Significant Discrepancy In Peripheral Blood Compared to Bone Marrow BCR-ABL Transcript Levels In Chronic Phase Chronic Myeloid Leukemia (CML)

Abstract Abstract 4471 Chronic myeloid leukemia (CML) is associated with the reciprocal t(9;22)(q34;q11) translocation, which generates the BCR-ABL fusion oncogene and is the most common myeloproliferative disease affecting adults. The clinical outcome in this disease has been revolutionized with the use of imatinib mesylate (Gleevec), a targeted tyrosine kinase inhibitor, and molecular surveillance, with the development of quantitative PCR (qPCR) approaches to measure BCR-ABL transcript levels. A number of guidelines outlining follow-up strategies for patients with chronic phase CML on imatinib therapy have been established. Once a patient is stable, a typical recommendation includes peripheral blood (PB) monitoring by qPCR of BCR-ABL levels every 3–6 months to determine response or relapse, with consideration of annual bone marrow (BM) examinations to assess for cytogenetic evolution. At the Queen Elizabeth II Health Sciences Centre and IWK Health Centre in Halifax, Nova Scotia, 34 patients with chronic phase CML on imatinib were identified from 2006 to 2008, with 36 paired samples, where transcript levels were assessed in both PB and BM within one week of each other. In 24 of the cases, the BCR-ABL transcript levels in PB and BM were within 0.5 log values of each other. In the remaining 12 cases, BCR-ABL transcript levels differed by greater than 0.5 log. Three cases had higher BM levels, but surprisingly, 9 patients had a higher BCR-ABL transcript level in the PB. In all cases, BCR-ABL levels were assessed by Q-RT-PCR using the ABI7500 instrument and primers and probe designed to detect p210 and p190 breakpoints. Results were recorded as a ratio of %BCR-ABL to GAPDH that was amplified as an internal control. There was no significant difference in clinical, morphological or laboratory parameters between these patients and others who had comparable PB and BM BCR-ABL levels. These findings highlight the need to compare BCR-ABL transcript levels derived from the same tissue during longitudinal monitoring. Moreover, while potentially due to stochastic factors, the striking observation of higher PB BCR-ABL transcript levels raises the question of which tissue represents the most accurate source for monitoring of BCR-ABL transcript levels and whether there is value in confirming a significant change in PB transcript level with BM evaluation. The discrepant levels in PB and BM could not be attributed to technical issues; the timing of sample processing from collection and quality of mRNA were comparable and no variability was observed in GAPDH levels to account for the difference. Without a technical explanation, the mechanism underlying this phenomenon remains uncertain. We speculate that it may reflect CML stem cell geography with one possibility being that the CML niche may be located external to the BM. Further studies are needed to confirm these observations. If corroborated, then revision of surveillance approaches for chronic phase patients may be indicated. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽

10.1182/blood.v122.21.4041.4041 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4041-4041

Author(s):

Cintia Do Couto Mascarenhas ◽

Maria Helena Almeida ◽

Eliana C M Miranda ◽

Bruna Virgilio ◽

Marcia Torresan Delamain ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Taqman Probe ◽

Molecular Response ◽

Imatinib Treatment ◽

First Line ◽

Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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.

Download Full-text

The Predictive Value of Early Molecular Response in Chronic Phase CML Patients Treated with Dasatinib First Line Therapy

Blood ◽

10.1182/blood.v118.21.785.785 ◽

2011 ◽

Vol 118 (21) ◽

pp. 785-785 ◽

Cited By ~ 2

Author(s):

David Marin ◽

Corinne Hedgley ◽

Richard E Clark ◽

Jane F Apperley ◽

Letizia Foroni ◽

...

Keyword(s):

Peripheral Blood ◽

Predictive Value ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Transcript Level ◽

Molecular Response ◽

Costal Margin ◽

Molecular Responses ◽

Transcript Levels ◽

International Scale

Abstract Abstract 785 We assessed the correlation between molecular response at 3 and 6 months of dasatinib 100mg daily treatment and subsequent cytogenetic and molecular responses in 150 newly-diagnosed chronic phase CML patients treated with front line dasatinib in the UK SPIRIT 2 study (imatinib vs dasatinib). The median age was 54 years (range 18.4–82.1); 90 patients were male. The Sokal risk distribution was: 39 low, 65 intermediate and 46 high. At diagnosis 26 patients had splenomegaly >10cm below the costal margin; median WBC and platelet count were 65.7 (2.2-428) and 404 (101-2,433). The median hemoglobin level was 11.0 g/dl (4.17-15.8). The median percentage of blasts and basophils in peripheral blood was 0.4% (0-13.5) and 3.6% (0-19.2) respectively. The dose of dasatinib was adjusted according to tolerance. BCR-ABL1 transcripts in the peripheral blood were analyzed at 12 week intervals using RQ-PCR. Results were expressed as percentage ratios relative to an ABL1 internal control and expressed on the international scale. Complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts (RQ-PCR negative) and ABL1 control >40,000 (the median ABL1 control in the CMR samples was 96,000). In addition, we also explored a less stringent definition of CMR, namely CMR4.5 which was recently defined by the EUTOS group as BCR-ABL1 ratio of 0.0032 on the international scale, consistent with a 4.5 log reduction in the transcript level, without necessarily being RQ-PCR negative. With a median follow up of 15 months (range 6–29) the 2 year cumulative incidences (CI) of CCyR, MMR, CMR4.5 and CMR were 84.5, 72.1, 24.1 and 5.6% respectively. The median BCR-ABL/ABL ratios at 3, 6, 12 and 24 months were 0.830%, 0.093%, 0.040% and 0.034% respectively. We investigated the predictive value of the BCR-ABL1 transcript levels at 3 (>10% vs ≤10% and >1% vs ≤1%) and 6 months (>1% vs ≤1%) of dasatinib therapy on the 2 years CI of cytogenetic and molecular responses. The 135 patients who at 3 months had a BCR-ABL1/ABL1 ratio ≤10% and the 81 patients who had a ratio ≤1% had a significantly better 2 year CI of CCyR (89.1% vs 50.2%, p=0.02 and 100% vs 84.7%, p=0.01), MMR (83.7% vs 14.2%, p=0.004 and 85.2% vs 54.3 p<0.001), CMR4.5 (25.0% vs 0%, p<0.18 and 37.6 v 3.3% p=0.001) but not CMR (6.7 vs 0%, p=0.51 and 7.1 vs 0% p=0.46). Similarly, the 109 patients who at 6 months had a transcript ratio ≤1% had a better 2 year CI of MMR (86.3 vs 13.9%, p<0.001), CMR4.5 (31.2 vs 0%, p=0.03) and CMR (14.3 vs 0%, p=0.04) than the remaining patients. We used a receiver operating characteristic (ROC) curve to identify the optimal cut-off in the transcript level at 3 and 6 months that would predict the probability of each outcome with maximal sensitivity and specificity. Table 1 shows the results of applying the optimal cutoffs for each outcome in the 3-month analysis. Then we investigated whether the various outcomes could be better predicted using the cut-offs defined at 3 or at 6 months (including both the 1 and 10% cut-offs and the newly identified cut-offs) by using a multivariate model. For each outcome the cut-off defined at 3 months shown in Table 1 was superior. No pre-therapy patient characteristics were an independent predictor for cytogenetic or molecular response.Table 1.CI of the various responses according to cut-offs identified in the ROC analysis.3 month BCR-ABL1/ABL1 ratio (%)n2 year CI (%)pCCyR10493.3p<0.001≤2.724675.9>2.72MMR7987.6p<0.001≤0.967152.7≥0.96CMR4.55649.7p<0.001≤0.378947.1>0.387CMR4220.1p=0.01≤0.241080>0.24 The key finding from this analysis is that patients who achieve a transcript level ≤10% after 3 months of dasatinib (135 of 150) have an 89.1% probability of eventually achieving CCyR, compared to 50.2% for patients with higher transcript levels (p=0.02). This preliminary observation may allow the identification of around 10% of dasatinib-treated patients for whom other forms of treatment might be considered although our conclusions require verification in further studies. The predictive power of RQ-PCR assessment can be greatly improved by identifying the optimal cut-offs for the specific outcomes, which is particularly important when predicting for the achievement of CMR. It remains uncertain whether these differences in response will translate into differences in survival and the SPIRIT 2 study continues to address this question. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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.

Download Full-text

Clinical Relevance of Failure to Achieve Early Molecular Response in Chronic Myeloid Leukemia in Chronic Phase

Blood ◽

10.1182/blood.v126.23.5160.5160 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5160-5160

Author(s):

Ji Yun Lee ◽

Sung Hee Lim ◽

Hae Su Kim ◽

Kwai Han Yoo ◽

Haa-Na Song ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Outcomes ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

Line Treatment ◽

First Line ◽

Transcript Levels ◽

Significant Difference ◽

First Line Treatment

Abstract Purpose The early molecular response (EMR, ≤ 10% BCR-ABL1 at 3 months) of tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML) in chronic phase (CP) has been reported to have strong correlation with long-term outcome. We aim to investigate the prognostic interaction of the EMR and major molecular response (MMR). Methods We retrospectively reviewed data for a total of 165 patients with newly diagnosed CML-CP who received TKIs (imatinib, nilotinib, or dasatinib) as first-line treatment between January 2003 and April 2013. Of the total 128 patients who were regularly monitored by peripheral blood molecular analysis, 85 had a BCR-ABL1 assessment at 3 months and were finally included in the analysis. Results The median age of all patients was 49 years and 87.1% received imatinib as first line treatment. High risk group by Sokal and EUTOS were 29.4% and 14.1%, respectively. Patients with EMR (n = 56, 65.9%) had a tendency to have low risk disease and to be treated with 2nd generation of TKIs. With a median follow-up duration of 53.6 months (range, 5.4-131.3), the 5-year OS, 5-year FFS, and 5-year EFS were 92.5%, 74.8%, and 68.0%, respectively. Median time to achieve MMR was 11.1 months (95%CI, 8.4 - 13.8). The outcomes at 5 year comparing patients whose BCR-ABL1 transcript levels ≤ 10% vs >10% at 3 months were as follows: OS, 92.2% (95% CI 84.9-99.1) vs 92.8% (95% CI 83.7-102.3), p = 0.819; FFS, 84.7% (95% CI, 75.6-94.4) vs 57.4% (95% CI, 39.0-75.0), p < 0.001; and EFS, 73.6% (95% CI 62.5-85.5) vs 57.8% (95% CI 40.0-76.0), p = 0.050. Six (10.7%) of 56 patients with BCR-ABL1 transcript levels ≤ 10% at 3 months failed to achieved an MMR and 18 (62.1%) of 29 patients with > 10% at 3 months achieved an MMR. Based on these heterogeneous clinical outcomes, we further explored subgroup analysis according to the achievement of MMR for refined discrimination of survival outcomes. There was no significant difference of clinical outcomes between ≤ 10% vs > 10% at 3 months among the patients who achieved MMR (OS, p = 0.376; FFS, p = 0.793; and EFS, p = 0.266). In patients who did not achieved MMR, only FFS was significantly difference between ≤ 10% vs > 10% at 3 months (OS, p = 0.489; FFS, p = 0.014; and EFS, p = 0.199). Conclusion Patients who failed to achieve EMR but finally reached MMR have excellent prognosis that whether we have to change TKI for EMR failure is to be addressed by ongoing prospective clinical trials. Disclosures Jang: Alexion Pharmaceuticals: Research Funding.

Download Full-text

Prediction of Response to Imatinib by Prospective Quantitation of BCR-ABL Transcript in Late Chronic Phase Chronic Myeloid Leukemia PatientsBy GIMEMA Working Party on CML.

Blood ◽

10.1182/blood.v104.11.4672.4672 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4672-4672

Author(s):

Giovanni Martinelli ◽

Gianantonio Rosti ◽

Fabrizio Pane ◽

Marilina Amabile ◽

Simona Bassi ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Working Party ◽

Progression Free Survival ◽

Prediction Of Response ◽

Free Survival ◽

Blood Samples

Abstract Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Early prediction of response to imatinib cannot be anticipated. We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for bcr-abl transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day. Bone marrow samples were collected before treatment, after 3, 6 and 12 months or at the end of study treatment (12 months) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy. The amount of Bcr-Abl transcript was expressed as the ratio of Bcr-Abl to β2-microglobulin (β2M). We show that, following initiation of imatinib, the early Bcr-Abl level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome after 6 and 12 months of treatment, and that these early trends were also predictive of progression-free survival.

Download Full-text

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.

Download Full-text

Pediatric Chronic Myeloid Leukemia with Megakaryocytic Blast Crisis as Initial Presentation: Case Report and Review of Literature

National Journal of Health Sciences ◽

10.21089/njhs.54.0171 ◽

2021 ◽

Vol 5 (4) ◽

pp. 171-174

Author(s):

Tuba Iqbal ◽

◽

Amber Younus ◽

Uzma Zaidi ◽

Jawad Hassan ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

De Novo ◽

Pediatric Population ◽

Blast Crisis ◽

Chronic Phase ◽

Transcript Level ◽

Young Female

Abstract: Background: Pediatric Chronic Myeloid Leukemia (CML) is a rare entity accounting for 2-3% of pediatric malignancies. CML rarely presents as Blast Crisis (BC) at the time of diagnosis, and megakaryocytic blast crisis is even rarer. Case Presentation: We herein, report a case of a young female, 10-year-old who presented with anemia, leukocytosis and massive splenomegaly. Clinical features, peripheral film and bone marrow findings were consistent with CML in megakaryocytic blast crisis. Bone marrow cytogenetic analysis revealed karyotype of 46, XX, t(9:22)(q34;q11.2) in 20 metaphases and BCR-ABL P210 by PCR was detected with transcript level of 83%, which further confirmed our diagnosis. Conclusion: De novo presentation of chronic myeloid leukemia with megakaryocytic blast crisis is rarely observed in pediatric population with very few cases published till now. We are presenting this case because of its rarity, likelihood of misdiagnosis as AML (M7) and poor prognosis, if not treated precisely. Keywords: Chronic Myeloid Leukemia (CML), Acute Myeloid Leukemia (AML), Blast Crisis (BC), Acute Megakaryocytic Leukemia (AMKL), Chronic Phase (CP), Accelerated Phase (AP), Tyrosine Kinase Inhibitor (TKI).

Download Full-text

Hypercvad Plus Imatinib or Dasatinib for Patients with Lymphoid Blastic Phase of Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.3766.3766 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3766-3766

Author(s):

Paolo Strati ◽

Hagop M. Kantarjian ◽

Deborah A. Thomas ◽

Susan M. O'Brien ◽

Elias J. Jabbour ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Agent ◽

Chronic Phase ◽

Transcript Levels ◽

Advanced Phase ◽

Blastic Phase ◽

Starting Dose

Abstract Abstract 3766 Background: Chronic Myeloid Leukemia (CML) may progress at advanced phase at the rate of 1–1.5% per year. Blastic phase (BP) CML (defined by a bone marrow blast count >30%) can show lymphoid features in up to 20–30% of cases. With the use of single agent imatinib or dasatinib, median overall survival (OS) ranges between 7 and 11 months. Combination therapy may offer an improved outcome. We analyzed the outcome of patients (pts) with lymphoid BP-CML treated with hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone (HCVAD) plus imatinib or dasatinib. Methods: 32 pts with lymphoid BP-CML were treated at MD Anderson with HCVAD plus imatinib or dasatinib between 2000 and 2011. The starting dose of imatinib was 400 mg (2 pts), 600 mg (20 pts) and 800 mg (1 pt). The starting dose of dasatinib was 50 mg (1 pt), 100 mg (7 pts) and 140 mg (1 pt). Survival curves were calculated using Kaplan-Meier estimates and were compared using the log-rank test. Results: the median age was 48 (22–74) and 72% were male. Four (12%) pts had a de novo diagnosis, 21 (66%) were previously treated with a tyrosine kinase inhibitor (TKI) for chronic phase (CP) and 3 (9%) for BP. At diagnosis, median WBC was 23.4 (1.1–165.4) x109/L, hemoglobin 10.6 (6.3–16.4) g/dL, platelets 51 (6–526) x109/L, blasts 33 (0–91)%, basophils 0 (0–2)%, creatinine 1 (0.6–1.5) mg/dL, albumin 3.8 (2–4.7) g/dL, bilirubin 0.5 (0.2–3.4) mg/dL, alanine aminotransferase 34 (12–446) IU/L; on bone marrow, median blasts were 78 (26–97)%, basophils 0 (0–4)% and additional chromosomal aberrations (ACA) were found in 15/24 (62%) pts, affecting mostly chromosome (chr) 7 (60%), chr9 (40%), chr8 (33%) and chr1 (27%). Before BP diagnosis, median Philadelphia (Ph) positivity by FISH was 67% (0–96); 6/14 (43%) pts showed a Ph mutation (Y253H, T315I, Q252H, F317L, E255K, M244V) at time of progression to BP. Median time from CML diagnosis to BP was 18 (2–33) months, with no significant differences according to previous Ph FISH positivity or CML therapies. Imatinib was added to HCVAD in 23 pts and Dasatinib in 9. Complete Remission (CR) was obtained in 27 (84%) of them (78% with imatinib, 100% with dasatinib). Twenty-three of 27 (87%) CR were achieved after 1stcycle of induction. Early mortality (i.e., within 60 days) occurred in 3 pts. Patients received a median of 4 (1–8) cycles of HCVAD. At the time of CR, median BCR-ABL transcript levels were 1.7 (0–100). The levels decreased to a median of 0.01 (0–100) after 3–4 cycles of therapy; 7/27 (26%) pts achieved negative values of BCR-ABL transcripts after a median of 2 (1–4) months. Three (43%) of 7 pts who achieved complete molecular remission relapsed. MRD by flow cytometry became negative in 15/17 (88%) pts: 14 after induction, 1 after 2 months. Six (40%) of the pts with negative flow cytometry for MRD relapsed. Thirteen pts received SCT in remission: 4 relapsed and died after SCT. Median Progression Free Survival (PFS) was not reached and was longer among SCT recipients (p=0.03) and patients who had a negative flow cytometry at the time of CR (p<0.001). OS was 17 (7–27) months and was longer in patients with no more than 1 line of treatment for CP of CML, with ACA (p=0.01) and among SCT recipients (p<0.001). Among patients who had a CR, OS was longer if flow cytometry was negative at the time of CR (p=0.02) and if BCR-ABL transcript levels were < 1.7% (p=0.01) at the time of CR or <0.025% as best result (p=0.03). Conclusions: HCVAD plus imatinib or dasatinib is an effective regimen for pts with lymphoid BP CML, particularly when followed by SCT. ACA and less than 1 treatment for CML are positive prognostic factors. Better results are observed if negative flow cytometry and low levels of BCR-ABL transcripts are achieved with therapy. Disclosures: Ravandi: BMS: Honoraria, Research Funding.

Download Full-text

Outcome of transplantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia

Blood ◽

10.1182/blood-2002-05-1615 ◽

2003 ◽

Vol 101 (2) ◽

pp. 446-453 ◽

Cited By ~ 55

Author(s):

Ahmet H. Elmaagacli ◽

Rudolf Peceny ◽

Nina Steckel ◽

Rudolf Trenschel ◽

Hellmut Ottinger ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Peripheral Blood Stem Cells ◽

Peripheral Blood Cd34 ◽

Cd34 Cells ◽

Blood Stem Cells

Outcomes of highly purified CD34+ peripheral blood stem cell transplantation (PBSCT) for chronic phase chronic myeloid leukemia (CML) (n = 32) were compared with those of PBSCT (n = 19) and of bone marrow transplantation (BMT) (n = 22) in the HLA-compatible sibling donor setting. Median follow-up was 18 months after CD34+-PBSCT and unmanipulated PBSCT and 20 months after BMT. CD34+-PBSCT was associated with delayed T-cell immune reconstitution at 3 months and 12 months after transplantation compared with PBSCT (P < .001) or BMT (not significant [NS]). The estimated probability of grades II to IV acute graft-versus-host disease (GVHD) was 60% ± 13% for the PBSCT group, 37% ± 13% for the BMT group, and only 14% ± 8% for the CD34+-PBSCT group (CD34-PBSCT versus BMT,P < .01; and CD34-PBSCT versus PBSCT,P < .001). The probabilities for molecular relapse were 88% for CD34+-PBSCT, 55% after BMT, and 37% after PBSCT (CD34+-PBSCT versus PBSCT,P < .03). Cytogenetic relapse probability was 58% after CD34+-PBSCT, 42% after BMT, and 28% after PBSCT (NS). After CD34+-PBSCT, 26 of 32 patients received a T-cell add-back. Hematologic relapse occurred in 4 of 22 patients after BMT, in 3 of 19 patients after PBSCT, and in only 1 of 32 patients after CD34+-PBSCT. The occurrence of a hematologic relapse in patients receiving CD34+-PBSC transplants was prevented by donor leukocyte infusions, which were applied at a median of 4 times (range, 1-7 times) with a median T-cell dose of 3.3 × 106 × kg/body weight [at a median] beginning at day 120 (range, 60-690 days). The estimated probability of 3-year survival after transplantation was 90% in the CD34+-PBSCT group, 68% in the PBSCT group, and 63% in the BMT group (CD34-PBSCT versus BMT, P < .01; and CD34-PBSCT versus PBSCT, P < .03). Transplantation of CD34+-PBSCs with T-cell add-back for patients with CML in first chronic phase seems to be safe and is an encouraging alternative transplant procedure to BMT or PBSCT.

Download Full-text