Therapy of chronic myelogenous leukemia with recombinant interferon- gamma

Recently, we reported that recombinant interferon-alpha (rIFN-alpha) can induce hematologic remissions and cytogenetic improvement in newly diagnosed Philadelphia (Ph)-positive chronic myelogenous leukemia (CML) patients. Although IFN-gamma is a structurally distinct molecule, this agent suppresses in vitro hematopoietic progenitor cells in a fashion similar to that of IFN-alpha. Therefore, we initiated a study of rIFN- gamma at doses of 0.25 to 0.5 mg/m2/d intramuscularly in patients with Ph-positive benign-phase CML. Twenty-six of 30 patients entered in the study were evaluable. Six patients have achieved a complete hematologic response; four, a partial hematologic response. The median follow-up period of patients who are in complete remission is 7.5 months (range, 5 to 12 months). No relapses have occurred among the complete responders. So far, five patients have had cytogenetic improvement with emergence of 5% to 45% diploid cells in the bone marrow. Fever and flulike symptoms were the most common side effects, with partial tolerance often developing after about 1 week. The majority of patients tolerated therapy with minimal change in performance status. In conclusion, rIFN-gamma has demonstrated clinical activity in CML. On the basis of these observations and the in vitro synergistic growth- inhibitory effects of IFN-alpha and IFN-gamma, we have started trials of combination IFN therapy in CML patients.     

Therapy of acute myelogenous leukemia

Over the past 10 years, there have been substantial advances in the treatment of AML. Intensive induction chemotherapy using 7-day courses of cytarabine and daunorubicin or amsacrine produce remission in 60% to 85% of patients. Median remission duration is 9 to 16 months. In some series, 20% to 40% of patients are in continuous remission for 2 years or more; many of these patients remain in remission for 5 years or longer and some may be cured. Bone marrow transplantation has evolved as a useful therapeutic modality capable of achieving long-term survival in some circumstances in which chemotherapy is relatively ineffective. Its precise role in the initial therapy of AML remains to be defined, but it is likely to be beneficial in selected patients. These data indicate substantial recent progress in the treatment of this disease, which was almost uniformly fatal 30 years ago. The fact that most patients relapse within 1 to 2 years reflects a lack of progress in developing effective postremission therapy. Maintenance chemotherapy, immunotherapy, and CNS prophylaxis have little role in AML. It is unclear whether consolidation or intensification extend remissions or increase the proportion of long-term survivors; controlled randomized trials should answer this question within the next few years. Future progress in the treatment of AML awaits the development of more sensitive methods for detecting residual leukemia, more effective use of current therapeutic modalities and the introduction of new effective drugs. Most data suggest that early intensive treatment is of key importance for achieving cures. However, we cannot presently distinguish between patients cured by initial treatment and those who required further chemotherapy.     

Treatment-related chronic myelogenous leukemia

 Treatment-related (Tr) AML and MDS after chemotherapy, radiotherapy, or the combination of both have been well characterized. However, tr-CML seems to differ from these better-known entities in frequency, clinical course, and prognosis. Tr-CML cannot be distinguished from de novo CML cytogenetically, and, in contrast to tr-AML and tr-MDS, typical chromosomal aberrations related to tr-CML have not been described. Treatment-related CML is a late effect of cytotoxic or immunosuppressive therapy which might be increasingly recognized due to a higher number of patients treated with intensive therapy regimens. We review here the available data on incidence of tr-CML as well as the affected individual's characteristics with regard to different treatment options in malignant and nonmalignant diseases. Received: November 19, 1998 / Accepted: April 20, 1999     

Therapy of acute myelogenous leukemia.

Treatment of acute myelogenous leukemia (AML) is divided into remission induction and post-remission therapy. Remission induction is usually with cytarabine and an anthracycline. Daunorubicin is commonly used but recent data suggest idarubicin or mitoxantrone are equally effective, possibly better. High-dose cytarabine has also been used for remission induction but is not proven superior. Post-remission treatment is typically with two or more courses of drugs similar to those used for remission induction. Other studies use non-cross resistant drugs and/or high-dose cytarabine. Although some data favor use of high-dose cytarabine, no approach is clearly superior. There is considerable controversy whether persons in first remission and with an HLA-identical sibling should receive a bone marrow transplant immediately or after relapse. Although transplant results appear superior, especially in persons less than 20 years of age, the most effective strategy may be reserving transplants for persons failing chemotherapy. This strategy also applies to persons receiving autologous transplants or transplants from alternative donors, like HLA-matched related or unrelated persons.     

Biotherapy of chronic myelogenous leukemia

The aim of this review is to summarize the current knowledge on the clinical results of biotherapy of chronic myelogenous leukemia (CML) and potential mechanisms of the antitumor action of interferon alpha. IFN alpha treatment induces hematologic and cytogenetic remissions in patients with chronic phase CML. In addition, the duration of the chronic phase is prolonged by IFN alpha resulting in a significant survival benefit. In two randomized clinical trials this survival benefit was demonstrated in all chronic phase CML patients independent of their risk scores. Moreover, IFN treatment also delays the onset of clinical relapse after allogeneic bone marrow transplantation. The critical mechanisms of IFN action have not yet been identified. Both direct and indirect antiproliferative mechanisms have been described. In particular, differential regulation of growth promoting and growth inhibiting cytokines represents an attractive hypothetical mechanism of IFN action. Nevertheless, no leukemia specific IFN activities explaining cytogenetic remissions and/or delay of disease progression have been identified. Further research on that field are required to further improve biological CML therapies.     

Cytogenetics of chronic myelogenous leukemia

The fundamental pathogenetic significance of the Ph chromosome abnormality in CML has been clarified by molecular studies. However, this balanced reciprocal t(9;22) is probably not the primary event in the pathogenesis of this disease, at least at a cytogenetic level. The cause of Ph variants in +/- 5% of patients is still unknown. Improvements in cytogenetic techniques and molecular studies in a limited number of cases indicate that simple variants do not exist: Region 9q34 appears to be involved in all types of Ph variants. There is tentative evidence that these variants may in fact represent a clonal evolution from a standard t(9;22). The types of additional secondary abnormalities found in Ph variants are the same as those commonly found in standard cases. Ph negative CML represents a heterogeneous group of myeloproliferative/myelodysplastic disorders. The various mechanisms that could lead to Ph negativity are discussed. Some karyotypically normal cases and those showing a chromosome abnormality other than the Ph during the chronic phase have shown the same molecular changes as found in Ph positive CML. The types of clonal changes accompanying transformation to an acute phase are similar to those seen in myeloid disorders as a whole. The prognostic karyotypic factors in predicting imminent metamorphosis to the acute stage and during the acute phase are discussed. The extent of clonal evolution, the type of secondary abnormalities, and their relationship to the hematopoietic lineage of blast cells should be assessed. The nonrandom clonal changes found in 80% of cases are +Ph, +8, i(17q), +19, and loss of the Y. The significance of +Ph is possibly related to amplification of the bcr/abl fusion gene product, but the reason for the other persistent nonrandom changes is still speculative. Recent cytogenetic data indicate that the specific changes observed in various types of ANLL may be seen in corresponding types of MT, such as t(15;17) in promyelocytic transformations and abnormalities of 3q21-3q26 in megakaryoblastic transformations. Patients with LT usually have an early precursor B phenotype associated with a better prognosis. They tend to have either normal or hypodiploid karyotypes. An i(17q) is never seen and +8 and +19 are absent in most series. Duplication of the Ph and loss of the Y are common to both MT and LT. Data relating 14q+ abnormalities to LT are presently ambiguous.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clonality in juvenile chronic myelogenous leukemia

Juvenile chronic myelogenous leukemia (JCML) is a myeloproliferative disease in which morbidity and mortality are primarily caused by nonhematopoietic organ failure from myelomonocytic infiltration or by failure of the normal bone marrow. Morphologic evidence of maturation arrest, karyotypic abnormalities, and progression to blast crisis are infrequent events. Viral infections and other reactive processes can initially mimic the clinical course of JCML, creating diagnostic problems. Because of the rarity of JCML and technical limitations, formal clonality studies have not been reported previously. Nine female JCML patients were identified by clinical criteria, characteristic 'spontaneous' in vitro cell growth, and negative cultures and titers for various viral agents. Peripheral blood and bone marrow samples were obtained at the time of diagnosis for cell separation and RNA and DNA isolation. To assess clonality, X-chromosome inactivation patterns were evaluated using three different, recently developed polymerase chain reaction-based clonality assays. All nine female JCML patients showed evidence for monoclonal origin of mononuclear cells at the time of diagnosis. Cell separation studies further traced the monoclonal origin back to at least the most primitive myeloid progenitor cell. Reversion to a polyclonal state was demonstrated after bone marrow transplant and also in one patient following treatment with 13-cis retinoic acid. This demonstration of clonality in JCML delineates it from the reactive processes and provides a basis for molecular genetic strategies to identify causally associated mutations.     

Splenic function in chronic myelogenous leukemia

Spleen function was evaluated by measurement of the clearance of autologous heat-damaged 99mTc-labelled erythrocytes from the circulation and into the spleen and the enumeration of pitted erythrocytes by interference contrast microscopy, and the spleen area was determined by scintillation scanning. All measurements were performed on 12 patients with chronic myelogenous leukemia and compared with 10 controls with apparently normal spleens, 6 splenectomized subjects and 9 patients with a reactive splenomegaly. Patients with CML had spleen function test results similar to normal controls in spite of having enlarged spleens whose projection area did not differ from that of the patients with reactive splenomegaly. Thus, patients with CML have a decreased spleen function per unit volume and signs of splenic hypofunction in the peripheral blood. The reduction of spleen function per unit volume in CML is the result of a severe decrease of the splenic blood perfusion which could result from the combined effects of the myeloid metaplasia and the increased whole-blood viscosity due to high white-cell counts.     

Molecular biology of chronic myelogenous leukemia

In this review we have described molecular consequences of the t(9;22) translocation typical of CML and some cases of ALL. This data indicates an important role for abl and bcr and suggest some common mechanisms of activation of c-abl related tyrosine kinase activity. This data also provides insight into the relationship between Ph1 positive, Ph1 negative CML and Ph1 positive ALL. Although this data answers some questions, they raise others; eg, what is the molecular basis of the t(9;22) translocation? How does increased abl related kinase activity eventuate in CML? Finally, this data reviewed suggests that factors other than abl and bcr must play a role in CML. Definition of these factors will be important in the future.     

Current therapy of chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder molecularly defined by the BCR-ABL gene and its products. The protein encoded by this chimeric gene is a constitutively activated tyrosine kinase that alters multiple signal transduction pathways inducing malignant transformation. Until recently, treatment options for patients with CML consisted of hydroxyurea, interferon-based therapies or allogeneic stem cell transplantation (alloSCT). Treatment decisions were generally based on the age of the patient and the phase of the disease. Recently, several new therapies have been developed that may change the natural history of CML and patient prognosis. In particular imatinib mesylate (ST1571, Gleevec) an oral Bcr-Abl kinase inhibitor, has demonstrated activity in all phases of CML, and may replace interferon and alloSCT as the initial therapy for this disease. Other agents and therapies with potential value, either alone or in combination, include polyethyleneglycol (PEG) interferon, homoharringtonine, decitabine, oral cytarabine, and growth factor modulation. In this article, we discuss the biological and clinical characteristics of CML, as well as the different therapeutic alternatives for patients with this disorder.