scholarly journals Blast and accelerated phase CML: room for improvement

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 122-128
Author(s):  
Joan How ◽  
Vinayak Venkataraman ◽  
Gabriela Soriano Hobbs
Keyword(s):  
Kinase Inhibitors ◽  
De Novo ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Small Population ◽  
Trial Participation ◽  
Management Approach ◽  
Advanced Phase ◽  
Investigational Agents

Abstract Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). With TKI therapy, the percentage of patients who progress to accelerated phase (AP) or blast phase (BP) CML has decreased from more than 20% to 1% to 1.5% per year. Although AP- and BP-CML occur in a minority of patients, outcomes in these patients are significantly worse compared with chronic phase CML, with decreased response rates and duration of response to TKI. Despite this, TKIs have improved outcomes in advanced phase CML, particularly in de novo AP patients, but are often inadequate for lasting remissions. The goal of initial therapy in advanced CML is a return to a chronic phase followed by consideration for bone marrow transplantation. The addition of induction chemotherapy with TKI is often necessary for achievement of a second chronic phase. Given the small population of patients with advanced CML, development of novel treatment strategies and investigational agents is challenging, although clinical trial participation is encouraged in AP and BP patients, whenever possible. We review the overall management approach to advanced CML, including TKI selection, combination therapy, consideration of transplant, and novel agents.

Current Therapies for Chronic Myeloid Leukemia

2008 ◽  
Vol 21 (2) ◽  
pp. 116-125
Author(s):  
Laureen K. Kenealy ◽  
Courtney B. Christenson ◽  
Casey B. Williams
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Management Strategies ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Current Therapies

Management strategies for patients with chronic-phase chronic myeloid leukemia (CML) have changed dramatically since the introduction of imatinib into clinical trials in 1998. Imatinib is generally accepted, at present, to be the most appropriate initial therapy for newly diagnosed chronic-phase CML; however, a proportion of patients will not respond adequately. Many of these patients may benefit from alternative treatment strategies, including second- and third-generation BCR-ABL kinase inhibitors and allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, with continued improvements in molecular monitoring, it is much more clinically routine to measure ongoing treatment efficacy or characterize pending disease relapse via molecular analysis. The challenge is to now combine molecular monitoring information with timely treatment decisions to achieve the best possible outcomes. Additionally, unanswered questions about HSCT remain, and include (1) What is the role of allogeneic HSCT in CML? (2) What type of transplant, reduced-intensity or myeloablative, should be performed? The goal of this article is to provide an overview of where we stand in the treatment of CML in 2008.

Medical Management of CML

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 371-375 ◽  
Author(s):  
Neil P. Shah
Keyword(s):  
Medical Therapy ◽  
Progressive Disease ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Management Strategies ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Abl Kinase ◽  
Advanced Phase ◽  
Selective Kinase Inhibitor

AbstractManagement strategies of patients with chronic-phase chronic myeloid leukemia (CML) have been revolutionized by the BCR-ABL–selective kinase inhibitor imatinib, which is substantially improving median survival. However, a proportion of patients suffer progressive disease on imatinib therapy. Importantly, patients who are particularly at risk for developing progressive disease can be identified with appropriate monitoring of disease burden. Many of these patients may benefit from alternative treatment strategies, including second-generation kinase inhibitors such as dasatinib. As a result of improvements in medical therapy, allogeneic stem cell transplantation is increasingly deferred despite its known curative potential. It is anticipated that outcomes with medical therapy will continue to improve with the availability of effective second- and third-generation kinase inhibitors, and the percentage of patients progressing to the advanced phase of the disease is projected to decline. The future of kinase inhibitor therapy for CML may involve combinations of ABL kinase inhibitors.

Cadherin-13, a Mediator of Calcium-Dependent Cell-Cell Adhesion, Is Silenced by Methylation in Chronic Myeloid Leukemia and Correlates With Pretreatment Risk Profile and Cytogenetic Response to Interferon Alfa

2003 ◽  
Vol 21 (8) ◽  
pp. 1472-1479 ◽  
Author(s):  
Jose Roman-Gomez ◽  
Juan A. Castillejo ◽  
Antonio Jimenez ◽  
Francisco Cervantes ◽  
Concepcion Boque ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Early Stage ◽  
Methylation Status ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Interferon Alfa ◽  
Advanced Phase

Purpose: Cadherin-13 (CDH13) is a newly characterized cadherin molecule responsible for selective cell recognition and adhesion, the expression of which is decreased by methylation in a variety of human cancers, indicating that the CDH13 gene functions as a tumor suppressor gene. Although defective progenitor-stromal adhesion is a well-recognized feature of chronic myeloid leukemia (CML), the role of CDH13 abnormalities has not been evaluated in this disease. Patients and Methods: We examined the methylation status of the CDH13 promoter in 179 chronic phase (CP)-CML patients and in 52 advanced-phase samples and correlated it with mRNA expression using methylation-specific polymerase chain reaction (PCR) and reverse transcriptase PCR. Results: Aberrant de novo methylation of the CDH13 promoter region was observed in 99 (55%) of 179 of CP-CML patients, and 90 of the patients failed to express CDH13 mRNA (P < .0001). Advanced-stage samples (n = 52) showed concordant methylation results with their corresponding CP tumors, indicating that CDH13 methylation was not acquired during the course of the disease. Nevertheless, absence of CDH13 expression was more frequently observed among Sokal high-risk patients (P = .01) and was also independently associated with a shorter median progression-free survival time (P = .03) and poor cytogenetic response to interferon alfa treatment (P = .0001). Conclusion: Our data indicate that the silencing of CDH13 expression by aberrant promoter methylation occurs at an early stage in CML pathogenesis and probably influences the clinical behavior of the disease.

scholarly journals Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2521
Author(s):  
Gabriel Etienne ◽  
Stéphanie Dulucq ◽  
Fréderic Bauduer ◽  
Didier Adiko ◽  
François Lifermann ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
De Novo ◽  
Chronic Phase ◽  
Risk Scores ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
First Line ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

Patients with Chronic Myeloid Leukemia with Variant Philadelphia Chromosome (Ph) Translocations Have a Similar Outcome as Those with Classic Ph When Treated with Imatinib or 2nd Generation TKI

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3228-3228 ◽  
Author(s):  
Nicolas Batty ◽  
Hagop Kantarjian ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Initial Therapy ◽  
P Value ◽  
Limited Information ◽  
2Nd Generation ◽  
Chromosome Variant

Abstract Background: Variant Philadelphia chromosome (Ph) translocations frequently involving 1-2 additional chromosomes besides 9 and 22 and represent 5–10% of patients (pts) with chronic myeloid leukemia (CML). The European LeukemiaNet recommendations provide a warning for patients with variant translocations, although there is limited information about their outcome after therapy with tyrosine kinase inhibitors (TKI). Our prior analysis mostly among pts who had failed prior interferon suggested that these pts had similar outcome to those with classic Ph translocations when treated with imatinib (El-Zimaity et al; Br. J Haematol 2004). Aims: To explore the characteristics and outcome of patients with variant translocations treated with frontline imatinib or 2nd generation TKI (dasatinib or nilotinib) after imatinib failure. Methods: We reviewed the outcome of all pts with CML treated at our institution in 3 groups: early chronic phase (CP) receiving imatinib as initial therapy, and CP treated with 2nd generation TKI after Imatinib failure, accelerated phase (AP) treated with 2nd TKI after imatinib failure. Results of pts with variant Ph were compared to those with classic Ph. Results: Among 554 pts (278 CP frontline imatinib, 190 CP post imatinib failure, 86 AP post Imatinib failure) 33 (6%) had variant Ph (21[8%], 6[3%], 6[7%], in each of the 3 groups, respectively). Median follow up is 55 months (mo) (2 – 90), 24 (1 – 53) mo and 29 (5 – 46) mo, respectively, for the 3 groups. Results are summarized in the following tables: Frontline Imatinib Therapy Percentage Variant Ph Classic Ph P value N=21 N=255 MCyR 95 95 1 CCyR 86 89 0.49 2-yr EFS 83 93 0.93 2-yr TFS 94 96 0.7 2-yr OS 100 99 0.48 Second generation TKI Variant Ph Chromosome Variant Ph Classic Ph P value Chronic Phase N = 6 N = 78 MCyR 100 75 0.34 CCyR 100 72 0.34 2-yr EFS 100 80 0.27 2-yr OS 100 98 0.71 Accelerated Phase N=6 N=80 MCyR 33 38 1 CCyR 33 32 1 2-yr EFS 25 41 0.41 2-yr OS 100 89 0.44 Conclusion: Pts with variant Ph have a similar prognosis to those with classic Ph translocations when treated with imatinib as initial therapy or with 2nd generation TKI after imatinib failure. The warning category for these patients may no longer be needed in the era of TKI.

scholarly journals Outcome of Patients with Myelofibrosis after Ruxolitinib Failure: Role of Disease Status and Treatment Strategies in 214 Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4277-4277 ◽  
Author(s):  
Francesca Palandri ◽  
Elena Maria Elli ◽  
Nicola Polverelli ◽  
Massimiliano Bonifacio ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Disease Status ◽  
Advisory Board ◽  
Advisory Committees ◽  
Transfusion Dependency ◽  
Investigational Agents

Abstract Introduction . Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time. Aims . To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test). Results . After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%). The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%). After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received >2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4). A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7). Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p<0.001), transfusion dependency (p<0.001) and driver mutation status (with triple-negative pts having the worst survival compared to JAK2V617F and CALR-mutated pts, p=0.01). During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p<0.001). In pts who discontinued RUX in chronic phase, the use of second generation TKIs and other investigational agents tended to prolong survival compared to the administration of conventional medical treatments (i.e. HU, danazole, ESA) (Figure 1b, p=0.07) Discussion . After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 164-164 ◽  
Author(s):  
Lorenzo Falchi ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Susan O'Brien ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Molecular Responses ◽  
Free Survival

Abstract Abstract 164 Background: The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives: To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods: Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results: A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was: <MMR in 17% of pts, MMR in 13%, MR4 in 5%, MR4.5 in 19%, UND in 44%. In IM400 pts MR was <MMR in 28% of pts, MMR in 10%, MR4 in 8%, MR4.5 in 14%, UND in 40%. In IM800 pts MR was <MMR in 14% of pts, MMR in 8%, MR4 in 5%, MR4.5 in 19%, UND in 54%. In NILO pts MR was <MMR in 18% of pts, MMR in 20%, MR4 in 7%, MR4.5 in 22%, UND in 33%. In DASA pts MR was <MMR in 18% of pts, MMR in 18%, MR4 in 7%, MR4.5 in 23%, UND in 39%. There was a trend for earlier achievement of MR with NILO: median times to MMR, MR4, MR4.5 and UND were 12, 17.4, 17.9 and 25.1 months, respectively, for IM400 pts; 5.8, 8.7, 11.8 and 23.7 months, respectively, for IM800 pts; 5.7, 7, 8.3 and 16.4 months, respectively, for NILO pts; 5.7, 8.8, 17.4 and 27.2 months, respectively, for DASA pts. To analyze the relationship between the degree of MR and clinical outcome we excluded pts not achieving a CCyR as their best response since the clinical significance of CCyR is well known. For the remaining 438 pts, the depth of molecular remission was inversely correlated with the risk of losing CCyR (19%, 16%, 11%, 7%, 2% in pts with <MMR, MMR, MR4, MR4.5 and UND, respectively) or losing MMR (31%, 42%, 24%, 2%, respectively), as well as the risk of events (22%, 20%, 15%, 12%, 3%, respectively), transformation (3%, 5%, 0%, 1%, 0%, respectively), or death (25%, 11%, 8%, 6%, 4%, respectively). The 6-year OS for pts with <MMR, MMR, MR4, MR4.5 and UND is 74%, 84%, 95%, 96% and 99%, respectively (p<.0001); transformation-free survival (TFS) is 95%, 93%, 100%, 99% and 100%, respectively (p<.014); event-free survival (EFS) is 74%, 74%, 86%, 89% and 99%, respectively (p<.0001). To adjust for the lead-time to achieve deeper responses, we then calculated OS, TFS and EFS rates at 6 years according to the depth of molecular response at 18 or 24 months. Results are summarized in table 1. Conclusion: Most patients treated with TKI as initial therapy for early CP CML achieve a MR during the course of treatment. BCR-ABL transcripts become undetectable in a significant fraction of them. Achieving a MMR or better at 18 months or 24 months is associated with significantly superior 6-years OS, TFS and EFS. These result suggest that deeper molecular responses (MMR and beyond) are associated with clinical benefit, with a particularly good outcome for those achieving undetectable transcript levels. Disclosures: Off Label Use: Imatinib, dasatinib and nilotinib frontline for chronic phase chronic myeloid leukemia on clinical trial. Kantarjian:Bristol-Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Ravandi:Bristol-Myers-Squibb: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Poor Response To Imatinib In Patients With Secondary Chronic Myelogenous Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5170-5170
Author(s):  
Jonathan Thompson ◽  
Kendra L. Sweet ◽  
Ling Zhang ◽  
Jasleen K Randhawa ◽  
Christopher R. Chitambar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cervical Cancer ◽  
Radiation Therapy ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Alkylating Agents ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Sokal Score

Abstract Introduction High dose ionizing radiation and chemotherapy, particularly alkylating agents and topoisomerase II inhibitors, are well known causes of secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Similarly, radiation exposure has been linked to chronic myelogenous leukemia (CML) in large epidemiologic studies of atomic bomb survivors and patients who received high-dose radiation for ankylosing spondylitis and cervical cancer. Patients with secondary AML have poorer survival outcomes compared to de novo AML patients. Little information exists on outcomes of patients with secondary CML. In our study, we investigated treatment responses in patients with secondary CML who have been treated with tyrosine kinase inhibitors (TKIs). Study Design Eight patients who developed CML after receiving chemotherapy, radiation therapy or both were identified between three academic institutions. Retrospective chart review was performed, and information was collected regarding the clinical characteristics and treatment of the patients’ first malignancies. Data about the patients’ CML was also gathered, including time between previous malignancy treatment and diagnosis of CML and type of CML treatment. Finally, hematologic, cytogenetic, and molecular responses to treatment were assessed. Results The mean age of our patients at diagnosis of CML was 58. Three patients were previously diagnosed with breast cancer, two with colorectal cancer, one with peripheral T-cell lymphoma, one with chronic lymphocytic leukemia, and one with Waldenstrom’s macroglobulinemia. One of the patients with colorectal cancer also had a history of cervical cancer, for which she received radiation therapy. Six of eight patients (75%) received radiation therapy prior to onset of CML, and six of eight patients (75%) had previously received chemotherapy, two of whom received alkylating agents. On average, patients developed CML eight years after receiving treatment for the previous malignancy (range 3 to 18 years). All of the patients were diagnosed in chronic-phase CML. Based on the Sokal score, three patients (37.5%) had low risk CML, two (25%) had intermediate risk CML, one (12.5%) had high risk CML, and the Sokal score was unable to be calculated in two (25%) patients due to limited information. Six of the eight patients (75%) received imatinib as initial therapy. Only two of these six patients (33%) achieved a complete cytogenetic response (CCyR). The patient who received up-front nilotinib was the only patient who developed molecularly undetectable leukemia to initial therapy. Seven of the eight patients (87.5%) were alive at a mean four year follow-up. One patient had CML with additional cytogenetic abnormalities at diagnosis and progressed to blast-phase. Discussion This case series is the first study to specifically examine outcomes in secondary CML patients treated with TKIs. The data raise questions regarding the efficacy of imatinib in patients with secondary CML. Only two of the six patients who received imatinib achieved a CCyR. This is a significantly lower response rate than would be expected in de novo CML. This study suggests a role for the newer tyrosine kinase inhibitors as initial therapy in patients with secondary CML. Larger observational studies are needed to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

Efficacy Of Different Therapeutic Approaches In Blastic Phase Of Chronic Myeloid Leukemia: Single Centre Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5173-5173
Author(s):  
Elza Lomaia ◽  
Ekaterina Romanova ◽  
Larisa Girshova ◽  
Yulia Alexeeva ◽  
Eugenia Sbityakova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Therapy ◽  
Advanced Phase ◽  
Blastic Phase

Abstract Dramatic changes in overall survival of patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) have occurred since tyrosine kinase inhibitors (TKIs) were implemented in the treatment strategy. But there are still many issues in therapy of advanced phase disease, especially in blastic phase (BP). Allogeneic stem cell transplantation (alloSCT) is still the only curative option for CML BP, so all efforts should be focused on bringing pts to alloSCT. Thus optimal approach to obtain at least stable hematologic response before alloSCT is needed. Since 2008, 14 pts (4 more pts with isolated extramedullary BP were not included) with CML BP were admitted to our clinic. These were 8 males and 6 females with a median age of 44 years (range; 21-63) at the time of BP. The types of BP were: biphenotypic (n=1), undifferentiated (n=1), myeloid (n=8) and lymphoid (n=4). All pts except 2 (1 with BP and 1 with accelerated phase) were initially diagnosed as CP. Median time from diagnosis to BP was 37 months (range; 0-83). Before BP all pts except 2 were pretreated with imatinib and 6 of them, after failing imatinib, received one or more new TKIs. First line therapy in BP was monotherapy with new TKI (n=5) or chemotherapy (“7+3”, “RACOP”, low doses of Ara-C, “Hyper-CVAD”, “Dexa+VCR”) with or w/o TKI (n=9). Responses are specified in table 1. FLAG regimen was subsequently given to 5 pts as second or more line therapy after failure of previous monoTKI (n=1) or Rx + TKI (n=4). Median time from BP to FLAG was 3,5 months (range; 1,5-21). The best response to FLAG therapy was complete hematologic (n=1), complete cytogenetic with (n=1) or w/o (n=1) major molecular response. There were no responses in 2 cases. All responders maintain their response after median follow up (FU) of 2 months (range; 1,5-5). All patients treated with FLAG are alive (2 after alloSCT, 3 pending alloSCT). Only 1 ptn reached alloSCT w/o any Rx after monoTKI. AlloSCT was successful in 4/5. Median FU time for patients alive after alloSCT is 12 months (range; 3,5-25). For whole group after a median FU of 14 months, 7/14 (50%) pts are alive, including 4 pts after alloSCT. Estimated 3-year overall survival for all pts is 54% (fig. 1). Conclusion All CML BP patients treated with TKIs alone lost their response in a short time. Responses were much more durable in pts treated with Rx +/- TKIs. FLAG regimen was effective even in pts with failure to previous Rx+TKIs. The majority of pts after alloSCT are alive. Chemotherapy, including FLAG with concomitant or subsequent TKIs, had advantage over monoTKI both in overall and progression free survival in CML BP. Disclosures: Lomaia: Novartis: Honoraria, Travel grants Other; Bristol-Myers Squibb: Honoraria, Travel grants, Travel grants Other. Zaritskey:University of Heidelberg: Research Funding.

scholarly journals Clinical Entity and Outcomes of Therapy-Related Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: Surveillance By the Chronic Myeloid Leukemia Cooperative Study Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3084-3084
Author(s):  
Noriyoshi Iriyama ◽  
Tomoiku Takaku ◽  
Eriko Sato ◽  
Maho Ishikawa ◽  
Tomonori Nakazato ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Chronic Phase ◽  
Study Group ◽  
Molecular Response ◽  
Cooperative Study ◽  
Cooperative Study Group

Abstract Background and Aim: Therapy-related chronic myeloid leukemia (TR-CML), which is defined as CML that developed after exposure to cytotoxic chemotherapy and/or radiotherapy, rarely exists in clinical practice, although its incidence rates are relatively lower than those of acute myeloid leukemia or myelodysplastic syndromes, accounting for 1.2-30.4% of secondary leukemias. The clinical behavior of TR-CML, including patient outcome, is reportedly not different from that of de novo CML before the era of imatinib treatment. While the recent advancement of CML treatment by the introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved treatment outcomes in patients with CML, little is known about the treatment response and outcomes in patients with TR-CML treated with TKI. In this regard, we investigated the clinical entity of TR-CML in the era of TKIs, including treatment response to TKI and prognosis, in patients enrolled to the CML Cooperative Study Group. Patients and Methods: We retrospectively reviewed the data of patients enrolled in the CML Cooperative Study to identify patients diagnosed with TR-CML. This study included patients aged >15 years who were diagnosed with CML in the chronic phase between April 2001 and January 2016, and treated with any TKIs as initial therapy and followed up for at least 3 months. The study was approved by the research ethics board of each institution and conducted in accordance with the Declaration of Helsinki. A major molecular response (MMR) was defined as ≤0.1% on the International Scale (IS) or 100 copies of the BCR-ABL1 transcript/μg RNA in a transcription-mediated amplification and hybridization protection assay. A deep molecular response (DMR) was defined ≤0.0032% in the IS. Event-free survival (EFS) was defined as the period from the date of initial treatment with TKI to the date of onset of the first adverse event (loss of treatment efficacy, progression to the accelerated or blastic phase, or any cause of death) or the last follow-up. Statistical analyses were performed by using EZR. Results and Discussion: We identified 308 patients with newly diagnosed CML in the chronic phase, including 11 (3.6%) with TR-CML and 297 with de novo CML. Regarding the primary cancer, 2 of the 11 patients had breast cancer and the remaining 9 had prostate cancer, pharyngeal cancer, mesothelioma, lung cancer, colon cancer, ureter cancer, acute leukemia, gastric cancer, or bladder cancer, respectively. Eight cases were treated with chemotherapy, 2 were treated with radiotherapy, and the remaining case was treated with both chemotherapy and radiotherapy. The results of a cytogenetic analysis by G-banding were exclusive t(9;22)(q34;q11) in all the patients. The median time to diagnosis of CML from the initiation of chemotherapy and/or radiotherapy was 7 years (range, 1.2-33 years). No significant differences in patient age, sex, white blood cell count, hemoglobin level, platelet count, or European Treatment and Outcome Study risk were observed between the TR-CML and de novo CML groups. Among the patients whose cytogenetic and/or molecular responses were assessable, all had excellent treatment response to TKI. Seven patients unexpectedly reached MMR within 6 months after TKI initiation. Finally, 8 patients attained DMR or undetectable leukemia in the bone marrow and the remaining 3 attained MMR. The 5-year EFS of the patients in the de novo CML group was 90%. None of the patients in the TR-CML group experienced any adverse event. In conclusion, in the present study, we revealed that patients with TR-CML could attain a good clinical course with TKI therapy. Detailed investigations of TR-CML may provide new insights into the CML biology. Disclosures Iriyama: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Takaku:Bristol: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Nakazato:Mundipharma KK: Research Funding. Fujita:Chugai Pharmaceutical Co.,LTD: Honoraria. Tokuhira:Bristol Myers Squibb Co., Ltd: Honoraria; Pfizer Co., Ltd: Honoraria; Eizai Co., Ltd: Honoraria. Kawaguchi:Novartis: Honoraria.

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