Increased Expression of TIGIT/CD57 in Peripheral Blood/Bone Marrow NK Cells in Patients with Chronic Myeloid Leukemia

The antitumor activity of NK cells in patients with chronic myeloid leukemia (CML) is inhibited by the leukemia microenvironment. Recent studies have identified that the expression of TIGIT, CD57, and KLRG1 is related to the function, maturation, and antitumor capabilities of NK cells. However, the characteristics of the expression of these genes in the peripheral blood (PB) and bone marrow (BM) from patients with CML remain unknown. In this study, we used multicolor flow cytometry to assay the quantity and phenotypic changes of NK cells in PB and BM from de novo CML (DN-CML) and CML patients acquiring molecular response (MR-CML). We found that the expression of TIGIT, which inhibits NK cell function, is increased on CD56+ and CD56dim NK cells in DN-CML PB compared with those in healthy individuals (HIs), and it is restored to normal in patients who achieve MR. We also found that the expression of CD57 on NK cells was approximately the same level in PB and BM from DN-CML patients, while decreased CD57 expression was found on CD56+ and CD56dim NK cells in HI BM compared with PB. Additionally, those two subsets were significantly increased in DN-CML BM compared to HI BM. The expression of CD57 correlates with replicative senescence and maturity for human NK cells; therefore, the increase in TIGIT on PB NK cells together with an increase in CD57 on BM NK cells may explain the subdued NK cell antileukemia capacity and proliferative ability in DN-CML patients. These results indicate that reversing the immune suppression of PB NK cells by blocking TIGIT while improving the proliferation of BM NK cells via targeting CD57 may be more effective in removing tumor cells.

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Consistency Of RQ-PCR Analysis Results In Peripheral Blood and Bone Marrow Samples In Chronic Myeloid Leukemia Patients: Relevance From The Practical and Logistic Point Of View

Blood ◽

10.1182/blood.v122.21.2592.2592 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2592-2592

Author(s):

Giovanna Rege-Cambrin ◽

Carmen Fava ◽

Enrico Gottardi ◽

Filomena Daraio ◽

Emilia Giugliano ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Wilcoxon Test ◽

Molecular Response ◽

Two Samples ◽

The Mean

Abstract Background Consensus has been achieved that standardized molecular quantitative analysis (RQ-PCR) on peripheral blood (PB) is a suitable method for monitoring residual disease in chronic myeloid leukemia (CML). However, BM is still obtained at specific timepoints, and in a number of cases, only bone marrow (BM) sample collected for cytogenetic analysis is available. Being one of the laboratory involved in the standardization process of molecular monitoring for CML patients, we decided to perform a comparative analysis of BM and PB samples in order to evaluate the consistency of the results. Methods Between March 2009 and January 2013, 230 consecutive RQ-PCR tests to assess BCR-ABL transcript levels from simultaneously collected PB and BM samples were performed (for a total of 460 analysis) on 77 patients affected by Ph+ CML in chronic phase treated in our center. All samples were analyzed in the same laboratory following international guidelines (Cross N, Leukemia 2012) and results were expressed according to the International Scale; ABL1 was used as control gene. Time from blood-drawn to processing was within 3-4 hours. Results Among the 230 pairs, 3 were considered as not evaluable because of inadequate material; for the purpose of this study, the remaining 227 pairs were considered as “evaluable”. 204 pairs were classified as “fit” when both BM and PB ABL amplification resulted in more than 10.000 copies; 23 pairs were considered unfit for ABL1 <10.000 in either one of the two samples (21) or both (2). The mean number of ABL1 copies in all evaluable samples was 35.639 for BM (SD 21.465) and 30.958 for PB samples (SD 18.696). Correlation analysis was performed on the whole population and in 4 subgroups: No Complete Cytogenetic Response (CCyR, 22%), CCyR without Major Molecular Response (MMR), (21.6%), CCyR with MMR (excluding patients with MR4 or better,19.8%), and CCyR with MR4 – MR4.5 (32,6%). Cytogenetic response was not available in 9 BM samples (4%), not included in the subgroup analysis. Spearman correlation of BCR/ABL ratio values between PB versus BM paired samples resulted in a statistically significant correlation in all groups, both for evaluable and fit pairs. Correlation was stronger in samples that were not in MMR or better (table 1 and figure 1). The Wilcoxon test showed that the mean difference of BCR/ABL values between paired PB and BM samples was not significantly different from zero (in evaluable and fit pairs by considering the whole population). Concordance was further analyzed by the K test which resulted in a coefficient equal to 0.627, corresponding to a notable degree of concordance. For patients in CCyR, agreement on classification of response (MMR, MR4, MR4.5) between paired PB and BM samples was observed in 125/168 evaluable pairs; 22 out of the 43 evaluable cases of disagreement were due to technical failures (in 10 BM and 12 PB samples). In 14 of the remaining 21 cases, PB was more sensitive. Conclusions In a single center experience of molecular analysis, BCR/ABL ratio was highly consistent in BM and PB samples. In less than 10% of the cases a single test did not reach the required sensitivity of 10.000 ABL copies and the double testing allowed to obtain a valid result. This may be especially valuable in evaluating an early response (i.e. at 3 months), when the amount of disease has prognostic relevance. The analysis will be expanded to include samples coming from different centers to evaluate a possible role of timing and transport on data consistency. Disclosures: Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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Impact of Proteomic Profile of Peripheral Blood and Bone Marrow Sera on Molecular Response in Patients with Chronic Myeloid Leukemia: Preliminary Data

Blood ◽

10.1182/blood.v124.21.5515.5515 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5515-5515

Author(s):

Nicola Sgherza ◽

Vito Garrisi ◽

Giacoma De Tullio ◽

Simona Serratì ◽

Angela Iacobazzi ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Preliminary Data ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Differentially Expressed ◽

Molecular Response ◽

Proteomic Profile ◽

Group A ◽

Group B

Abstract BACKGROUND. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by an aberrant protein (BCR–ABL) which is a constitutively active tyrosine kinase. According to the latest ELN recommendations for the management of CML, molecular response (MR) is best assessed according to the International Scale (IS) as the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control transcripts. It is expressed and reported as BCR-ABL1% on a log scale where 10%, 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a decrease of respectively 1 (MR1), 2 (MR2), 3 (MR3), 4 (MR4), 4.5 (MR4.5) logs below the standard baseline that was used in the IRIS study. Recent advances in the proteomic field have allowed us to better understand the biology of several cancer types and/or discover new candidate biomarkers, but very few data are available in CML. AIMS. The purpose of this study was to evaluate a possible correlation between depth of MR and proteomic profile in sera samples obtained from the peripheral blood and bone marrow of CML patients. PATIENTS AND METHODS Samples were consecutively and prospectively obtained from 20 CML patients observed between January and June 2014 at the Hematology Unit of the National Cancer Research Centre “Istituto Tumori Giovanni Paolo II” in Bari, Italy. Each individual involved in the study signed an informed consent form authorizing the Institute to utilize their biological tissues for research purposes. All patients at diagnosis displayed the classic t(9;22) Ph chromosome according to standard cytogenetics. The BCR/ABL transcript at RT-PCR was b3a2 in 13 patients and b2a2 in 7 patients. Peripheral blood and bone marrow samples were centrifuged within 30 minutes of sample taking. Serum specimens were immediately collected and frozen at −80°C. Twenty sera from peripheral blood were sampled from 5 patients in MR1 response, four in MR2, eight in MR3, two in MR4 and 1 patient at diagnosis; for eleven patients serum from bone marrow was also available; in particular 2 were sampled from patients in MR1, 3 in MR2, 4 in MR3, 1 in MR4 and 1 at diagnosis. Patients were grouped in two cohorts: the first comprised those with lower molecular response to MR3 (group A: 10 patients) and the second greater than or equal to MR3 (group B: 10 patients). The association of proteomic profile with molecular response was performed using the SELDI ToF Mass Spectrometry platform. Each specimen was spotted on an IMAC30 metal affinity protein-chip, prepared according to the manufacturer's instructions, and analyzed in duplicate. RESULTS Fourteen differentially expressed peaks were highlighted when comparing peripheral sera from group A and group B, but none was statistically significant. When comparing 11 available serum samples from the bone marrow of groups A (6) and B (5), four peaks (m/z 10629, m/z 3889, m/z 7772, m/z 7987) were reported as differentially expressed in a statistically significant way (p<0.05). Focusing the differential expression analysis in peripheral sera only on MR1 patients (including one patient at diagnosis) versus MR4 patients, one peak at m/z 11092 was identified as significantly and differentially expressed (p < 0.05) (Figure 1). Similarly, comparing bone marrow sera only from MR1 and MR4 patients respectively, 32 peaks were differentially expressed. Once again the peak at m/z 11092 resulted under expressed in MR1 patients, and interestingly the single patient at diagnosis had the lowest value. No statistical differences were evidenced when comparing peripheral blood and bone marrow sera obtained from b3a2 and b2a2 patients. CONCLUSIONS These preliminary data suggest that an over-expression of m/z 11092 in serum obtained from peripheral blood and bone marrow could be associated with a deeper molecular response; further investigations are needed on a larger number of patients in order to confirm or refute our results and, to definitively characterize the peak at m/z 11092. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Discontinuation of Imatinib Therapy After Achieving a Molecular Response in Chronic Myeloid Leukemia Patients.

Blood ◽

10.1182/blood.v114.22.859.859 ◽

2009 ◽

Vol 114 (22) ◽

pp. 859-859 ◽

Cited By ~ 23

Author(s):

Francois-Xavier Mahon ◽

Delphine Rea ◽

Francois Guilhot ◽

Francoise Huguet ◽

Franck Emmanuel Nicolini ◽

...

Keyword(s):

Pilot Study ◽

Chronic Myeloid Leukemia ◽

Nk Cells ◽

Myeloid Leukemia ◽

De Novo ◽

Single Agent ◽

Detection Threshold ◽

Molecular Response ◽

Number Of Patients

Abstract Abstract 859 Background Imatinib (IM) has greatly improved survival rates in chronic myeloid leukemia* (*CML). However, all patients (pts) must continue treatment for an unknown period of time. A pilot study of the first pts who discontinued IM therapy was previously reported (Rousselot et al. Blood 2007;109:58–60). The multicentre study Stop Imatinib (STIM) was initiated in July 2007 in order to evaluate the persistence of complete molecular remission (CMR) after stopping IM, and to determine the factors that could be associated with CMR persistence. Methods Inclusion criteria were IM treatment duration of at least 3 years and sustained CMR. Sustained CMR was defined as BCR-ABL/ABL levels below a detection threshold corresponding to a 5-log reduction (undetectable signal using RQ-PCR) for at least 2 years. Molecular relapse, defined as RQ-PCR positivity, was taken into account if confirmed in two successive assessments. In cases of molecular relapse, pts were re-challenged with IM at 400 mg daily. Results From the pilot study, 8 among 15 patients are still in CMR with a median follow up of 42 months (range 37-49). The number of patients enrolled in the STIM study was 69. 34 patients had received interferon alpha (IFNa) prior to IM and 35 pts were de novo. Median follow-up (range) was 17 months (6-24). 37 pts relapsed (loss of CMR) within the first 6 months and two patient relapsed after more than 6 months (M7 ,M18). At M12, the probability of remaining in CMR was 45% (95% CI: 33-56%). For previously treated with IFN (n=34) this probability was 44% (95% CI: 27-59%) versus 46% (95% CI: 29-61%) for de novo pts (p=0.93, overall). All patients in molecular relapse were sensitive again after imatinib re-challenge (decreasing BCR-ABL level, achievement CMR again). Male pts had a better probability of survival without molecular relapse (p=0.02) and a trend was observed for the low Sokal risk group (p = 0.06). Peripheral NK cells counts prior to IM discontinuation were significantly lower in relapse pts (mainly cytotoxic cells CD56dim) as compared to the non relapse pts(p=0.005). Conclusions We have confirmed that CMR can be sustained after discontinuation of imatinib with a long follow-up, particularly in male patients and in pts with cytotoxic NK cells in their peripheral blood. Using stringent criteria, it is possible to stop treatment in patients with sustained CMR, even in those treated with IM as a single agent. (ClinicalTrials.gov number, NCT00478985 [ClinicalTrials.gov]) Disclosures: Mahon: Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria. Guilhot:Novartis Pharma: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

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An Atypical Initial Presentation of Chronic Myeloid Leukemia with Central Nervous System and Lymph Node Blast Crises

Case Reports in Oncology ◽

10.1159/000447711 ◽

2016 ◽

Vol 9 (2) ◽

pp. 415-421 ◽

Cited By ~ 3

Author(s):

Khadega A. Abuelgasim ◽

Saeed Alshieban ◽

Nada A. Almubayi ◽

Ayman Alhejazi ◽

Abdulrahman R. Jazieh

Keyword(s):

Central Nervous System ◽

Bone Marrow ◽

Nervous System ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Single Agent ◽

Chronic Phase ◽

Current Evidence ◽

Molecular Response

We describe the case of a young man with therapy-naive chronic myeloid leukemia who did not initially have any peripheral blood or bone marrow excess blasts but presented with extramedullary myeloid blast crises involving the central nervous system and multiple lymph nodes. Conventional cytogenetic tests were positive for t(9;22)(q34:q11) as well as for trisomy 8, 14 and 21 and del(16q). The patient’s peripheral blood and bone marrow were positive for the BCR-ABL oncogene when analyzed by fluorescence in situ hybridization and polymerase chain reaction. He achieved good clinical, radiological, cytogenetic and molecular response to acute myeloid leukemia induction chemotherapy combined with 16 doses of triple intrathecal chemotherapy and oral dasatinib (second-generation tyrosine kinase inhibitor) treatment. Due to his poor general condition, he was treated with 24 Gy of whole-brain radiation therapy, as allogeneic stem cell transplantation was not feasible. Although extramedullary CNS blast crises are usually associated with a very poor outcome, our patient remains in complete cytogenetic and molecular remission, on single-agent dasatinib, 4 years after the diagnosis with no current evidence of active extramedullary disease. This suggests that dasatinib has a role in controlling not only chronic-phase chronic myeloid leukemia, but also its CNS blast crisis.

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Comparison of BCR-ABL1 quantification in peripheral blood and bone marrow using an International Scale-standardized assay for assessment of deep molecular response in chronic myeloid leukemia

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-1172 ◽

2020 ◽

Vol 58 (8) ◽

pp. 1214-1222

Author(s):

Georg Greiner ◽

Franz Ratzinger ◽

Michael Gurbisz ◽

Nadine Witzeneder ◽

Hossein Taghizadeh ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Quantitative Polymerase Chain Reaction ◽

Molecular Response ◽

International Scale

AbstractBackgroundMonitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens.MethodsWe examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS.ResultsA good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates.ConclusionsIn summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.

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Clinical significance of dasatinib-induced pleural effusion in patients with de novo chronic myeloid leukemia

Hematology Reports ◽

10.4081/hr.2018.7474 ◽

2018 ◽

Vol 10 (3) ◽

Cited By ~ 1

Author(s):

Aya Nakaya ◽

Shinya Fujita ◽

Atsushi Satake ◽

Takahisa Nakanishi ◽

Yoshiko Azuma ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Features ◽

Myeloid Leukemia ◽

De Novo ◽

Late Onset ◽

Molecular Response ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Treatment Agent

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PEpositive patients was higher than that of PEnegative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

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Production of colony-stimulating activity by human natural killer cells: analysis of the conditions that influence the release and detection of colony-stimulating activity

Blood ◽

10.1182/blood.v74.1.156.bloodjournal741156 ◽

1989 ◽

Vol 74 (1) ◽

pp. 156-164

Author(s):

V Pistoia ◽

S Zupo ◽

A Corcione ◽

S Roncella ◽

L Matera ◽

...

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Natural Killer ◽

Peripheral Blood ◽

Nk Cell ◽

K562 Cells ◽

Cell Suspensions ◽

Normal Peripheral Blood ◽

Colony Stimulating Activity ◽

Culture Supernatants

Highly purified natural killer (NK) cell suspensions were tested for their capacity to release colony-stimulating activity (CSA) in vitro. NK cell suspensions comprised primarily CD16+ cells and were devoid of CD3+ T cells, CD15+ monocytes, and of B cells. CSA was detected in the NK cell supernatants and sustained the growth of myeloid colonies from both normal peripheral blood and bone marrow. CSA could be in part inhibited by pretreating NK cell culture supernatants with a specific goat anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antiserum. The inhibition, however, was never complete, a finding that suggests that additional factors were responsible for CSA. Incubation of NK cells with K562 cells (an NK-sensitive target) or with normal bone marrow cells resulted in the appearance of a strong colony- inhibiting activity (CIA) in the culture supernatants. Such CIA was demonstrable in an experimental system where bone marrow or peripheral blood progenitors were induced to form myeloid colonies in the presence of conditioned medium by CSA-producing giant cell tumor (GCT) cells. Stimulation of NK cells with NK-insensitive targets failed to induce CIA production. Neutralizing antitumor necrosis factor (TNF) monoclonal antibodies (MoAbs) were found capable of inhibiting CIA present in the supernatants of NK cells stimulated with K562 cells. Following treatment with anti-TNF antibodies, CSA was again detectable in the same supernatants. This finding indicates that induction of TNF production did not concomitantly switch off CSA production by NK cells. Pretreatment of NK cells with recombinant interleukin-2 (rIL-2) or gamma interferon (r gamma IFN) did not change the amount of CSA released. However, treatment with rIL-2 caused the appearance of a factor in the NK cell supernatants capable of sustaining the formation of colonies of a larger size.

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Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment

Blood ◽

10.1182/blood.v76.11.2337.bloodjournal76112337 ◽

1990 ◽

Vol 76 (11) ◽

pp. 2337-2342

Author(s):

IM Clauss ◽

B Vandenplas ◽

MG Wathelet ◽

C Dorval ◽

A Delforge ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Interferon Alpha ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Bone Marrow Cells ◽

Healthy Controls ◽

Ifn Alpha ◽

Inducible Genes ◽

Marrow Cells

Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However, some patients are resistant and others develop late resistance to the IFN- alpha treatment. To understand the molecular mechanism of this resistance, we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients, two responsive patients, and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied, including the low-molecular- weight 2′-5′oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.

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Real-Life Management of Children and Adolescents with Chronic Myeloid Leukemia: The Italian Experience

Acta Haematologica ◽

10.1159/000491546 ◽

2018 ◽

Vol 140 (2) ◽

pp. 105-111 ◽

Cited By ~ 1

Author(s):

Fiorina Giona ◽

Michelina Santopietro ◽

Giuseppe Menna ◽

Maria Caterina Putti ◽

Concetta Micalizzi ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Real Life ◽

Chronic Phase ◽

Optimal Management ◽

Molecular Monitoring ◽

Italian Experience ◽

Adults And Children

Background: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. Methods: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. Results: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines’ recommendations. Conclusions: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

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