Adoptive Donor T-Cell Infusions Are Necessary and Efficient To Induce Lasting Molecular Remissions after Highly Purified CD34+ Sibling Donor Transplants for First Chronic Phase Chronic Myeloid Leukemia - Final Report and Long-Term Follow-Up of a Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3017-3017
Author(s):  
Ahmet Elmaagacli ◽  
Rudolf Peceny ◽  
Michael Koldehoff ◽  
Hellmut Ottinger ◽  
Rudolf Trenschel ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Secondary Malignancy ◽  
Molecular Remission ◽  
Transcript Levels ◽  
Peripheral Blood Cd34

Abstract Since September 1998, we prospectively studied the feasibility of transplantation using purified peripheral blood CD34+ cells from HLA-identical sibling donors in first chronic phase chronic myeloid leukemia (CML). A total of 60 patients (pts) with a median pretransplant risk score of 2 (range 1–4) has been included in this study. One patient received an unmanipulated graft due to poor CD34+ donor cell mobilization, while three pts (5%) were successfully retransplanted with an unmanipulated graft from the primary donor after secondary graft failure (n=2) or from an unrelated donor after hematologic relapse (n=1). As part of the study protocol, all pts were closely monitored for BCR-ABL transcripts using real-time RT-PCR analysis of peripheral blood cells as well as BCR-ABL-interphase FISH and metaphase karyotyping of marrow cells. Of the 60 pts, 56 were eligible for the application of donor lymphocyte infusions (DLI), but 7 pts did not receive DLI due to sustained molecular remission and complete chimerism. Thirty-one pts (52%) received DLI because of increasing BCR-ABL transcript levels or hematologic relapse, and 18 pts (30%) as programmed T-cell add-back. The median starting dose was 0.33 (0.01 – 10) x 106 CD3+ cells per kg with a median maximum dose 3.3 (0.17 – 100) x 106 CD3+ cells per kg. DLI induced a lasting reduction of median BCR-ABL transcript levels (BCR-ABL/GAPDH ratio) of more than 3 log10 and the estimate of being in a complete molecular remission at 7 years is 83% ± 5%. Six pts. (10%) did not respond to DLI, but 4 of these pts. attained a cytogenetic and molecular response by imatinib and/or interferon treatment. The cumulative risk of grades II-IV acute GvHD is 15% ± 5% for all study pts, and the risk of chronic GvHD is 25% ± 6%, respectively. After a median follow-up period of 46 (range 6 – 86) months for all pts, the cumulative 7-year survival estimate is 91% ± 4% (survival rate 92%). Causes of death were disease progression, secondary malignancy, liver failure, septicemia, and systemic capillary leak syndrome in one patient each. In conclusion, the concept of highly purified peripheral blood CD34+ cell transplantation in conjunction with adoptive DLI is associated with a particularly low risk of non-relapse mortality and allows induction of lasting molecular disease control in the majority of first chronic phase CML patients.

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 ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 446-453 ◽  
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.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4471-4471
Author(s):  
Jason N Berman ◽  
Wenda Greer ◽  
Ridas Juskevicius ◽  
Conrad V Fernandez ◽  
Mark Bernstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Health Centre ◽  
Chronic Phase ◽  
Transcript Level ◽  
Transcript Levels ◽  
Significant Difference

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.

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

Blood ◽  
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.

BCR Gene Breakpoint and Type of BCR/ABL-Transcript in Children with Chronic Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4863-4863
Author(s):  
Meinolf Suttorp ◽  
Susanne Viehmann ◽  
Alexander Claviez ◽  
Yvonne Martiniak ◽  
Jochen Harbott
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Pediatric Leukemia ◽  
Total Study Population ◽  
Exon 2 ◽  
Study Population ◽  
The Impact

Abstract The hallmark of chronic myeloid leukemia (CML) is the reciprocal translocation t(9;22)(q34;q11) which creates a hybrid BCR/ABL gene that is transcribed into a chimeric mRNA. In the 8.5-kb mRNA either exon b2 or exon b3 of the major breakpoint cluster region (M-bcr) is coupled to C-ABL exon 2. These two junction variants (b2a2 or b3a2) differ in size by 75 nucleotides and can be selectively amplified by semi-nested PCR. A controversy exists whether or not the type of transcript and/or the breakpoint site exerts an influence on the clinical course of CML in adult patients (Mills KI 1991; Foiretos T 1993; Melo JV 1996). CML is a rare disease in childhood contributing only 2 – 3 % of all pediatric leukemia cases. This may be the reason why there are only scant data from small series of children with CML giving information on the transcript variant present at diagnosis. During an 11 year period (1995 – 2005) 203 pts younger than 19 years (median age: 11.4 yrs; 101 boys, 102 girls) with Philadelphia-chromosome positive CML were treated within the multicenter GPOH-trial “CML-paed”. 85% of the pts were diagnosed in chronic phase (CP). Treatment was performed by hydroxyurea +/− interferon and pts were scheduled for stem cell transplantation (SCT) from an HLA-matched family donor within 6 months after diagnosis and from an unrelated donor within 12 months. Bone marrow and/or peripheral blood specimen for molecular analysis were collected at diagnosis and during follow-up examinations at 3 – 6 months intervals. RT-PCR with analysis of the breakpoint and transcript type was performed in 154 pts (77.4 % of the total study population). 133 pts exhibited a Major-BCR rearrangement, 5 pts a minor-BCR rearrangement and in 16 pts both rearrangements were present. In pts with M-BCR either 55 pts expressed the b2a2 transcript (37 %) or the b3a2 transcript (37 %), respectively. Both types of transcripts were found either simultaneously or alternately during follow-up examinations in 38 pts (25 %). One pt showed an atypical rearrangement which is awaiting further classification. No statistical significant differences (p &gt; 0.05) could be found with respect to hematological parameters at diagnosis (white cell count, platelets count, percentage of basophils in peripheral blood), clinical findings (liver size, spleen size) and disease status (CP versus advanced phase). The impact of either transcript upon the course of the disease (e.g. duration of chronic phase) was not analyzed because 70 % of the study population was transplanted early within 1 year after diagnosis. We conclude that in contrast to some reports in adults the type of BCR breakpoint seems to have no impact in pediatric pts with CML.

The Combination of Interferon-Alpha with Imatinib in Early Chronic Phase Chronic Myeloid Leukemia Patients Induces a Significant Improvement of the Molecular Responses in the First Two Years of Treatment: Results From Three Studies From the GIMEMA CML Working Party.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2192-2192 ◽  
Author(s):  
Francesca Palandri ◽  
Fausto Castagnetti ◽  
Ilaria Iacobucci ◽  
Marilina Amabile ◽  
Gabriele Gugliotta ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Interferon Alpha ◽  
Prospective Studies ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Transcript Levels ◽  
Ifn Alpha ◽  
Number Of Patients

Abstract Abstract 2192 Poster Board II-169 Thanks to its striking effectiveness, imatinib (IM) is the current standard of therapy in chronic myeloid leukemia (CML). However, Interferon-alpha (IFN-alpha) has induced a low but reproducible curative effect in some CML patients, inducing durable remissions lasting even after therapy discontinuation. For this reason, the interest on the possible use of IFN-alpha in the treatment of CML is still substantial, and very recently some newer prospective studies from the French and the German Groups have proposed the re-introduction of IFN-alpha in the front-line treatment of early chronic phase CML (ECP-CML), in association with IM (Rousselot et al, Haematologica 2009;94:abs.1093; Hehlmann et al, Haematologica 2009;94:abs. 0478). We compared the response of 495 ECP-CML patients, enrolled into three different prospective studies promoted by the GIMEMA CML WP (419 treated with imatinib 400mg and 76 treated with imatinib 400mg plus IFN-alpha) (study protocols NCT00511121, NCT00514488 and NCT00511303). Cytogenetic analysis was performed by standard banding techniques and cytogenetic response was rated according to the European LeukemiaNet guidelines. Molecular response was assessed on peripheral blood cells by a standardized quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) method on an ABI PRISM 7700 Sequence Detector (Perkin Elmer, Faster City, CA). BCR-ABL transcript levels were expressed as a percentage according to the IS. Patients were equally distributed by Sokal risk in the two cohorts. Median follow-up was 43 mos (range, 12- 67) in the IM group and 54 mos (range, 11-63) in the IM+IFN-alpha group. Compliance to IM was excellent in both groups, with 90 to 95% of patients receiving IM 400 mg/daily throughout the follow-up. Conversely, the proportion of patients continuing IFN-alpha dropped from 41% at 12 mos to 18% at 18 mos, 13% at 24 mos, 3% at 36 mos; by the end of the fourth year, all patients were off IFN-alpha. The number of patients in CCgR was higher in the IM+IFN-alpha than in the IM group at 6 mos (60% vs 42%, p=0.002) but not from 12 mos on (Table 1). The number of patients in MMolR was higher in the IM+IFN-alpha than in the IM group at 6, 12 and 24 mos, but not later on (Table 2). Also the number of patients with undetectable Bcr-Abl transcript levels was higher in the IM+IFN-alpha group at 12 months (15% vs 5%, p=0.003) but not later on (19% vs 18% at 48 mos). These data support the preliminary analysis of the French SPIRIT group, reporting a higher rate of MMolR after initial treatment with IM and IFN-alpha as compared to IM alone. The loss of the difference from 24 mos on could be explained by the fact that almost all patients had discontinued IFN-alpha during the first two years, pointing out that the low compliance to the combination may limit its utility in practice. ACKNOWLEDGEMENT The Italian Association Against Leukemia-lymphoma and myeloma (BolognAIL), The Fondazione del Monte di Bologna e Ravenna, The Italian Ministery of Education (PRIN 2005, No. 20050 63732_003, and PRIN 2007, No 2007F7 AE7B_002), The University of Bologna, The European Union (European LeukemiaNet). Disclosures: Pane: Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding. Saglio:Celgene: Honoraria; Novartis: Honoraria.

Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 3-year (yr) follow-up (f/u).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6509-6509 ◽  
Author(s):  
Hagop Kantarjian ◽  
Ian W. Flinn ◽  
Stuart Goldberg ◽  
Udomsak Bunworasate ◽  
Maria Aparecida Zanichelli ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Tolerability Profile ◽  
Newly Diagnosed ◽  
Transcript Levels ◽  
Landmark Analysis ◽  
Acceptable Tolerability Profile

6509^ Background: In ENESTnd, nilotinib significantly reduced progression to AP/BC and demonstrated superior rates of MMR, MR4, and MR4.5 vs imatinib with f/u of 2 yrs. Methods: 846 pts with Ph+ CML-CP were randomized to nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283). Here, we report 3-yr f/u data. Results: Both nilotinib doses continued to demonstrate significantly higher rates of MMR, MR4, and MR4.5 vs imatinib. In a landmark analysis, pts with BCR-ABL transcript levels ≤ 10% at 3 months (mo) had a higher probability of achieving MMR by 1 and 2 yrs vs pts with transcript levels > 10%. No new progressions occurred on treatment since the 2-yr analysis; rates of progression to AP/BC including events on treatment (n = 2, 3, 12) and those occurring both on treatment and after discontinuation (n = 9, 6, 19) were significantly lower for nilotinib 300 mg BID and nilotinib 400 mg BID vs imatinib, respectively. At 3 yrs, OS considering only CML-related deaths was significantly higher for nilotinib vs imatinib. The safety profiles of nilotinib and imatinib were similar to those at 2 yrs. Conclusions: 3-yr f/u confirms the superiority of nilotinib vs imatinib and an acceptable tolerability profile for the treatment of pts with newly diagnosed Ph+ CML-CP. [Table: see text]

scholarly journals Efficacy and Tolerability after Unusually Low Doses of Dasatinib in Chronic Myeloid Leukemia Patients Intolerant to Standard-Dose Dasatinib Therapy

2010 ◽  
Vol 4 ◽  
pp. CMO.S6413 ◽  
Author(s):  
Mariana Serpa ◽  
Sabri S. Sanabani ◽  
Israel Bendit ◽  
Fernanda Seguro ◽  
Flávia Xavier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Patient Treatment ◽  
Hematological Toxicity ◽  
Drug Discontinuation ◽  
Once Daily ◽  
Starting Dose

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase ( n 2) and accelerated phase ( n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.

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