Second-generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia in whom imatinib therapy has failed.

BACKGROUND: It has not been clearly established whether second-generation tyrosine kinase inhibitors actually improve the survival of patients with chronic myeloid leukemia in chronic phase who are given nilotinib or dasatinib therapy after treatment failure with imatinib. DESIGN AND METHODS: To address this issue we compared the survival of 104 patients in whom first-line therapy with imatinib failed and who were then treated with second-generation tyrosine kinase inhibitors with the outcome of 246 patients in whom interferon-α therapy failed and who did not receive tyrosine kinase inhibitor therapy. RESULTS: Patients treated with second-generation tyrosine kinase inhibitors had longer overall survival than the interferon controls (adjusted relative risk= 0.28, P=0.0001). However this survival advantage was limited to the 64.4% of patients in whom imatinib failed but who achieved complete cytogenetic response with the subsequent tyrosine kinase inhibitor (adjusted relative risk =0.05, P=0.003), whereas the 35.6% of patients who failed to achieve complete cytogenetic response on the second or third inhibitor had similar overall survival to that of the controls (adjusted relative risk=0.76, P=0.65). CONCLUSIONS: Patients in whom imatinib treatment fails who receive sequential therapy with second-generation tyrosine kinase inhibitors have an enormous advantage in survival over controls (palliative therapy); this advantage is, however, limited to the majority of the patients who achieve a complete cytogenetic response.

Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia.

Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.

Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

BACKGROUND: Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors. DESIGN AND METHODS: We analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors. RESULTS: The system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response. CONCLUSIONS: Factors measurable before starting treatment can accurately predict response to second-generation tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.

Survival of patients with chronic-phase chronic myeloid leukaemia on imatinib after failure on interferon alfa.

Until the recent introduction of imatinib, interferon alfa was the standard treatment for patients in the chronic phase of chronic myeloid leukaemia. We compared survival of 143 such patients, who did not respond to interferon alfa and were treated with imatinib, with that of 246 historical controls who received conventional treatment. Patients on imatinib showed an overall survival advantage (relative risk 0.54, 95% CI 0.31-0.93). However, although patients on imatinib who achieved at least some degree of cytogenetic response after 6 months had better survival than controls (0.13, 0.05-0.39), those with no cytogenetic response to imatinib had significantly worse survival (1.69, 1.09-2.64). Our findings suggest that cytogenetic responders obtain benefit from imatinib but patients who show no cytogenetic response should be given alternative treatment without delay. We confirmed these results in a case-matched analysis.

The impact of the combination of baseline risk group and cytogenetic response on the survival of patients with chronic myeloid leukemia treated with interferon alpha.

BACKGROUND AND OBJECTIVES: This study was aimed at examining major cytogenetic response (MCR) as a valid predictor of the course of chronic myeloid leukemia (CML) and at assessing the survival of CML patients treated with interferon alpha (IFN) in dependence on the combination of MCR (yes or no) with the baseline risk group of the New CML score. MCR was defined as a reduction of Philadelphia chromosome-positive bone marrow cells to

Treatment of CML using IFN-alpha: impact on quality of life.

Treatment of chronic myeloid leukaemia (CML) with IFN-alpha (IFN) is known to confer significant survival benefit, but the drug's impact on quality of life (QoL) in CML is unclear. We describe a cross-sectional comparison of QoL in patients randomised to long-term treatment with IFN versus no IFN within the UK MRC CML 3 trial, assessing the long-term consequences and psychosocial side effects of IFN therapy. Patients completed the EORTC QoL QLQ-C30, an in-house leukaemia/IFN questionnaire, a brief assessment of sexual functioning and demographic details. In total, 163 eligible patients completed questionnaires (85% response). Patients receiving IFN reported significantly worse QoL for emotional, cognitive and social functioning, pain and dyspnoea (P<0.01), and marginally worse fatigue, nausea and vomiting (P<0.05). As expected from other IFN use, those on IFN experienced more flu-like and febrile symptoms and skin problems than those not on IFN. In all, 35% of patients stopped IFN before questionnaire completion. This made no material difference to the results, except that those continuing on IFN had slightly better self-assessed Global health/QoL than those who had stopped (P<0.03). IFN treatment adversely affected sexual health after allowing for age and gender. In conclusion, IFN treatment has a significant adverse impact on QoL. Patient awareness of the survival benefits and these QoL effects should enable better-informed decision-making. The impact on QoL of IFN dose, and of imatinib therapy versus IFN in early CP CML, are being investigated. QoL will need evaluating in future studies of combination treatment (IFN+imatinib).

Panhypopituitarism secondary to a macroprolactinoma manifesting with pancytopenia: case report and literature review.

OBJECTIVE: To present a case of pancytopenia associated with hypopituitarism secondary to a macroprolactinoma. METHODS: We report the clinical features on presentation and results of laboratory investigation. Findings on magnetic resonance imaging are illustrated. The response to hormone replacement therapy is summarized. RESULTS: A 46-year-old man was referred with pancytopenia and secondary hypothyroidism. Laboratory investigation revealed hypopituitarism and a substantially increased prolactin level. Magnetic resonance imaging of the head demonstrated a macroprolactinoma. Hematologic investigation disclosed no other cause for the pancytopenia. Hormone replacement therapy was initiated with hydrocortisone, levothyroxine, and testosterone. Cabergoline was used to induce regression of the prolactinoma. A rapid improvement was seen in the cytopenias, with normalization of the blood cell counts after 8 months of treatment. This result has been sustained during 29 months of follow-up. CONCLUSION: Pancytopenia associated with hypopituitarism has been reported in the literature as a rare occurrence limited to isolated case reports, predominantly associated with Sheehan syndrome. To our knowledge, this is the first reported case of pancytopenia associated with a macroprolactinoma. This finding is noteworthy because prolactin alone has been reported to support hematopoiesis in animal studies.