scholarly journals Significance of Increasing Levels of Minimal Residual Disease in Patients With Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Complete Cytogenetic Response

2009 ◽  
Vol 27 (22) ◽  
pp. 3659-3663 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jianqin Shan ◽  
Daniel Jones ◽  
Susan O'Brien ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Therapeutic Interventions ◽  
Molecular Response ◽  
Complete Cytogenetic Response

Purpose The aim of this study was to evaluate the clinical relevance of increases in quantitative polymerase chain reaction (QPCR) levels in patients with chronic myelogenous leukemia (CML) who are in complete cytogenetic response (CGCR) on therapy. Patients with Philadelphia chromosome (Ph)–positive CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by QPCR studies for minimal molecular disease. The clinical significance of increasing levels of QPCR in patients in CGCR is uncertain. Patients and Methods One hundred sixteen patients in durable CGCR, and on imatinib therapy for at least 18 months, had increases in QPCR levels (documented at least twice consecutively) as defined by literature reports. These were further analyzed by the achievement of major molecular response (MMR) defined as QPCR ≤ 0.05%, as well as by the degree of increase in QPCR. Results Only 11 (9.5%) of 116 patients with increases in QPCR had CML progression; 10 of them were among 44 patients (23%) who either lost a MMR or never had a MMR, and had more than 1 log increase of QPCR. Conclusion Most patients with increases in QPCR remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have more than 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions.

Significance of Rising Levels of Minimal Residual Disease in Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+ CML) in Complete Cytogenetic Response (CGCR)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 445-445 ◽  
Author(s):  
Hagop M Kantarjian ◽  
Jianqin Shan ◽  
Dan Jones ◽  
Susan O’Brien ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Disease Status ◽  
Myelogenous Leukemia ◽  
Therapeutic Interventions ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Cell Transplant

Abstract Background . Patients with Ph+ CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by quantitative polymerase chain reaction (QPCR) studies for minimal molecular disease. The clinical significance of rising levels of QPCR in CGCR is uncertain. Study Aims . To evaluate the relevance of increases of QPCR levels in patients with CML in CGCR on therapy. Study Group and Methods . Of 258 patients on imatinib therapy for newly diagnosed CML, 116 patients in durable CGCR on imatinib therapy for at least 18 months had significant QPCR increases (documented at least twice) as defined by literature reports. These were analyzed by the achievement of major molecular response (MMR; QPCR < 0.05%), and by the degree of QPCR increase. Results. The outcome of patients by disease status (still in MMR vs. loss of MMR vs. never in MMR) and by the QPCR level increase are shown in the Table. Only 13 of 116 patients (11%) with significant QPCR increases had CML progression; 11 of them were among 44 patients (25%) who either lost a MMR or never had a MMR, and had > 1 log increase of QPCR. The 5-year survival of all 116 patients was 92%, suggesting the minimal relevance of QPCR increases in patients in CGCR. Conclusion . Most patients with significant QPCR increases remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have > 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions. Allogeneic stem cell transplant should not be considered in view of the excellent survival. Outcome of Patients in CGCR by QPCR Increases Disease Status QPCR Log increase No. Patients CML Progression Median follow-up from QPCR increase in months (range) Persistent MMR Any 28 0 36 (3–62) Loss of MMR >0.5–1 12 0 34 (14–59) >1–2 25 3 31 (6–52) >2 11 4 45 (20–57) Not in MMR <1 32 2 35 (10–70) >1 8 4 25 (12–56)

High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 2873-2878 ◽  
Author(s):  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Complete Cytogenetic Response

Abstract Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC < 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)

Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3435-3435
Author(s):  
J. Valentin García-Gutiérrez ◽  
Pilar Herrera ◽  
Marta Jimenez-Rolando ◽  
María Tenorio ◽  
María Calbacho ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Major Molecular Response

Abstract Abstract 3435 Background: Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims: To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods: We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results: 22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions: In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR. Disclosures: No relevant conflicts of interest to declare.

Dasatinib (BMS-354825) is active in Philadelphia chromosome–positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 497-499 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Claude Nicaise ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Src Kinase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Kinase Activation ◽  
Complete Hematologic Response

Abstract Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl–mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph &lt; 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P &lt; .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2154-2154 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Francoise Huguet ◽  
Gabriel Etienne ◽  
Delphine Réa ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Molecular Remission

Abstract The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.

scholarly journals Detection of MRD may predict the outcome of patients with Philadelphia chromosome–positive ALL treated with tyrosine kinase inhibitors plus chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (7) ◽  
pp. 1214-1221 ◽  
Author(s):  
Farhad Ravandi ◽  
Jeffrey L. Jorgensen ◽  
Deborah A. Thomas ◽  
Susan O’Brien ◽  
Rebecca Garris ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Multiparameter Flow Cytometry ◽  
Molecular Response ◽  
Cell Transplant ◽  
Treatment Intensification ◽  
Philadelphia Chromosome Positive

Abstract From 2001 to 2011, 122 patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia were treated with chemotherapy + imatinib (n = 54) or + dasatinib (n = 68). One hundred fifteen (94%) achieved complete remission (CR) including 101 patients who achieved it with only 1 induction course and had at least 1 minimal residual disease (MRD) assessment; 25 patients underwent an allogeneic stem cell transplant in first CR and were excluded, leaving 76 patients as the subject of this report. MRD monitoring by multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (PCR) was performed at the end of induction and at ∼3-month intervals thereafter. Median age was 54 years (range, 21-84 years). There was no difference in survival by achievement of at least a major molecular response (MMR; BCR-ABL/ABL &lt; 0.1%) at CR (P = .22). Patients achieving MMR at 3, 6, 9, and 12 months had a better survival (P = .02, .04, .05, and .01, respectively). Negative MFC at CR did not predict for improved survival (P = .2). At 3 and 12 months, negative MRD by MFC was associated with improved survival (P = .04 and .001). MRD monitoring by PCR and MFC identifies patients who benefit from treatment intensification in first CR.

scholarly journals European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Blood ◽  
2013 ◽  
Vol 122 (6) ◽  
pp. 872-884 ◽  
Author(s):  
Michele Baccarani ◽  
Michael W. Deininger ◽  
Gianantonio Rosti ◽  
Andreas Hochhaus ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Optimal Response ◽  
Frequent Monitoring ◽  
Leukemia Treatment

Abstract Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

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