Interferon alpha for chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation

Interferon alpha (IFN alpha) induces cytogenetic responses in patients with chronic myeloid leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT). The purpose of this study was to analyze the therapeutic role of IFN alpha in this setting. The experience of a single institution and the published results on this topic were evaluated. We have included patients who received IFN alpha as a single agent, excluding those patients who received previous or simultaneous donor leukocyte infusions. The outcomes of 11 patients treated in our center and those of 108 previously reported patients have been analyzed. Five out of 11 patients treated in our institution obtained a complete cytogenetic response (CGR). Two patients continue in complete cytogenetic response 3.5 and 8.2 years later, and the qualitative RT-PCR is negative for bcr-abl RNA. The CGR has been transient in one patient, and follow-up is short in the other two. Secondary effects have been acceptable, with myelosuppression as the main toxic effect. Graft-versus-host disease did not occur. The literature review identified 108 patients treated with IFN alpha as sole therapy for relapsed CML. Cytogenetic response and CGR seem to be better in patients with cytogenetic relapse, as compared to patients with hematologic relapse (61% vs. 45% and 45% vs. 28%, respectively). Several patients remained in CGR for more than 5 years. This overview also suggests that CGR is more frequent when IFN alpha is used in patients relapsing after non T-depleted BMT. IFN alpha induces complete cytogenetic response in nearly half of the patients with CML who relapse after allogeneic BMT, with acceptable toxicity. We believe that these results using IFN alpha as a front-line therapy for CML relapsing after BMT warrant a randomized comparison with donor lymphocyte infusions.     

Autografting in chronic myeloid leukemia

Autografting (or autologous stem cell transplant [ASCT]) followed by "rescue" with Philadelphia chromosome (Ph)-negative hematopoietic progenitor cells (HPC) remains a good procedure to guarantee prolonged survival for patients mobilized and autografted soon after diagnosis. Among 50 autografted patients who were treated with interferon alpha (IFN-alpha) and imatinib (for cytogenetic relapse after IFN-alpha), 41 are alive at a median of 51 months (range, 8 to 106 months). Twenty-eight (56%) patients maintain major cytogenetic remission after ASCT + IFN-alpha +/- imatinib. Such results are probably better than those achieved by IFN-alpha alone and are similar to the best results obtained in younger patients after allografting with human leukocyte antigen (HLA)-identical sibling donors. The integration of imatinib, during the coming years, into an autografting procedure could represent important progress towards developing a cure for chronic myeloid leukemia (CML) patients who cannot undergo conventional allografting.     

Advanced-phase chronic myeloid leukemia

Chronic myeloid leukemia (CML) typically runs a biphasic or triphasic course, with diagnoses usually made in the chronic phase (CP). Without effective treatment, patients eventually progress to a blastic phase (BP), frequently through an intermediate or accelerated phase (AP). Because the definition of AP varies among studies, comparisons of outcome and prognosis are difficult. The management of patients in these advanced phases of the disease has been much less satisfactory than that of patients in CP. Treatment with interferon-alfa (IFNalpha)-based therapy is ineffective for most patients in AP and for all of those in BP. Imatinib mesylate has demonstrated significant activity AP and BP disease, although the results are inferior compared to treatment in CP. In AP, 82% of patients achieve a hematologic response, with 24% achieving a major cytogenetic remission (MCR). Early MCR (within 3 months of diagnosis) provides a survival advantage over patients who do not achieve this response or achieve it later. In BP, 21% of previously treated patients and 36% of previously untreated patients have responded to imatinib, and up to 17% of patients may achieve a major cytogenetic response. However, responses are frequently short-lived. Several agents are being investigated for treatment of advanced-phase CML, including decitabine (DAC), homoharringtonine (HHT), troxacitabine, clofarabine, farnesyl transferase (FTase) inhibitors (FTI), and others. Many have also proven to be synergistic with imatinib in vitro and combination studies are ongoing. Continued investigation of these approaches is needed to improve the long-term prognosis of advanced-phase CML.     

Monoclonal antibodies in chronic myeloid leukemia

Specific surface structure on cells can be recognized by means of monoclonal antibodies. For the diagnostics of haematologic neoplasmas this means the possibility to classify unknown proliferating cells into blood cell systems, e. g. to differentiate whether they are of myeloid or lymphatic origin. Also in chronic myeloid leucosis (CML) representing a neoplastic disease of relatively mature myeloid blood cells and their precursors there are clinical and experimental indications of a disturbance of the immune function. In investigations made by the author the number of immune cells (T and B lymphocytes, monocytes) in the peripheral blood of patients having CML was determined. The results obtained with 20 patients examined in the various phases of the disease were compared to those obtained with control persons. The examination result proves that in dependence on the phase of the disease it is possible to detect first a reduction of the cells (B lymphocytes) identifiable with the monoclonal antibody BMA 0130 that the result is also a reduction of the T cells, though of a minor extent, primarily at the expense of BL-TH4 cells identified with the monoclonal antibody and that already in the chronic phase of CML with basophilia the number of monocytes strongly decrease and are almost missing at all in the peripheral blood in advanced phases.     

Management decisions in chronic myeloid leukemia

Until recently, interferon-alfa or interferon plus cytarabine was considered the best initial treatment for newly diagnosed chronic myeloid leukemia (CML) patients not eligible for allogeneic stem cell transplantation. The remarkably rapid and apparently durable control of hematologic features and the high rate of cytogenetic response achieved with imatinib used as a single agent suggest that this drug could prolong life substantially. However, response to the drug is variable between patients and here criteria are tentatively suggested for defining response and nonresponse or response failure. It is likely that patients who fail to respond to imatinib may benefit from alternative therapy initiated as early as possible. The issue of whether to offer allogeneic stem cell transplant to any newly diagnosed patient is addressed and a possible strategy is suggested. Undoubtedly, the suggestions made here will require revision as we acquire further information on the utility of imatinib.     

Intracardiac mass in chronic myeloid leukemia

Chronic myeloid leukaemia (CML) is a neoplastic disorder of myeloid cell lines and is a less aggressive disease compared to acute myeloid leukemia (AML). Although cardiovascular complications are not uncommon, intracardiac thrombosis in CML is rarely reported. Herein, we report a case of CML presenting with an intracardiac thrombus attached to the posterior mitral leaflet, and subsequently resulting in peripheral embolization.     

Managing resistance in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disorder that affects 5000 new patients per year in the United States. Prior to 10 years ago, durable remission was rare and patients often underwent bone marrow transplantation with substantial morbidity and mortality. Fortunately, CML has been the epicenter of exciting advances in cancer therapy with the discovery of the Bcr-Abl gene fusion and the subsequent development of imatinib mesylate, a small molecule tyrosine kinase inhibitor, to target the kinase activity of the bcr-abl protein product. Despite unprecedented durability for complete hematologic, cytogenetic, and molecular responses seen with front-line imatinib therapy, many patients require alternative therapy because of drug intolerance, suboptimal response, primary resistance, secondary resistance, or progression to advanced phase disease. Further, up to 5% of patients present with advanced disease that does not sustain a durable response to tyrosine kinase inhibitors. Thus, up to one third of CML patients require alternate therapy. Chronic myeloid leukemia has become an exemplary model system for understanding molecular targeting and overcoming mechanisms of drug resistance. This review will discuss potential mechanisms of resistance and ongoing research into novel targets and agents for CML resistant to standard of care.     

Interferon-alfa for chronic myeloid leukemia

Interferon-alfa (IFNalpha) became the first-line agent for the treatment of chronic myeloid leukemia (CML) because it prolongs survival significantly compared to conventional chemotherapy (CHT). Responses to IFNalpha and the benefits from achieving a response are greater in low-risk than in high-risk patients. The best therapeutic results are obtained in low-risk patients who achieve a complete hematologic response (CHR) within 3 to 6 months, a major cytogenetic response (MCgR) within 1 year, and a complete cytogenetic response (CCgR) thereafter. Cytogenetic responses (CgRs) to IFNalpha are stable and durable, so that about 50% of complete responders become long-term survivors. Combining IFNalpha with other drugs, like arabinosyl cytosine (AC), and with other treatments, like autologous stem cell transplantation (autoSCT), may provide additional benefit, although this has not been proven. The biologic and molecular bases of the action of IFNalpha are still poorly understood, but are worth investigating further to determine whether it will still have a therapeutic role when used in combination with the protein tyrosine kinase inhibitors and other new agents.     

Splenectomy in chronic myeloid leukemia and myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is a collective term that describes the related disorders AMM, PPMM, and PTMM. The chronic myeloid disorders include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia (myelofibrosis). These disorders display varying propensities for pathologic enlargement of the spleen which can lead to mechanical discomfort, hypercatabolic symptoms, anemia, thrombocytopenia, and portal hypertension. Splenectomy has been found to be of little benefit in the early stages of chronic myeloid leukemia. Similarly, the benefit of splenectomy in advanced cases is limited to symptomatic palliation and treatment of delayed engraftment after allogeneic bone marrow transplantation. Although polycythemia vera and essential thrombocythemia are also characterized by splenomegaly, splenectomy is not considered a therapeutic option in the absence of transformation of the disease into myelofibrosis with myeloid metaplasia. Splenectomy has been studied most in myelofibrosis with myeloid metaplasia. Although there is no clear survival advantage to splenectomy in this disorder, the surgical procedure can result in substantial palliation of mechanical discomfort, hypercatabolic symptoms, portal hypertension, and anemia. However, the procedure is associated with an approximately 9% mortality rate, and the postsplenectomy occurrence of extreme thrombocytosis, hepatomegaly, and leukemic transformation is of major concern.     

T-lymphoid blast crisis in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is considered to be a pleuripotential stem cell disorder with the capacity to differentiate into myeloid, erythroid, megakaryocytic, and lymphoid cell lines. Consequently, blast crisis (BC) involving each of the above lineages has been well described. Among lymphoblastic crises, differentiation frequently occurs along B-cell lineage. We report four patients of CML who terminated in T-cell extramedullary BC in lymph nodes after a variable duration of chronic phase. The T-lineage was established by characteristic cytochemical staining and reactivity with a panel of anti-T-cell monoclonal antibodies. All four cases were Philadelphia (Ph) chromosome positive and demonstrated the Ph chromosome and associated anomalies (extra Ph, +19) in the lymph nodes. Our data adds to the growing evidence that CML is a disorder of the common stem cell from which T, B, and myeloid precursors originate.     

Overcoming drug resistance in chronic myeloid leukemia

PURPOSE OF REVIEW: Despite the excellent clinical results with imatinib in chronic myeloid leukemia, most patients have minimal residual disease and others will develop resistance and may eventually progress. Thus there is a need for developing approaches to overcome and prevent resistance to imatinib. RECENT FINDINGS: Several new agents have been developed with significant activity in imatinib-resistant chronic myeloid leukemia. A second generation of more potent tyrosine kinase inhibitors, some with dual activity against Abl and Src, have shown very impressive results. Other agents, such as hypomethylating agents, farnesyl transferase inhibitors and homoharringtonine, have also shown preclinical and clinical promise. The use of vaccines as a way of providing an immunomodulatory approach to chronic myeloid leukemia is starting to develop as a major strategy to achieve eradication of the disease. SUMMARY: Multiple effective agents are being developed to overcome resistance to imatinib. The challenge for the future is to incorporate them into effective strategies that can eliminate the disease and cure all patients with chronic myeloid leukemia.