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The significant changes in reticulin fibrosis observed between the baseline and post-imatinib treatment among three patients. Patient 1-A (×400) and B (×200), Patient 2-C (×100) and D (×200), Patient 3-E (×400) and F (×200). (A, C and E show pre-imatinib fibrosis whereas B, D and F display fibrosis at last bone marrow biopsy (LBMB) in each patient).
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Aims Before the era of tyrosine kinase inhibitors (TKIs), the presence of bone marrow fibrosis (MF) in patients with chronic myeloid leukaemia (CML) has been established as a poor prognostic factor. The aim of the present study was to evaluate the effects of imatinib treatment on MF and the prognostic significance of MF at this new era of CML thera...
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Background:
Several clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-A...
Background:
Recent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons...
After normal survival has been achieved in most patients with chronic myeloid leukemia (CML), a new goal for treating CML is survival at good quality of life, with treatment discontinuation in sustained deep molecular response (DMR; MR4 or deeper) and treatment-free remission (TFR). Four tyrosine kinase inhibitors (TKIs) have been approved for firs...
Myeloid Sarcoma (MS) is diagnosed by an extramedullary proliferation of immature granulocytic cells. Its association with chronic myeloid leukemia (CML) is rare. CML is characterized by BCR-ABL1 gene rearrangement and therapies with tyrosine kinase inhibitors (TKI) are very effective. However, TKI resistance may occur secondary to the development o...
Large randomized clinical trials and prior meta-analyses indicate that second-generation BCR-ABL tyrosine kinase inhibitors (TKIs) improve surrogate biomarkers in patients with chronic myeloid leukemia (CML) without providing survival benefits. The objective is to evaluate the long-term efficacy and the occurrence of vascular occlusion with second-...
Citations
... Interestingly, imatinib seems to be able to either slow down or reverse MF (Beham-Schmid et al., 2002;Bueso-Ramos et al., 2004;Thiele et al., 2004;Buesche et al., 2007). An open question is whether the degree of MF at diagnosis has an impact on response to TKI treatment, with different studies showing conflicting results (Kantarjian et al., 2005;Buesche et al., 2007;Tanrikulu Simsek et al., 2016). Importantly, Buesche et al. (2007) showed that MF before start or within the first 3 months of imatinib therapy did not influence the probability of achieving a complete hematologic response during imatinib treatment. ...
... Frontiers in Pharmacology frontiersin.org 09 2003), it seems to be less relevant nowadays, due to the enormous success of TKIs and the drastic improvements in patient management that were introduced (Kantarjian et al., 2005;Tanrikulu Simsek et al., 2016). BM fibrosis at diagnosis has been shown to revert in the majority of patients upon TKI treatment (Buesche et al., 2007;Eliacik et al., 2015;Narang et al., 2017) and we likewise observed this in patient 11. ...
... BM fibrosis at diagnosis has been shown to revert in the majority of patients upon TKI treatment (Buesche et al., 2007;Eliacik et al., 2015;Narang et al., 2017) and we likewise observed this in patient 11. Tanrikulu Simsek et al. (2016) furthermore confirmed a decrease in fibrosis grades after long-time imatinib treatment. It has to be noted that in a few single patients imatinib treatment was associated with induction of BM fibrosis (Buesche et al., 2007;Shanmuganathan et al., 2019) and interestingly, in patient 3 of our cohort we see development of low-grade fibrosis after 5.5 years of imatinib treatment. ...
The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR::ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.
... During treatment with imatinib, bone marrow changes showed normalisation of erythropoiesis accompanied by marked reduction of granulocytes and megakaryocytes and impressive regression of fibre content [36]. Besides the fact that the marrow fibrosis reduces during the duration of imatinib therapy, it was found that the degree of marrow fibrosis at diagnosis has no negative impact on the therapeutic response to imatinib therapy [37], while other studies reported the opposite [38,39]. Also, it was determined that imatinib leads to a decrease in the initially enhanced MVD combined with a decrease in luminal distension [40]. ...
In this study the correlation and the prognostic value of the morphometric parameters of angiogenesis for optimal therapeutic response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukaemia (CML), i.e. complete cytogenetic response (CCgR) and major molecular response (MMoR), were investigated. Microvascular density (MVD) and a number of different size- and shape-related morphometric parameters of microvessels of bone marrow biopsy from 40 CML patients and 20 controls were examined. Microvessels of bone marrow were examined by using immunohistochemical staining for CD34 and quantified in the region of the most intense vascularisation by using image analysis.
CML patients had significantly higher angiogenesis parameters when compared with controls. A statistically significant correlation was found between some parameters of angiogenesis and evaluated CCgR and MMoR. For achievement of CCgR, lower values of MVD, minor axis, area, circularity, and roundness and higher value of aspect ratio, while for achievement of MMoR only lower values of MVD have been identified as positive prognostic factors.
Besides confirming increased angiogenesis in CML patients, this study also demonstrated prognostic significance of the degree of angiogenesis for the clinical outcome and identified angiogenic predictive factors for achieving optimal response on TKIs therapy.
... Previous studies also documented higher survival in patients with lower grades of fibrosis 6,8 underscoring the importance of this finding and its potential prognostic implications in the follow-up of HSCT recipients, however fibrosis could improve with the administration of pharmacologic agents, as recently shown. 20 There are limitations in our study, including a small number of patients in both, autologous and allogeneic groups and heterogeneous disease categories, also bone marrow was studied once; however, the findings are relevant as they highlight important aspects of the dynamics of transplant recovery after RIC and the complex interaction between BM histological and functional recovery. ...
Changes in bone marrow (BM) architecture and its remodeling after hematopoietic stem cell transplantation (HSCT) following a reduced-intensity conditioning regimen for treating malignant hematologic diseases are poorly documented. We assessed these changes and their correlation with the clinical course to investigate the dynamics of this process.
Hematological toxicity is a common adverse effect of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML). We retrospectively investigated the incidence of hematological toxicity after TKI administration in 143 CML patients and parameters associated with hematological toxicity. Severe hematological toxicity (grade 3–4) existed in 26 (18.2%) patients. Marrow fibrosis (MF), age, Sokal score, and spleen enlargement were associated with severe hematological toxicity. Further multivariate analysis showed that only MF was an independent predictor. Complete cytogenetic response(CCyR) rates and major molecular response (MMR) rates with grade 3–4 hematological toxicity were 42.3% and 26.9%, respectively, significantly lower than patients with grade 1–2 and without hematological toxicity (p = .032 for CCyR and p = .044 for MMR). Similar results were observed regarding progression-free survival (PFS) and overall survival (OS) (p = .011 for PFS and p = .037 for OS). This study indicated that MF was an independent predictor of severe hematological toxicity of TKIs.
The myeloproliferative neoplasms are a group of diseases, having in common that they result from proliferation of a clone of neoplastic myeloid cells derived from a mutated haemopoietic stem cell. In the 2008 classification and the 2016 revision of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues the designation of this group of conditions is 'myeloproliferative neoplasms' rather than 'myeloproliferative disorders' or 'myeloproliferative diseases'. In the case of chronic myeloid leukaemia, prior to the introduction of therapy with tyrosine kinase inhibitors, acute transformation was very frequent and occurred at a median interval of only 2‐3 years. The 2001 WHO classification adopted the concept of a group of haematological neoplasms with features of both the myelodysplastic syndromes and the myeloproliferative neoplasms. This concept has been retained in the 2008 classification and its 2016 revision.
Pediatric chronic myeloid leukemia (ped-CML) is rare and ped-CML with fibre accumulation in the bone marrow (MF) is thought to be even rarer. In adults (ad-CML), fibrosis represents an adverse prognostic factor. So far, the pro-fibrotic changes in the bone marrow microenvironment have not been investigated in detail in ped-CML. From a total of 66 ped-CML in chronic phase, biopsies were analysable and 10 had MF1/2 (MF1, n=8/10; MF2, n=2/10). We randomly selected 16 ped-CML and 16 ad-CML cases with and without fibrosis (each n=8) as well as 18 non-neoplastic controls. Bone marrow samples were analysed with a real-time PCR-based assay (including 127 genes for pediatric cases) and by immunohistochemistry. We found increased expression of megakaryocytic genes in ped-CML. The number of megakaryocytes and pro-platelets are increased in CML patients but the most significant increase was noted for ped-CML-MF1/2. Anti-fibrotic MMP9 expression was lower in children than in adults. Cell mobilisation-related CXCL12 was decreased in young and adult patients with CML but not the corresponding receptor CXCR4. In summary, fibre accumulation in ped-CML-MF1/2 is associated with increased megakaryocytic proliferation and increased interstitial pro-platelet deposition. Deregulated expression of matrix modulating factors shifts the bone marrow microenvironment towards fibrosis.Leukemia accepted article preview online, 27 February 2017. doi:10.1038/leu.2017.73.
