Interferon Used as First - Line CML Therapy

Dr. Bishop provides a round-up of presentations given at theHematologic Malignancies symposium, held in conjunction with theMid-Atlantic Oncology Program's 13th Annual Scientific Conference.

ATLANTA, Ga--More than 75 investigators from around the worldpresented updates of ongoing clinical trials and initial datafrom new trials involving hematologic malignancies. This reportincludes results of studies from Italy, France, and the UnitedStates on treatments for acute and chronic leukemias.

An Italian study suggests that alpha-interferon should be thefirst-line treatment for chronic myelogenous leukemia (CML) patientswho are not candidates for allogeneic transplantation, MicheleBaccarani, MD, University Hospital of Udine, Italy, said in hisupdate of the Italian Cooperative Groups study of alpha-interferonversus hydroxyurea (Hydrea) in the treatment of newly diagnosedCML.

Dr. Baccarani emphasized that allogeneic stem cell transplantationmay be curative in up to 50% to 70% of CMLpatients; however, allogeneictransplantation is limited to approximately 15% of patients, dueto age restrictions and donor availability.

In this study, patients who were ineligible to undergo allogeneicstem cell transplantation were randomized to receive alpha-interferonor hydroxyurea. The endpoints of this trial were hematologic response;karyotypic response, ie, reduction in the number of cells expressingthe Philadelphia chromosome; and overall survival.

If patients randomized to receive alpha-interferon did not achievea hematologic response by 6 months, the drug was discontinued.Likewise, among the remaining patients in this arm, the drug wasdropped if a karyotypic response was not achieved by 1 year.

Median survival for patients randomized to receive alpha-interferonwas 6 years, compared with 4 years for patients randomized toreceive hydroxyurea (P = .001). Patients who received alpha-interferonappeared to have a slower progression from chronic phase to acceleratedphase and blast crisis. The survival advantage was only observedin patients who achieved a karyotypic response, which occurredin approximately 30% of the study patients.

These results were in slight contrast to the randomized trialconducted by the Medical Research Council (UK), which reporteda survival advantage for patients receiving alpha-interferon evenif they did not achieve a karyotypic response.

Dr. Baccarani suggested that alpha-interferon should be consideredfirst-line treatment for patients who are ineligible for allogeneicstem cell transplant, and that the drug should be continued untilthere is no evidence of response. He emphasized that even thoughthese results are an improvement in the treatment of CML, alpha-interferoncan be associated with significant morbidity and cost.

Investigators should strive to improve on these results, he said,as well as the results achieved with allogeneic stem cell transplantation.Alternative forms of therapy, including transplantation from unrelateddonors, autologous stem cell transplantation, and investigationaldrugs such as homoharringtone, need to be pursued.

Expanding Role for 2-CdA

Dr. Lawrence Piro, of Scripps Clinic and Research Foundation,La Jolla, Calif, discussed the expanding role of the purine analog2-chlorodeoxyadenosine (2-CdA, cladribine, Leustatin) in the treatmentof hematologic malignancies. The purine analogs are unique inthat they are cytotoxic to both resting and dividing lymphocytes.

In previously treated patients with chronic lymphocytic leukemia(CLL), 2-CdA has been shown to have single-agent activity resultingin significant responses. As part of a phase II trial, 20 patientswith previously treated CLL received 2-CdA at 0.1 mg/kg/day bya 7-day continuous intravenous infusion.

Five patients (25%) achieved a complete remission, and 12 patients(60%) achieved a partial remission, for an overall response rateof 85%. The median duration of response was greater than 8 months,with a range of 3 to 27 months. The primary toxicity observedin this trial was myelosuppression, with 20% of patients experiencinggrade III to IV thrombocytopenia.

Other speakers at the meeting noted that 2-CdA is now being usedin combination with other agents, such as alkylating agents andintercalating agents, to take advantage of the purine analog'sability to inhibit DNA repair.

Dr. Michael Grever, of Johns Hopkins Oncology Center, cautionedthe audience on the combination of 2-CdA and corticosteroids.This combination results in significant toxicity, primarily infections,with little additional therapeutic benefit, he said.

Dr. Piro also reported on the use of 2-CdA in patients with low-gradenon-Hodgkin's lymphoma. Twenty-eight patients with previouslyuntreated low-grade disease were given 2-CdA, again at a doseof 0.1 mg/kg/day by continuous infusion.

Ten of these low-grade NHL patients (35%) achieved a completeresponse, and 15 patients achieved a partial response with 2-CdAas single-agent therapy. Again, myelosuppression was the primarytoxicity, with 7% to 18% of patients experiencing severe neutropenia,anemia, or thrombocytopenia.

Dr. Piro noted that 2-CdA has also been used for the treatmentof myeloid leukemias. Treatment of adult patients with CML resultedin an 83% hematologic remission rate, but no karyotypic responseswere observed, he said.

Researchers from St. Jude Children's Research Hospital reportedthat 8 of 17 children with acute myelogenous leukemia (AML) achieveda complete response after 2-CdA treatment. However, no completeresponses were observed in adult AML patients treated with 2-CdAat Memorial Sloan-Kettering Cancer Center.

All-Trans-Retinoic Acid in AML

Dr. Raymond Warrell, of Memorial Sloan-Kettering Cancer Center,reported on trials using all-trans-retinoic acid (RA) in the treatmentof patients with acute promyelocytic leukemia (APL; French-American-Britishclassification M3). [See "FDA Advisory Panel Recommends Vesanoid, Zinecard".] In 43 (88%) of 49 newly diagnosed APL patients, a completeremission was achieved using RA as the sole agent for induction.Similarly, 25 of 30 previously treated patients with APL achieveda complete remission with RA.

Compared with historical controls, early mortality was not affectedby RA; however, relapse-free survival and overall survival weresignificantly increased.

Dr. Warrell commented on the "retinoic acid syndrome"that has been observed in approximately 40% of patients receivingRA.

The syndrome is characterized by leukocytosis, rash, fever, andrespiratory distress; a transient leukocytosis (more than 20,000cells/mm³) is observed in more than half of all patientstreated with RA. However, the syndrome does not correlate withthe degree of leukocytosis. If left untreated, retinoic acid syndromeis associated with a 75% mortality rate.

Treatment with high-dose corticosteroids (dexamethasone, 10 mgIV every 12 hours for 3 or more days) inhibits the progressionof the syndrome in the majority of patients. Patients who failtreatment with corticosteroids should be treated with full-dosechemotherapy.

High-Risk ALL

The optimal postremission therapy in adult patients with acutelymphocytic leukemia (ALL) remains controversial. This is especiallytrue when the patient has an HLA-matched sibling and is eligiblefor allogeneic stem cell transplantation. Dr. Catherine Sebban,Lyon, France, presented results from LALA87, a multicenter trialattempting to address this issue.

Of 284 eligible patients, 257 were entered into the study. Eligibilityincluded a diagnosis of ALL, complete remission after scheduledchemotherapy, age from 15 to 40 years, and the availability ofan HLA-matched sibling for bone marrow donation.

These patients received cyclophosphamide (Cytoxan, Neosar) andtotal body irradiation followed by allogeneic bone marrow transplantationas their form of consolidation. Patients who did not have an HLA-matchedsibling were included in the control arm. Control arm patientsreceived one course of consolidation chemotherapy, and then wererandomized to receive either autologous bone marrow transplantationor further chemotherapy.

The allogeneic bone marrow transplantation group included 116patients, with 141 in the control arm. In an intention-to-treatanalysis, there was no difference between the two arms. However,patients with high-risk ALL (Philadelphia positive, undifferentiatedALL, WBC more than 30, age more than 35 years) had an improvedoutcome with allogeneic bone marrow transplantation.

Overall survival at 5 years for high-risk patients (n = 41) whoreceived allogeneic bone marrow transplantation was 44%, as comparedto 20% (P = 0.03) for high-risk patients in the control arm (n= 55). Disease-free survival was also significantly improved inhigh-risk patients who underwent allogeneic transplantation (P= 0.01).

These data suggest that allogeneic transplantation should be incorporatedas part of the postremission treatment for high-risk ALL patientsin first complete remission.

Dr. Bishop is assistant professor of medicine and directorof the Leukemia Program, University of Nebraska Medical Center,Omaha.