Prospects for achieving treatment-free remission in chronic myeloid leukaemia

In addition to the best possible overall survival, discontinuation of the tyrosine kinase-inhibitor (TKI) treatment [treatment free remission (TFR)] without observing a recurrence of the disease has become a major goal of the therapy of chronic myelogenous leukemia (CML). Many clinical studies have demonstrated that TFR is possible, although for the moment limited to a fraction of the CML patients able to achieve a stable deep molecular response (DMR). The factors associated to the possibility of remaining in TFR or of losing it, have been investigated by a number of controlled and observation clinical trials and although total TKI treatment duration, DMR duration and stability and, more recently, also the depth of the molecular response obtained at the time of discontinuation have been shown to be significant elements, most of the factors associated with a higher possibility of a successful discontinuation still remain elusive and are here reviewed.     

BCR-ABL inhibitors: Updates in the management of patients with chronic-phase chronic myeloid leukemia

Objectives

This article reviews recent clinical experiences with first-line and second-line second-generation BCR-ABL inhibitors and discusses considerations for selection of therapy for patients with chronic-phase chronic myeloid leukemia.

Methods

We reviewed recent publications on PubMed and abstracts from major congresses relevant to the topic.

Results

Therapeutic options for front-line treatment have increased with the approval of two second-generation BCR-ABL inhibitors, dasatinib and nilotinib. Both agents are also treatment options for patients with resistance or intolerance to front-line imatinib. More recently, bosutinib, ponatinib, and omacetaxine have also been approved for patients with resistance or intolerance to prior therapy.

Discussion

Expanded treatment options coupled with rapidly changing treatment guidelines have led to numerous questions regarding the selection and monitoring of therapy. Common concerns include how to best select therapy based upon patient-specific comorbidities, monitoring and interpretation of treatment outcomes, and optimization of dosing when side effects occur.     

甲磺酸伊马替尼治疗慢性粒细胞白血病附加异常Ph阳性克隆的预后意义

目的探讨甲磺酸伊马替尼（伊马替尼）治疗后慢性粒细胞白血病（CML）具有附加异常的Ph阳性克隆的演变及其预后意义。方法收集37例CML加速期和急变期患者的骨髓标本培养24h,G显带进行核型分析。结果伊马替尼治疗前患者的附加染色体种类主要有双Ph、＋8、i（17q）等,其次还有-Y、除i（17q）外17号的异常、inv（3q）等,以及少见的易位和其他异常。伊马替尼治疗后具有附加异常的Ph阳性克隆比例发生扩增、基本不变、比例下降、完全消失等4种形式的演变。24例加速期患者中有2例获得完全细胞遗传学缓解（CCyR）,13例急变期患者中2例获CCyR。附加异常克隆扩增／不变组的中位生存时间和无疾病进展时间显著短于比例下降／完全消失组（P〈0．05）。结论有附加染色体异常的Ph阳性CML患者伊马替尼治疗后附加异常克隆比例可以下降甚至完全消失,获得CCyR,并伴生存期延长。     

Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia

A 58-yr-old woman was diagnosed with Ph(+) chronic myeloid leukaemia in May 2001. She was initially treated with hydroxyurea and subsequently with interferon-alpha (IFN-alpha). Imatinib mesylate was started in April 2002 after failure of IFN-alpha to induce a cytogenetic response. The patient remained on treatment with imatinib mesylate for 3 months during which she suffered daily fever resulting in discontinuation of the treatment. Response evaluation performed shortly after discontinuing imatinib mesylate revealed a complete cytogenetic remission and a substantial molecular response. Fifteen months later, she was still enjoying a major cytogenetic response. This case illustrates that a short course of imatinib mesylate may result in a sustained haematological and cytogenetic response.     

Complete molecular remission of chronic eosinophilic leukemia complicated by CNS disease after targeted therapy with imatinib

Many cases of hypereosinophilia, formerly classified as hypereosinophilic syndrome, can now be characterized as chronic eosinophilic leukemia (CEL) based on the demonstration of characteristic genetic markers indicating clonality of hematopoiesis. Here we report on a 33-year-old male patient with central nervous system manifestations of CEL and an excellent response to low-dose imatinib (Glivec). Molecular analysis demonstrated a constitutive activation of the platelet-derived growth factor receptor-alpha (PDGFR-A) as the mechanism of responsiveness to imatinib.Abbreviations BM Bone marrow - CEL Chronic eosinophilic leukemia - CML Chronic myeloid leukemia - CNS Central nervous system - HES Hypereosinophilic syndrome - FIP1L1 FIP1-like gene - PB Peripheral blood - PDGFR-A/B Platelet-derived growth factor receptor-alpha/beta     

Clinical course of thrombocytopenia in patients treated with imatinib mesylate for accelerated phase chronic myelogenous leukemia

We studied 28 patients with accelerated phase chronic myelogenous leukemia (CML) who were enrolled on the Novartis expanded access study 114. Diagnosis of accelerated phase CML was based on karyotypic evolution (n = 9) and hematologic criteria (n = 18). All patients were begun on 600 mg/day of imatinib mesylate. Dose reductions to 400 mg/day and then 300 mg/day were prescribed for an absolute neutrophil count (ANC) of <0.5/microl or a platelet count of <20,000/microl. Twenty-seven of the 28 patients continued treatment for a median of 34 weeks. Eleven patients developed thrombocytopenia following an average of 8.4 +/- 1.4 weeks of therapy. The onset of thrombocytopenia was associated with disease progression in one patient and a decline in bone marrow megakaryocytes in the other 10. Nine patients recovered to a platelet count of >20,000/microl after an average of 19.7 +/- 1.8 weeks. Patients who developed thrombocytopenia had a longer duration of disease (9.39 vs. 4.35 years; P < 0.01) and were more likely to be diagnosed with accelerated phase CML by hematologic criteria. Hematologic responses in patients with and without thrombocytopenia were comparable; however, 31.3% of patients without thrombocytopenia had a complete cytogenetic response compared to none of those with thrombocytopenia. Grade III-IV thrombocytopenia is common in accelerated phase CML and may be a marker for the inability to achieve cytogenetic response using single agent imatinib mesylate.     

Molecular and cytogenetic response of chronic myelogenous leukemia treated with imatinib mesylate: one institutional experience in Japan

We retrospectively analyzed the clinical outcome of chronic myelogenous leukemia (CML) patients who received imatinib mesylate (IM) as initial therapy at Tokyo University Hospital. In all patients, molecular response as well as hematological and cytogenetic response was measured routinely. Our cohort showed respectable outcome with complete cytogenetic response (CR) of 82% in 1 year, and 97% in 5 years. The estimated progression free survival of 29 patients who were in chronic phase at diagnosis was 97% and the estimated OS was 92.4% at 5 years. Although IM interruption due to side effects was observed in about half of the cases, the discontinuation was only temporary in all cases. However, patients who showed persistent intolerance with adequate dose of IM (300 mg/day or more) showed poor molecular response.     

CNS blast crisis of chronic myelogenous leukemia in a patient with a major cytogenetic response in bone marrow associated with low levels of imatinib mesylate and its N-desmethylated metabolite in cerebral spinal fluid

Imatinib mesylate (STI571) is a very effective treatment option for Ph⁺ chronic myeloid leukemia (CML) in chronic phase. Secondary treatment failures have mostly been observed in patients with advanced stages of disease. We report the case of a patient who unexpectedly experienced blast crisis of the central nervous system although having achieved complete cytogenetic remission in the bone marrow. The levels of STI571 and its metabolite N-desmethyl STI were 40-fold lower in the cerebral spine fluid than in plasma. The risk of CNS disease has to be kept in mind when patients with CML in chronic phase who are at an increased risk for blastic transformation are treated with imatinib mesylate.     

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.     

t(5;6;12) associated with resistance to imatinib mesylate in chronic myeloid leukemia

A patient with t(9;22)-positive chronic myelogenous leukemia (CML) developed a resistance to therapy with imatinib mesylate (Glivec) which coincided with the appearance of t(5;6;12) in the same cells with t(9;22) [46,XX,t(5;6;12)(q14?;q21?;q23?),t(9;22)(q34;q11)]. She remains in a continuous chronic phase of CML. This is the first reported instance of karyotype evolution temporally associated, and possibly involved, with the induction of resistance to imatinib mesylate but without any signs of evolution of leukemia toward a more anaplastic and aggressive form.     

Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases

Although imatinib mesylate has shown encouraging activity in chronic myelogenous leukemia (CML), disease progression during therapy has been observed, manifested by clonal expansion of imatinib mesylate-resistant leukemia cells. On the other hand, myelosuppression related to treatment of imatinib mesylate is often managed with temporary interruption of treatment or dose reduction. We here report two CML patients who had imatinib mesylate-sensitive blast crisis (BC) immediately after discontinuation of imatinib mesylate therapy. The patients discontinued therapy because of neutropenia. Although there was no evidence of blastic phase during therapy, BC occurred 2 weeks after the withdrawal of treatment in both cases. Interestingly, additional chromosomal abnormalities were detected following the withdrawal of imatinib mesylate and disappeared by re-introduction of this agent. The same doses of imatinib mesylate was still effective and remission was sustained with imatinib mesylate alone again. Our report suggests the possibility that withdrawal of imatinib mesylate may lead to proliferation of blast clones even in patients showing good responses to imatinib mesylate without signs of disease progression.     

Ida-FLAG plus imatinib mesylate-induced molecular remission in a patient with chemoresistant Ph1+ acute myeloid leukemia

Imatinib mesylate is a potent, selective inhibitor of the tyrosine kinase activity of bcr-abl,which is now established as the state-of-the-art treatment for chronic, accelerated or even blastic phase of Philadelphia-positive [Ph(1)(+)] chronic myelogenous leukemia. It is also active in Ph(1)(+) acute lymphoblastic leukemia, but its role in Ph(1)(+) acute myeloid leukemia (AML) is less well investigated. We report here a patient with chemoresistant Ph(1)(+) AML, who responded promptly to one cycle of Ida-FLAG second-line chemotherapy by achieving complete morphologic, immunophenotypic, and cytogenetic remission but not a molecular one. The addition of imatinib mesylate led to a molecular remission, which is sustained for 10 months so far.     

Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study

This international study aimed to assess the effect of imatinib discontinuation in paediatric patients with chronic myeloid leukaemia (CML) after deep molecular remission (DMR) had been achieved and maintained for at least 2 years. The primary endpoint of this analysis was the molecular relapse-free survival, estimated by the non-parametric Kaplan-Meier method. Major endpoint was the estimated rate of patients without molecular relapse at 6 months. Fourteen patients were enrolled; 4 patients maintained DMR with a follow-up of 24 (two patients), 34 and 66 months, respectively, whereas 10 patients relapsed. All molecular relapses occurred within 6 months (median 3 months, range 1–6) after imatinib discontinuation. The overall probability of maintaining DMR at 6 months was 28·6%. No parameters associated with molecular relapse could be identified. Keeping in mind the rarity of paediatric CML, which contributed to the small size of the cohort, our findings illustrate that imatinib cessation after sustained DMR is successful in only limited numbers of patients, whereas much higher rates are reported in adult patients. Further research is needed to extend the cohort of paediatric CML patients who might achieve treatment-free remission with an ideal prerequisite of predicting the occurrence of molecular relapse l after imatinib cessation.     

甲磺酸伊马替尼治疗120例慢性髓性白血病的临床研究

目的观察甲磺酸伊马替尼（IM）治疗Ph染色体阳性和（或）BCR／ABL基因阳性的慢性髓性白血病（CML）的疗效和安全性。方法对90例Ph染色体阳性和（或）BCR／ABL基因阳性CML慢性期（CP）患者,持续口服IM,400mg／d;30例CML疾病进展期（加速期／急变期）患者,持续口服IM,600mg／d。服药期间定期复查血常规、骨髓细胞学、染色体和（或）BCR／ABL基因等指标,并随访观察。结果（1）CML—CP患者总的完全血液学缓解率（CHR）、完全细胞遗传学缓解率（CCyR）和完全分子遗传学疗效（CMR）分别为73．3％（66／90）、66．7％（60／90）、54．4％（49／90）;治疗前是否接受过干扰素治疗对CHR、CCyR和CMR均无明显影响;服药前病程≤6个月的CMR优于〉6个月者。初次达到CHR的时间与首次达CCyR的时间、首次达CCyR的时间与BCR／ABL首次转阴时间之间均存在相关性,而初次达CHR的时间与BCR／ABL首次转阴时间则无明显相关性。（2）进展期CML患者的CHR、CCyR、CMR分别为43．3％（13／30）、25．9％（7／27）、25．0％（7／28）,总病死率为30．0％（9／30）。（3）年龄≤25岁患者的病死率高于〉25岁者,差异有统计学意义（P〈0．05）。（4）白细胞减少达Ⅲ级者有19例（16．0％）,发生于治疗后5～20周。血小板减少达Ⅲ级者有21例（18．0％）,发生于治疗后3～16周。主要的非血液系统毒性为双下肢水肿、骨痛和皮疹等,但均程度轻微。结论IM对初治CML及经干扰素治疗失败的CML有较高的CHR及CCyR且起效迅速,对CML—CP疗效显著优于进展期;不良反应程度轻微,患者易于耐受。