Achieving early molecular response in chronic myeloid leukemia in chronic phase to reduce the risk of progression: clinical relevance of the 3‐ and 6‐month time points

Patients with chronic myeloid leukemia in chronic phase who achieve early molecular response (EMR; generally defined as BCR‐ABL ≤ 10% on the International Scale at 3 or 6 months) have improved outcomes. However, there is no consensus on whether EMR failure at 3 months requires a change in therapy, and the value of the 6‐month time point remains under debate. Some patients who do not achieve EMR at 3 months achieve significant decreases in BCR‐ABL levels by 6 months, whereas others have progressive disease. For patients who do not achieve EMR at either time point, the risk of disease progression is higher both between 3 and 6 months and over the longer term, underlining the therapeutic relevance of the 3‐ to 6‐month time period. For patients with EMR failure at 3 months, although there is currently no consensus on whether to switch therapy or wait until the 6‐month assessment, some patients may benefit from an early change in treatment. This review synthesizes key clinical data demonstrating improved outcomes associated with the achievement of EMR and discusses the relevance of the 3‐ and 6‐month time points on survival and the risk of disease progression. Several potential clinical situations are also presented to explore when a change in therapy may be considered.     

Location of the BCR/ABL Fusion Genes on Both Chromosomes 9 in Ph Negative Young CML Patients: An Indian Experience

The BCR/ABL gene rearrangement is cytogenetically visualized in most chronic myeloid leukemia (CML) cases. About 5–10 % of CML patients lack its cytogenetic evidence, however, shows BCR/ABL fusion by molecular methods. We describe two CML patients with Philadelphia (Ph) negative (−ve) and BCR/ABL positive by fluorescence in situ hybridization (FISH). Both the cases were in chronic phase at diagnosis. Conventional cytogenetics and different FISH assays were adopted using BCR/ABL probes. Home-brew FISH assay using bacterial artificial clone (BAC) for BAC-CTA/bk 299D3 for chromosomal region 22q13.31-q13.32 was performed in case 1. Both the patients were Ph-ve. In first case, dual color dual fusion (DCDF)-FISH studies revealed 1 Red (R) 2 Green (G) 1 Fusion (F) signal pattern in 80 % of cells indicating BCR/ABL fusion signals on chromosomes 9 instead of Ph and 2G2F signal pattern in 20 % of cells indicating two BCR/ABL fusions on both chromosomes 9q34 on presentation. In second case, FISH studies revealed the 1R1G1F signal pattern indicating BCR/ABL fusion signals on chromosomes 9 instead of Ph in 100 % of cells at presentation. During follow-up, both the patients exhibited 2G2F signal pattern indicating two BCR/ABL fusions on both chromosomes 9q34, which indicated a clonal evolution in 100 % cells. Both the patients did not achieve therapeutic response. Relocation of BCR/ABL fusion sequence on sites other than 22q11 represents a rare type of variant Ph, the present study highlights the hot spots involved in CML pathogenesis and signifies their implications in Ph−ve BCR/ABL positive CML. This study demonstrated the genetic heterogeneity of this subgroup of CML and strongly emphasized the role of metaphase FISH, especially in Ph−ve CML cases, as it detects variations of the classical t(9;22).     

The differences and correlations of BCR‐ABL transcripts between peripheral blood and bone marrow assays are associated with the molecular responses in the bone marrow for chronic myelogenous leukemia

Previous studies concerning BCR‐ABL mRNA levels by quantitative real‐time RT‐PCR (Q‐PCR) for chronic myelogenous leukemia (CML) have shown a significant concordance between peripheral blood (PB) and bone marrow (BM) assays. The objective of this study was to determine whether molecular monitoring using PB was comparable to using BM for CML. A comparative study was performed that analyzed the Q‐PCR results of 712 simultaneous PB and BM samples from 330 patients before and during imatinib therapy. For the 78 paired pretreatment samples, the level of BCR‐ABL mRNA in PB was lower than that in BM (P = 0.007). Although the overall amounts of BCR‐ABL mRNA in the PB and BM were comparable (P= 0.072) and there was a strong correlation (r = 0.839, P < 0.001) with the 634 paired on‐treatment samples, the depth of the molecular response in PB was lower than that in BM (P < 0.001). The level of BCR‐ABL mRNA in PB was lower than that in BM where the BM BCR‐ABL mRNA < 1 log reduction (P < 0.001) or ≥ 1–< 2 log‐reductions (P = 0.008) from the baseline, and higher than that where the BM BCR‐ABL mRNA ≥ 2 log‐reductions (P < 0.001). A strong correlation (r = 0.811, P < 0.001) was only found where the BM BCR‐ABL mRNA < 1 log reduction. We conclude that the differences and correlations of BCR‐ABL mRNA between PB and BM assays depend on the depth of the molecular response in BM for CML during imatinib therapy. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR‐ABL1 by Q‐RT‐PCR does not equate to eradication of the disease. Digital‐PCR (dPCR), able to detect 1 BCR‐ABL1 positive cell out of 10⁷, has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q‐RT‐PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q‐RT‐PCR for 36 months. Patients losing molecular remission (two consecutive positive Q‐RT‐PCR with at least 1 BCR‐ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow‐up of 21.6 months. Fifty‐two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not‐relapsed patients, 40 (37.0% of total) regained Q‐RT‐PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013–1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class ≥45 to <65 years and 33% of patients ≥65 years [P(χ²) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR+) and 36% (>45 years, dPCR‐). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse. Am. J. Hematol. 90:910–914, 2015. © 2015 Wiley Periodicals, Inc.     

Management of chronic myeloid leukemia presenting with isolated thrombocytosis and complex Philadelphia chromosome: A case report

Rationale:Chronic myelogenous leukemia (CML) with thrombocytosis and complex chromosomal translocation is extremely rare in clinical setting. Here, we reported the clinical and pathological characteristics of CML patients, which were characterized by thrombocytosis and complex Philadelphia chromosome translocation. Moreover, we also introduced our therapeutic schedule for this patient as well as review relative literature.Patient concerns:A 24-year-old female presented with night sweating, fatigue, and intermittent fever for 1 month.Diagnosis:Fluorescence in situ hybridization results revealed that breakpoint cluster region (BCR)-Abelson (ABL) gene fusion in 62% of the cells and karyotyping showed a complex 3-way 46, XY, t(9;22;11) (q34;q11;q13) [19/20] translocation. This patient was diagnosed with CML complicated with thrombocytosis and complex Philadelphia chromosome translocation.Interventions:The patients received continuously oral imatinib mesylate tablets (400 mg) once a day.Outcomes:After treatment with imatinib for 3 months, the BCR/ABL^IS was less than 0.1% and achieved major molecular response. Moreover, the BCR/ABL^IS of this patient achieved major molecular response. The BCR/ABL^IS values at 6 months and 12 months were less than 0.01% and 0.0032%, respectively. And no BCR/ABL fusion was detected in the next 2 years follow-up period.Lessons:Imatinib might represent a preferred therapeutic option for CML patients with rare thrombocytosis and complex chromosomal translocation. In addition, BCR/ABL fusion gene examination in patients with thrombocytosis might represent an effective strategy to avoid the misdiagnosis of this specific CML population.     

Phase IV study evaluating efficacy of escalated dose of imatinib in chronic myeloid leukemia patients showing suboptimal response to standard dose imatinib

The aim of this phase IV study was to (1) to define efficacy of escalating dose imatinib in chronic myeloid leukemia (CML) patients showing suboptimal response to standard dose imatinib and (2) to find markers that predict the response to escalating doses of imatinib. CML patients in chronic phase (CP) who failed to achieve optimal response with 400 mg/day imatinib or patients in accelerated phase (AP) or blast crisis (BC) who failed to achieve complete hematologic response after 3 months of 400–600 mg/day imatinib were enrolled. CP patients received 600 mg/day, while AP/BC patients received 600–800 mg/day imatinib. Patients received imatinib for at least 12 months or until the disease progression or intolerable toxicity. Along with cytogenetic response (CyR), molecular response was assessed with BCR-ABL/ABL ratio. Baseline BCR-ABL gene mutation test was performed. Seventy-one patients (median age, 49.0 years, M:F?=?50:21) received escalated dose imatinib. Grade 3 edema in two patients was the only nonhematologic toxicities more than grade 2. For evaluable patients, 30.8% of patients achieved CCyR at 6 months, and median time to treatment failure (TTFx) was 18.0 months. TTFx was longer in patients who achieved greater than 50% reduction in BCR-ABL/ABL within 6 months (early molecular responder (EMR)) compared with those who did not (non-EMR; p?<?0.001). Of 31 patients who had mutational status data, three had mutation. All mutants failed to achieve CCyR. In conclusion, escalated dose imatinib shows considerable efficacy with tolerable toxicity in CML patients showing suboptimal response to standard dose imatinib. EMR is an early predictive marker for positive imatinib response.     

EUTOS CML prognostic scoring system predicts ELN-based ‘event-free survival’ better than Euro/Hasford and Sokal systems in CML patients receiving front-line imatinib mesylate

Abstract

Objectives

The validity of the three currently used chronic myeloid leukemia (CML) scoring systems (Sokal CML prognostic scoring system, Euro/Hasford CML scoring system, and the EUTOS CML prognostic scoring system) were compared in the CML patients receiving frontline imatinib mesylate.

Patients and methods

One hundred and fourty-three chronic phase CML patients (71 males, 72 females) taking imatinib as frontline treatment were included in the study. The median age was 44 (16–82) years. Median total and on-imatinib follow-up durations were 29 (3.8–130) months and 25 (3–125) months, respectively.

Results

The complete hematological response (CHR) rate at 3 months was 95%. The best cumulative complete cytogenetic response (CCyR) rate at 24 months was 79.6%. Euro/Hasford scoring system was well-correlated with both Sokal and EUTOS scores (r = 0.6, P < 0.001 and r = 0.455, P < 0.001). However, there was only a weak correlation between Sokal and EUTOS scores (r = 0.2, P = 0.03). The 5-year median estimated event-free survival for low and high EUTOS risk patients were 62.6 (25.7–99.5) and 15.3 (7.4–23.2) months, respectively (P < 0.001). This performance was better than Sokal (P = 0.3) and Euro/Hasford (P = 0.04) scoring systems. Overall survival and CCyR rates were also better predicted by the EUTOS score.

Discussion

EUTOS CML prognostic scoring system, which is the only prognostic system developed during the imatinib era, predicts European LeukemiaNet (ELN)-based event-free survival better than Euro/Hasford and Sokal systems in CML patients receiving frontline imatinib mesylate. This observation might have important clinical implications.     

Chronic myelogenous leukemia: molecular and cellular aspects

Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and other hematopoetic cell lineages are involved in the process of clonal proliferation and differentiation. After a period of 4–6 years the disease progresses to acute-stage leukemia. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. Most of ABL is linked with a truncated BCR. The BCR/ABL fusion gene codes for an 8-kb mRNA and a novel 210-kDa protein which has higher and aberrant tyrosine kinase activity than the normal c-ABL-coded counterpart. Phosphorylation of a number of substrates such as GAP, GRB-2, SHC, FES, CRKL, and paxillin is considered a decisive step in transformation. An etiological connection between BCR/ABL and leukemia is indicated by the observation that transgenic mice bearing a BCR/ABL DNA construct develop leukemia of B, T, and myeloid cell origin. CML cells proliferate and expand in an almost unlimited manner. Adhesion defects in bone marrow stromal cells have been proposed to explain the increased number of leukemic cells in the peripheral blood. However, findings of our laboratory have shown that the BCR/ABL chimeric protein that is expressed in transfected cells may, under certain conditions, also increase the adhesion to fibronectin via enhanced expression of integrin. Our previous immunocytological studies on the expression of β1 and β2 integrins have found no qualitative differences between normal and CML hematopoietic cells in vitro. Even long-term-cultured CML bone marrow or blood cells continuously express those adhesion molecules that are characteristic of the cytological type. Recent experiments indicate that certain early CML progenitors may adhere to the stromal layer in vitro similarly to their normal counterparts. They cannot be completely removed by long-term culture on allogeneic stromal cells. At present, the only curative therapy is transplantation of allogeneic hematopoietic stem cells. Based on the molecular and cellular state of knowledge of CML, new therapies are being developed. BCR/ABL antisense oligonucleotides, inhibitors of tyrosine kinase, peptide-specific adoptive immunotherapy or peptide vaccination, and restoration of hematopoiesis by autologous stem cell transplantation following CML cell purging are examples of important approaches to improving CML treatment. Received: 22 June 1998 / Accepted: 28 August 1998     

Long‐term results of high‐dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long‐term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long‐term results of high‐dose IM (340 mg/m²/d) in CML patients in chronic phase (CP‐CML) aged <18 years at diagnosis. A total of 47 CP‐CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91·5% of the evaluable patients at a median time of 6 months. BCR‐ABL1 International Scale ≤ 0·1% (major molecular response; MMR) and ≤0·01% (molecular response; MR) at 12 months were 66·6% and 33%, respectively. During follow‐up, MMR and MR were achieved in 78·6% and 61% of children, respectively. IM was safely discontinued in 3 long‐term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression‐free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow‐up of 52 months (range 3–146), all patients are alive . High‐dose IM is a long‐term effective therapy in children and adolescents with CP‐CML.     

Phase II trial of HyperCVAD and Dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia

Dasatinib is a second generation tyrosine kinase inhibitor, with activity in imatinib resistant Ph‐positive ALL. We have treated 34 patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) (n = 19) or lymphoid blast phase of chronic myelogenous leukemia (CML‐LB) (n = 15) with the combination of dasatinib and the hyperCVAD regimen. Prior regimens included hyperCVAD plus imatinib (n = 11, 4 had transplant in first CR), other combination chemotherapy (n = 12), monotherapy with kinase inhibitors other than dasatinib (n = 9), and investigational agents (n = 2). Pretreatment ABL mutations were noted in 10 patients. The overall response rate was 91%, with 24 patients (71%) achieving complete response (CR), and 7(21%) CR with incomplete platelet recovery (CRp). Two patients died during induction and one had progressive disease. Twenty‐six patients (84%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 patients (42%) achieved complete molecular response, and 11 patients (35%) had major molecular response (BCR‐ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation. Grades 3 and 4 toxicities included hemorrhage, pleural and pericardial effusions and infections. The median follow‐up for patients with CML‐LB is 37.5 months (range, 7–70 months) with a 3‐year overall survival of 70%; 68% remained in CR at 3 years. For ALL patients, the median follow‐up is 52 months (range, 45–59 months) with a 3‐year survival of 26%; 30% remain in CR at 3 years. The combination of HyperCVAD regimen with dasatinib is effective in patients with relapsed Ph‐positive ALL and CML‐LB. Am. J. Hematol. 89:282–287, 2014. © 2013 Wiley Periodicals, Inc.