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Results of three studies show oncology is getting closer to curing ALL
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Three studies published in October explored new treatments for pediatric patients with acute lymphoblastic leukemia, and a new way of predicting which patients are likely to relapse. In an interview with HemOnc Today, Ching-Hon Pui, MD, PhD, said that, taken together, the results show real progress to finding a final cure for ALL.
The Journal of Clinical Oncology published the results and an accompanying editorial by Pui online Oct.5. In the COGAALL0031 study, Kirk R. Schultz, MD, from the Children¡¯s Oncology Group, and colleagues concluded that imatinib (Gleevec, Novartis) plus intensive chemotherapy dramatically improved three-year event-free survival without increasing toxicity for patients with Philadelphia chromosome-positive ALL. In the study CCG 1961, James B. Nachman, MD, from the University of Chicago Children¡¯s Hospital, and colleagues found that young adult patients showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy, and outcomes were so positive the researchers said there was no need for allogeneic stem-cell transplantation in first remission for these patients.
In results from the AIEOP-BFM-ALL 2000 study, Giuseppe Basso, MD, from the pediatric oncology laboratory, University of Padova, and colleagues showed that minimal residual disease as measured by flow cytometry 15 days after remission induction therapy was a powerful predictor for relapse.
COGAALL0031
Schultz and colleagues enrolled 92 patients with Ph+ ALL aged 1 to 21 years. Patients were assigned to 340 mg/m2 daily imatinib, with an intensive chemotherapy regimen and researchers compared them for toxicities with 65 patients with Ph-negative disease treated with identical chemotherapy without imatinib. Researchers progressively increased exposure to imatinib in five patient cohorts from 42 days in cohort one (n=7) to 280 continuous days in cohort five (n=50). Those patients with HLA-identical sibling donors underwent bone marrow transplant with adjuvant imatinib after transplantation for six months.
The three-year event-free survival for patients with continuous imatinib exposure in cohort five was 87.7% (95% CI, 64.5%-89.8%), a result better than anything previously observed, Pui said. The three-year event free survival in patients within cohort five treated with chemotherapy was at least as good as that for patients treated with sibling donor bone marrow transplant.
¡°The addition of tyrosine kinase inhibitors to intensive chemotherapy dramatically improved early treatment results. Nobody has ever been able to produce this kind of results,¡± Pui said in an interview. ¡°We need longer follow up because sometimes improved early results just reflect prolonged disease-free survival. Good early results may not translate into increased cure rates.¡±
The researchers found the frequency of grade-3 toxicities was roughly the same in the Ph+ALL and Ph-ALL groups.
¡°The higher imatinib dosing in cohort five appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction,¡± the researchers wrote.
¡°We¡¯re really looking forward to a long-term result to assure that Ph+ leukemia patients do not need transplantation for cure. That would be a major advance,¡± Pui said. ¡°Second, very intensive chemotherapy was also used. We want to know if the second generation of tyrosine kinase inhibitors like nilotinib (Tasigna, Novartis) or dasatinib (Sprycel, Bristol Myers Squibb) can further improve outcomes, and if we can reduce the intensity of chemotherapy with the use of tyrosine kinase inhibitors. The patients¡¯ quality of life will be much better and we could reduce the risk for developing chemotherapy-induced latecomplications.¡±
CCG 1961
In CCG 1961 Nachman and colleagues recruited 262 patients aged 16 to 21 years, with ALL.
per mcL. Following induction chemotherapy, patients underwent bone marrow aspiration on day seven. Those who had ¡Ü25% blasts were classified as rapid early responders (n=177). Those with more than 25% blasts were classified as slow early marrow responders (n=75). Ten patients did not undergo bone marrow evaluation.
Rapid response patients who achieved remission were then randomly assigned to standard- or increased-intensity postinduction therapy blocks and one or two interim maintenance and delayed intensification phases.
The researchers found that the five-year event free survival for patients assigned to increased-intensity therapy was 81.8% vs. 66.9% for the standard-intensity patients. Five-year survival for patients treated with augmented therapy was 83.2% vs. 75.6% for those assigned to standard intensity.
The five-year event-free survival for the slow early marrow responders was 70.7%.
¡°Our results establish that young adults ¡ have an event-free survival rate greater than 70% with chemotherapy alone and therefore do not meet criteria generally used to select patients for allogeneic stem-cell transplantation in first remission,¡± the researchers wrote. ¡°When a pediatric-type treatment regimen is used, routine use of stem-cell transplantation in first remission for this patient population seems unwarranted.¡±
Pui agreed that the results were strong enough to recommend against transplantation.
¡°There¡¯s really no definitive study in adolescents and young adults showing that transplantation improves outcomes,¡± he said. ¡°This study yielded superior results for adolescents and young adults, further supporting the idea that we shouldn¡¯t transplant them just because of their age.¡±
Pui added that patient outcomes were ¡°excellent,¡± but said he was concerned about the relatively high rate of second cancers. ¡°Potentially this complication can be avoided. Going forward, personalized therapy based on pharmacogenetics may improve the results even further.¡±
AIEOP-BFM-ALL 2000
In AIEOP-BFM-ALL 2000 study conducted in Italy, Basso and colleagues collected marrow samples from 633 patients with ALL aged 1 to 18 years treated at 39 centers. At day 15 of treatment, the researchers used flow cytometry to measure minimal residual disease (FCM MRD). Researchers segregated patients into three groups: standard-risk (<0.1% blast cells), intermediate-risk (0.1% to <10% blast cells) and high-risk (¡Ý10% blast cells).
The calculated five-year relapse rate was 7.5% in the standard-risk group, 17.5% in the intermediate-risk group and 47.2% in the high-risk group. Results of a multivariate analysis confirmed that FCM MRD in day 15 bone marrow was the most important prognostic factor in these patients.
¡°The value of early FCM MRD derived stratification in discriminating prognosis within a stratification based on polymerase chain reaction minimal residual disease (PCR MRD) was assessed by analyzing 633 patients with available data by both techniques,¡± the researchers wrote. Using PCR MRD the incidences of relapse were 10.8% in the standard-risk group, 26.3% in the intermediate-risk group and 55.7% in the high-risk group.
¡°Those patients classified by PCR MRD as standard-risk or high-risk had a very good or poor prognosis independently of FCM MRD results; however, for those patients in the intermediate-risk group by day 33 PCR MRD, day 15 FCM MRD further discriminated subgroups with different cumulative incidences of relapse.¡±
Morphological evaluation of day 15 bone marrow smear was performed at the treating center in 695 patients (85.3%). Of those patients, 503 were defined M1 (blast cells <5%) with a cumulative incidence of relapse of 11.1%. There were only 13 relapses (5.3%) among 247 patients with FCM MRD lower than 0.1%. The rate of relapse progressively increased to 36.8% in the 19 patients with FCM MRD ¡Ý10%.
Pui said FCM MRD is already a standard measure in Western medical centers, and because it is less expensive than PCR MRD and more accurate than morphologic examination, FCM MRD should also be useful in developing countries.
¡°Further refinement of risk-directed therapy will undoubtedly push the cure rates in ALL even higher,¡± he wrote. ¡°Ultimately, we can look forward to a new era of more effective and less toxic targeted therapy ushered in by advances in understanding both the genetic and epigenetic changes in leukemic cells, host pharmacogenetics, and the interactions between leukemic and other cell types.¡± ¨C by Jason Harris
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