacy of RIC regimens on children and AYA with CML, in chronic phase (CP) as well as advanced phase. Aims: To describe the long-term outcomes of children and AYA with all phases of CML treated with a RIC HSCT and to define potential prognostic factors for outcome. Patients and Methods: We retrospectively analyzed 3796 patients with CML using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation and included children and AYA under 30 years old at HSCT who underwent allo-HSCT between 2001 and 2014 and received TKI before HSCT. The myeloablative conditioning regimen was defined as TBI ≥ 8 Gy, busulfan > 8mg/kg, or melphalan > 180 mg/m2. Result: The characteristics of patients are summarized in Table 1. RIC was selected preferentially in patients with better status. The median follow-up of survivors was 64 months (3 - 171 months). There was no significant difference in 5-year overall survival (OS) among CP (124 cases), accelerated phase (AP) (23 cases) and blastic phase (BP) (53 cases) at diagnosis, 83%, 71% and 73%, respectively. In CP at diagnosis, 5-year OS was significantly higher in CP1 (89 cases) at HSCT than in CP2≤/AP/BP (35 cases) (89% versus 66%, p = 0.0004), and in CP1 at HSCT, there was no difference in 5-year OS between myeloablative conditioning (MAC) (58 cases) and RIC (31 cases) (both 89%) (Figure 1). However, 5-year OS in RIC was significantly higher in children (0-14 years old, 23 cases) than in AYA (15-29 years old, 8 cases) (95% versus 75%, p = 0.0495). Two of eight AYA patients with CP1 died after RIC HSCT due to grade IV acute GVHD-related complications without disease relapse, suggesting that the indications for RIC in AYA with CP1 should be carefully judged. In AP/BP at diagnosis, 5-year OS was significantly higher in the second chronic phase (CP2) (48 cases) at HSCT than in the third chronic phase (CP3)≤/AP/BP (28 cases) (82% versus 56%, p = 0.0073). However, the rate of major cytogenetic response (MCyR) at HSCT was significantly higher in CP2 than in CP3≤/AP/BP, and when focusing only on MCyR at HSCT in AP/BP at diagnosis, there was no difference in 5-year OS between CP2 at HSCT (40 cases) and CP3≤/AP/BP (13 cases) (83% versus 78%). On condition of MCyR at HSCT in AP/BP at diagnosis, regardless of the phase at HSCT, there was no difference in 5-year OS between MAC (46 cases) and RIC (7 cases: 2 in children and 5 in AYA) (79% versus 100%) (Figure 2), suggesting that even in AP/BP at diagnosis, RIC could be indicated for the patients with good response to TKI. On multivariate analysis, disease phase at HSCT and time from diagnosis to HSCT were independent predictors of OS in CP at diagnosis (Table 2), and cytogenetic response at HSCT and stem cell source in AP/BP at diagnosis (Table 3). There was no significant difference of OS between MAC and RIC. Conclusion: In HSCT for CML after TKI administration, the indications for RIC in children under 15 years old with CP1 are appropriate. In RIC HSCT for AYA patients under 30 years old with CP1, caution should be exercised in transplant-related mortality rather than disease progression. Furthermore, even in AP/BP at diagnosis, RIC could be indicated for children and AYA patients with MCyR at HSCT. Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis.: Honoraria.

Current treatment with Tyrosine-Kinase Inhibitors (TKI) has profoundly changed long-term prognosis of newly diagnosed Chronic Myeloid Leukemia (CML). However, the true disease/patient status at different time-points is still based on few data from controlled clinical studies (mainly based on "cumulative incidence" more than "effective situation" of any single patient at any single time from TKI start) and is still unclear in the real-life setting without selection criteria. In order to give an effective picture of their 5-year status, all consecutive CML patients newly diagnosed at our Institute until 6/2012 (i.e. with a minimum observation period of 5 years) and treated frontline with any TKI at any dosage in both controlled clinical trials or current clinical practice were retrospectively evaluated. On the whole, 259 patients, treated with imatinib (219) or 2nd generation TKI (2-TKI) (35 with nilotinib and 5 with dasatinib), were collected: the main features at diagnosis of the entire cohort and according to TKI are reported in the Table 1, without differences between the 2 groups. In the imatinib group, 13/219 patients (6%) received a reduced starting dose (< 400 mg/day), while all patients in the 2-TKI group started initial standard doses. At the 5-year evaluation, 227 pazienti (87.6%) were alive, 16 died (6.2%) and 16 (6.2%) were lost to follow-up. Among the 227 patients alive, 176 (67.9% of the entire cohort) were in Complete Cytogenetic Response (CCyR), 163 (62.9% of the entire cohort) were in Major Molecular Response (MMolR) and 121 (46.7% of the entire cohort) were in Deep Molecular Response (DMR). The remaining 51 patients alive at the 5th year (19.7% of the entire cohort) were in 2nd or subsequent line of treatment, due to intolerance in 13 cases (25.5%) or primary/secondary resistance in 38 (74.5%). Among the 16 deaths, 5 (1.9% of the entire cohort) were CML-related and 11 (4.3% of the entire cohort) were CML unrelated. Among the 16 patients lost to follow-up, 8 (3.1% of the entire cohort) were in response to 1st line treatment and 8 (3.1% of the entire cohort) were in 2nd line/resistant disease at the last visit. Six patients (2.3%) evolved in blastic phase and 8 (3.1%) developped a 2nd neoplasia. In the group treated frontline with 2-TKI there was a higher rate of patients alive in MMolR (p=0.038) but not in DMolR (p=0.137), with a lower rate of primary/secondary resistance (p=0.048) but a higher incidence of intolerance (p=0.002) compared to patients treated frontline with imatinib (Table 2). Five-year cumulative overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) of the entire cohort were 93.2% (IC 95% 90.2-96.2), 78.2% (IC95% 73.1-83.3) e 70.2% (IC95% 64.5 - 75.9), respectively. According to initial treatment, 5-year PFS was significantly better in the 2-TKI group (p=0.003), but no difference was observed between the 2 groups as to 5-year EFS (p=0.274) and 5-year OS (p=0.077). In conclusion, results achievable at 5 years with frontline TKI treatment in the current clinical practice are excellent, with at least two thirds of patients alive in MMolR and about half of patients also in DMolR under frontline approach: deaths CML-related in the first 5 years of treatment are very rare and less than 1 out 5 patients needs to change frontline approach for intolerance/resistance. The role of frontline 2-TKI in this real-life setting deserves further examinations in larger unselected cohorts at longer time-points. Disclosures Breccia: BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD.

Background: Presence of myelofibrosis on bone marrow examination is considered as poor prognostic factor in patients with chronic myelogenous leukemia (CML). Scant data is available on myelofibrosis, especially in the era of tyrosine kinase therapy. The present study was designed to analyze impact of myelofibrosis on outcomes in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP). Aims and objectives: The primary objective of this analysis was to study event free survival (EFS) and major molecular response rates (MMR) at one year in patients with CML-CP with myelofibrosis. Secondary objectives were to study the parameters impacting outcomes in patients with CML-CP with myelofibrosis Materials and methods: Study period: 2010 to 2016 Type of study: retrospective analysis. The diagnosis of CML-CP was done by demonstration of BCR-ABL translocation by polymerase chain reaction or fluorescence in situ hybridization. Event free survival was defined as the time from start of therapy to death, transformation to accelerated or blast phase, hematologic resistance or toxicity intolerance. Statistical analysis was done using SPSS software, version 25. Overall survival curves were plotted using the Kaplan-Meier method. Grade of myelofibrosis, EUTOS risk, age and compliance were analyzed on multivariate analyses. Results: Data of 147 patients with CML-CP with myelofibrosis at presentation was retrospectively collected, of which 79(53.7%) were males and 68(46.3%) were females. The baseline characters were tabulated in Table 1. Abdominal fullness (60.5%) was the most common symptom at presentation followed by fatigue (48.9%), weight loss (36.7%), fever (25.1%) and bleeding manifestations (12.9%). EUTOS risk was low in 94(64%) patients and high in 53 (36%) patients. Myelofibrosis grade 1, 2, 3 and 4 were seen in 20(13.6%), 36(24.5%), 38(25.9%) and 27(18.3%) patients respectively. Grade of myelofibrosis was not available in 26(17.7%) patients. Of 147 patients, outcome parameters were available in 92 patients. Of 92 patients, 34(37%) attained MMR at 1 year. At a median follow up of 46 months, event free survival was 60.9%. Of 92 patients, MMR at one year differed significantly in patients with grade 1 and 2 myelofibrosis (48.8%) compared to patients with grade 3 and 4 myelofibrosis (26.5%) (p=0.02). Event free survival was higher in patients with grade 1 and 2 myelofibrosis (76.7%) compared to patients with grade 3 and 4 myelofibrosis (46.9%) (p=0.005). Drug induced myelosuppression was seen in 27(29.3%) patients, of which 7(26%) patients received dose reduction. Phase transformation was seen in 6 patients, of which 1(16.7%) and 5(83.3%) patients were transformed to accelerated phase and blastic phase respectively. On multivariate analysis, only grade of myelofibrosis had significant impact on event free survival(p=0.013). Conclusion: In patients with newly diagnosed CML-CP, major molecular response was significantly lower for those with higher grade of myelofibrosis. Grade of myelofibrosis at presentation had significant impact on outcomes in CML-CP. Hence, bone marrow examination for presence and grade of myelofibrosis helps in prognosticating CML-CP patients. Disclosures No relevant conflicts of interest to declare.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression.

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase, and subsequently progresses to an accelerated or blastic phase. Although several genes are known to be involved in the progression to blastic phase, molecular mechanisms for the evolution toward blast crisis have not been fully identified. Oncogenic stimuli enforce cell proliferation, which requires DNA replication. Unscheduled DNA replication enforced by oncogenic stimuli leads to double strand breaks on DNA. We found the DNA damage-response pathway is activated in bone marrow of chronic-phase CML patients possibly due to an enforced proliferation signal by BCR-ABL expression. Since ataxia telangiectasia mutated (ATM) is a central player of the DNA damage-response pathway, we studied whether loss of this pathway accelerates blast crisis. We crossed Atm-knockout mice with BCR-ABL transgenic mice to test this hypothesis. Interestingly, the loss of one of the Atm alleles was shown to be enough for the acceleration of the blast crisis, which is supported by the finding of increased genomic instability as assayed by breakage-fusion-bridge (BFB) cycle formation. In light of these findings, the DNA damage-response pathway plays a vital role for determination of susceptibility to blast crisis in CML.

Background The prognostic significance of complete cytogenetic response (CCyR) is well defined in patients with chronic phase chronic myeloid leukemia treated with imatinib as first-line therapy. However, the effect on outcomes of obtaining molecular response itself and the depth of it is not clear. In this study we aimed to determine the frequency of complete molecular response (CMR) during long-term follow-up and the clinical significance of CMR on patient outcomes and survival. Patients and Methods We retrospectively evaluated the files of 178 chronic phase chronic myeloid leukemia patients using imatinib therapy. Forty-seven patients with missing data were excluded from the study and the assessment was done in 131 patients. CMR was defined as undetectable BCR-ABL transcripts using real-time quantitative polymerase chain reaction with a sensitivity level of ≥ 10 4 in 2 consecutive analyses at least 3 months apart. Cytogenetic and molecular monitoring during treatment was performed according to the European LeukemiaNet recommendations criteria. Our primary objective was to analyze the association of deeper molecular response with differences in progression-free survival (PFS). Results Eighty-eight patients (67%) achieved CMR at any time in a median of 65 months of follow-up. The rate of CMR was higher in patients who achieved CCyR at 12 months and major molecular response (MMR) at 18 months. Fewer events occurred in the CMR group than the MMR group (26.1% vs. 50.0%). Overall survival was not different in both groups. CMR was associated with longer PFS with borderline significance. Conclusion Prolonged imatinib therapy helps to achieve a deeper molecular response in the long-term. Achieving deeper molecular response at any time positively affects maintaining the cytogenetic and molecular responses, and decreases the transformation to accelerated and/or blastic phase. The slight prolongation in PFS did not reach statistical significance.

Although clinical trials of first- and second-generation tyrosine kinase inhibitors (TKIs) have been shown to improve the prognosis of chronic myeloid leukemia (CML), there is still uncertainty about the clinical features, treatment outcomes, adverse effects, and other possible problems of their use in the clinical setting. We retrospectively analyzed 51 CML patients treated with TKIs at a single institution between 2002 and 2014. The patients (median age: 53.8 years) were classified as having chronic (n = 48), accelerated (n = 2), or blastic phase (n = 1) CML. Our treatments included both 1st generation TKIs (60.8%) and 2nd generation TKIs (39.2%). We found that the overall response rates of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4 (molecular response 4) were 90.2%, 78.4%, and 64.7%, respectively. Second line 2nd generation TKIs had response rates equivalent to those of 1st line 1st generation TKIs. Moreover, 1st line 2nd generation TKIs tended to achieve an early response rate. Overall survival (OS) at 5 years was 93.2%. Sudden blastic crisis (BC) occurred in 2 CML patients receiving TKI with CCyR status. Hematopoietic stem cell transplantation was performed for BC (n = 1) and sudden BC (n = 2). Side effects of all grades (1-3) and grade 3 alone were 64.7% and 11.8%, respectively. Dose reduction, replacement with another TKI, or low dose TKI treatment may be useful methods to control side effects. Further reasons of TKI discontinuation were economic problems (n = 3) and pregnancy (n = 1). Consequently, our treatment strategy for CML demonstrated good response rate and OS. Currently, treatment discontinuation due to intolerance, resistance, economic problems, pregnancy, and sudden BC remains a concern in clinical practice.

In the elderly population, the accelerated and blastic phases of chronic myeloid leukemia (CML) are difficult to treat, not just because of the higher chance of acquired mutations than in younger individuals, but because of additional associated co-morbidities. Tyrosine kinase inhibitors are well-established in the treatment of the chronic phase of CML, and their use in advanced phases is ever-increasing. Elderly patients who are still eligible candidates for transplant can undergo reduced-intensity transplants from related or unrelated donors after reverting to chronic phase. Post-transplantation, these patients require adequate monitoring and therapy to prevent relapses. Newer modalities of treatment or interventions are urgently required in this complex group of patients.

Background Over the past years, the survival of patients with Philadelphia-positive chronic myeloid leukemia (CML Ph + ) has increased as a result of therapy with tyrosin kinase inhibitors (TKIs). Intolerance to TKIs has been described in approximately 20% of patients receiving treatment. We studied the incidence of imatinib intolerance in patients with CML Ph + and their outcome in our CML reference site, as there is no information about the evolution of patients intolerant to TKIs. Patients and Methods A group of 86 patients with CML Ph + receiving imatinib monotherapy who abandoned treatment were the basis for this study. We present the trends of their disease evolution. Results The median of age at diagnosis was 42 years. Within a year, 19 (22%) of 86 patients developed imatinib intolerance, all of them with grade III or IV disease that required imatinib dose reduction or discontinuation. Of these patients, 16 (84%) of 19 developed transformation to blastic phase. The cumulative incidences of blastic phase development were 47% in the nonintolerant group and 84% in the intolerant group. There was a relative risk for those with imatinib intolerance to develop blastic phase of 1.78 (95% confidence interval, 1.28 to 2.42) ( P Conclusion Most imatinib-intolerant patients develop blastic phase transformation, with a poor survival of 3 to 6 months; no effective rescue treatment is available. Future research should to determine whether the origin of this evolution is really due to the intolerance itself or whether it is due to a more aggressive form of the disease, perhaps related to genetic transformation.

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-ABL1less than or equal to0.01% on the International Scale or undetectable BCR-ABL1 with greater than or equal to10?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 less than or equal to3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4 at 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.

Ponatinib is a third generation tyrosine kinase inhibitor (TKI) active against wild type and mutant bcr/abl tyrosine kinase (including T315I). Ponatinib is approved for the treatment of adult patients with T315I mutation detected in CML (all phases) and in Ph+ ALL, for CML patients who are resistant to dasatinib or nilotinib and patients with Ph+ ALL who are intolerant or resistant to dasatinib and for whom subsequent imatinib treatment is not an optimal therapy. In phase II registration study (PACE), 267 patients with CML in chronic phase (CP), 83 in accelerated (AC) and 94 patients in blastic phase (BP) of CML or Ph+ALL were enrolled. T315I mutation was detected in 64, 18 and 46 patients, respectively. Two or more or three or more TKIs were used before ponatinib in 93% and 58% of patients, respectively for median period of 16.7 months. Major cytogenetic response (MCyR) by 12 months was achieved in 59% of CP CML patients (median follow-up 36 months), and major hematological response (MaHR) by 6 months in 55% of AC CML patients, and in 34% of BP CML and Ph+ALL patients (median follow-up 15.16 and 6 months, respectively). Efficacy of ponatinib as a first-line treatment for CP CML patients was shown in phase II and III trials. Serious adverse reactions have been reported with ponatinib, including vascular occlusion, heart failure and hepatotoxicity. Ponatinib is a valuable treatment option for patients with CML and Ph+ALL resistant or intolerant to previous therapy with TKIs and those with T315I mutation.

Excellent response rates and a good quality of life have been observed since the introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment. Consequently, some challenges began to appear in CML women in child-bearing age wishing to become pregnant. Currently, many women around the world are in stable major/complete molecular response MMR/CMR (MMR

Pre-T cell acute lymphoblastic leukemia is a relatively rare leukemia. Twenty to 30 % of adult B cell leukemia cases are Philadelphia chromosome positive and it has a therapeutic and prognostic significance. Incidence and outcome of Ph+ T cell acute lymphoblastic leukemia (T cell ALL) is unknown. Only about 25 cases of de novo Ph+ T cell ALL and 44 cases of Ph+ T ALL in blastic phase of CML has been reported. Differentiation between Ph+ Pre-T ALL/LBL and T cell lymphoblastic crises of chronic myeloid leukemia may be difficult. We report a case of adult T cell ALL having Philadelphia chromosome as the cytogenetic abnormality. He was treated with acute lymphoblastic leukemia induction chemotherapy and Imatinib and achieved complete remission.

Chronic myelogenous leukemia (CML) is a clonal hematological disorder, which is characterized by the presence of the classical or variant Philadelphia translocations. During the progression to blastic phase of the disease secondary chromosomal abnormalities may emerge. Such secondary chromosomal abnormalities are nonrandom, the more frequent ones being trisomy 8 and 19, supernumerary i(17q), and extra Philadelphia chromosomes. Furthermore, a minor percentage of the patients may acquire different secondary chromosomal abnormalities including translocations between other chromosomes. We report here a patient with Ph+ CML presenting secondary chromosomal abnormalities including t(4;11)(q21;q23), t(3;3)(q29;q23) and t(11;18)(q10;q10) during the course of CML progression.

Background Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. Methods In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. Results After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P = 0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P = 0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P

Chronic myeloid leukemia (CML) is generally diagnosed in the chronic phase. We have recently encountered two CML-blastic phase (BP) cases, a 71-year-old woman and a 74-year-old man, who resembled de novo acute leukemia. The complete blood count was normal at least 11 and 13 months before the presentation, respectively. The leukemic cells showed predominant lymphoid phenotype. The blasts and granulocytes were positive for BCR-ABL, indicative of CML-BP. Both patients were successfully treated with prednisone and vincristine, followed by Imatinib. Our cases indicate rare presentations of CML-BP with an extremely short chronic phase. Ph-positive de novo acute leukemia should be carefully distinguished from CML-BP.

Background/Aim. Imatinib mesylate, a tyrosine kinase inhibitor with specific activity against the breakpoint cluster region - Abelson murine leukemia (BCR-ABL) tyrosine kinase has been developed for treatment of chronic myelogenous leukemia (CML). Its hematologic and cytogenetic effects have been evaluated in a series of clinical trials. The aim of this study was to report hematologic and cytogenetic response in CML patients during the treatment with imatinib mesylate. Methods. A total of 21 patients were treated and observed from July 2006 to December 2008. The median time from CML diagnosis was no more than 12 months, so all the patients received previous treatment with hydroxyurea for which the median time was 3 months. The patients received imatinib mesylate in an effective oral dose of 400 to 800 mg daily, which was followed with peripheral blood counts, bone marrow examination, and cytogenetic studies at 6, 12, 18 and 24 months. Results. Complete hematologic responses were reported for 19 (90.48%) of 21 patients studied. Among 19 patients who had a response, 16 (86%) did so within 3 months. The best cytogenetic response rate at any time during the study treatment with imatinib mesylate, among 14 patients in which cytogenetic response evaluated was: complete cytogenetic response in 7 (50%) patients, partial cytogenetic response in 6 (42.9%) patients and minor cytogenetic response in 1 (7.1%) patient. No patients had progressed to accelerated or blastic phase. The most frequent adverse effects that seemed to be related to treatment with imatinib mesylate were edema and musculosceletal pain; overall, most were mild. Only one patient discontinued treatment because of hematologic toxic effects. Conclusion. The results obtained in this study confirm that imatinib mesylate induces a complete hematological and cytogenetic response in a high percentage of patients with chronic-phase CML.

The therapeutic armamentarium of chronic myeloid leukemia (CML) has been considerably improved after the introduction of first- and second-generation tyrosine-kinase inhibitors (TKIs). Accordingly, the natural history of the diseases has changed, and patients in complete molecular response now have the same life expectancy of their healthy coetaneous. Notwithstanding these results, ∼ 20 - 30% of patients do not respond optimally to TKIs therapy, and most of these patients are potential candidates to progress toward the accelerated or blastic phase of the disease. Unfortunately, patients who become resistant to both first- and second-generation TKIs develop BCR-ABL kinase domain mutations, against which TKIs have extremely low cross-activity. In particular, none of the TKIs, with the exception of ponatinib, has significant activity against T315 mutation, which is estimated to be present in ∼ 15 - 20% of patients carrying BCR-ABL mutations. The use of omacetaxine mepesuccinate/homoharringtonine for the treatment of TKI-resistant CML patients regained interest due to its mechanism of action independent of binding to the ATP-binding pocket. Therefore, the activity of this compound is independent from the presence of BCR-ABL1 mutations, which makes it an attractive option for the treatment of CML patients after TKI failure.

The proliferative and differentiating capacity was compared between immature normal marrow cells and marrow, blood or spleen cells from patients with chronic myeloid leukaemia (CML) in chronic and blastic phases. Low density cells highly enriched in myeloblasts and promyelocytes were cultured in diffusion chambers (DC) and implanted into the peritoneal cavity of mice pretreasted with cyclophosphamide. In CML of chronic phase cell production was higher than normal with the exception of spleen cells. Total cell production was lower in blastic phase than in CML chronic phase. The [3H]-TdR labelling index of myeloblasts of blastic phase CML increased considerably upon implantation in DC consistent with re-entry into active proliferation. Immature normal cells give rise mostly to macrophages while the corresponding CML cells of chronic phase give a much higher PMN production with peaks after 12–18 d. Also in CML of blastic crisis the blasts differentiate into mature PMNs, but the maturation time is shortened with peaks of PMNs after 5–10 d. DC cultures of spleen cells from patients with CML showed a less differentiating capacity with a very low PMN production compared to cultures of marrow or blood cells. Our results indicate intrinsic differences in growth and maturation capacity between normal immature granulopoietic cells and cells from patients with CML of chronic phase or blastic crisis. The results may also indicate intrinsic differences between spleen, blood or marrow cells in CML.

35 patients with refractory or relapsed acute leukemia received salvage chemotherapy using high-dose cytosine arabinoside 2 g/m2 intravenously for 3 hours every 12 h, in 8 doses, followed by continuous infusion of mitoxantrone 12 mg/m2/day for 2 d. 9 patients had acute myeloblastic leukemia (AML), (4 relapsed, 5 refractory), 20 had acute lymphoblastic leukemia (ALL) (11 relapsed, 9 refractory) and 6 had chronic myelogenous leukemia (CML) in the blastic phase (BP). 4 out of 9 AML and 16 out of 20 ALL achieved complete remission. Median survival was 6 months for all patients and 10 months for responders. A short (1.5 months) chronic phase was achieved in 3 patients with CML. The main toxic effect was hematologic. A pharmacokinetic study was performed on mitoxantrone. No correlation was found with clinical response. The combination of mitoxantrone and ara-C is an effective antileukemic regimen, especially in ALL.

We describe here a patient with Ph'-positive chronic myelogenous leukemia (CML) who developed a Ph'-negative blastic crisis. The blast DNA was analyzed on two different occasions, at the beginning of the blastic phase and at the end, shortly before the patient's death. Although cells from both samples had no Ph' chromosome marker (not even a masked one) we could detect a rearrangement of the bcr gene in the second DNA sample, using a '3'-bcr' probe. The same probe and a '5'-bcr' probe failed to detect any rearranged band in the first DNA sample. No rearrangement was identified at the c-myc and N-ras loci, while a slight c-myc amplification was evident in both DNA samples tested.

A myeloproliferative condition in blastic phase is described in an 18-year-old male who was also found to have a mediastinal malignant teratoma. Myeloid metaplasia was found in the lymph nodes and spleen, and an infiltration of granulocytic blast cells was observed in the bone marrow and the lymph nodes. Aneuploidy with an extra chromosome (trisomy 8) was present in bone marrow cells. To our knowledge the combination of a myeloproliferative disorder and a malignant teratoma has not been earlier described.

Objective B–lineage acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphatic blastic phase in adults have poor prognoses despite intensive chemotherapy. Novel targeted treatment modalities emerge, but their evaluation requires relevant in vitro models of lymphoblastic leukemia. Presently available cell lines do not fully represent this heterogeneous disease. Available in vitro culturing protocols do not support long–term proliferation of primary cells. We therefore aimed to develop a culture system that allows long–term proliferation of primary human B–lineage lymphoblastic leukemia. Materials and Methods Primary lymphoblastic leukemia cells were cultured in a defined serum–free medium, in the absence or presence of human hematopoietic growth factors or serum. Results In the defined serum–free medium, cells from 12 of 34 cases immediately proliferated in vitro. In the absence of hematopoietic growth factors and serum these cases proliferated for more than 1 year without signs of exhaustion. The culturing system supported different subtypes of lymphoblastic leukemia. Two chronic myeloid leukemia in lymphatic blastic phase, four bcr/abl–positive ALL, one etv6/abl–positive ALL, 2 e2a–pbx1−positive ALL, and one t(9;11)–positive ALL could be long–term expanded, as well as two ALL that displayed nontypical cytogenetics. Not all bcr/abl– or e2a–pbx1−positive ALL proliferated in vitro, demonstrating heterogeneity within these subtypes. The proliferating bcr/abl– and etv6/abl–positive cells displayed sensitivity to imatinib, demonstrating that their proliferation depended on the activity of these oncoproteins. Conclusion The serum–free culturing system may be a valuable instrument in the study of ALL cell biology, as well as in the evaluation of novel targeted therapeutics.

We identified different phenotypic subsets among 62 cases of chronic myeloid leukemia (CML) in blast crisis (BC) (26% B-lymphoblastic, and 74% various myeloblastic subsets) on bone marrow trephines and correlated the blast-phenotype with cytogenetics. Five of myeloid-BC had an associated 3q26 abnormality and two of these showed a megakaryoblastic-phenotype. While myeloid-BC was associated with additional copies of Philadelphia (Ph) (29%) (p=0.08), numerical abnormalities (51%) (p=0.007), trisomy-8 (29%) (p=0.08) and 17p-loss (22%), none of lymphoid-BC showed these abnormalities. Among myeloid-BC, CD34-negative cases were more often associated with trisomy-8, 17p-loss and numerical abnormalities, and the CD117-negative subset with additional copies of Ph (p