Cytogenetics Predict Outcome in Adult ALL
Cytogenetics Predict Outcome in Adult ALL
Abstract & Commentary
By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.
Synopsis: The prognostic importance of cytogenetics was evaluated in 200 adults between 15 and 65 years of age treated on a single ALL cooperative group protocol. Among the 140 having evaluable cytogenetic data, four risk categories were devised. Philadelphia chromosome positive t(9;22), unfavorable (monosomy 7, trisomy 8 or an 11q23 rearrangement), miscellaneous and normal. Overall survival of the miscellaneous group was similar to the normal karyotype patients whereas survival was considerably worse for both unfavorable and Ph + cytogenetic groups. The traditional adverse risk factors of older age and higher presenting white blood cell count were not associated with worse survival after adjusting for cytogenetics. In adult ALL, cytogenetics categories may be the strongest factor in predicting outcome.
Source: V. Pullarkat, et al. Blood. 2008;111:2563-2572.
Outcomes for pediatric acute lymphoblastic leukemia (ALL) have steadily improved with overall survival of 80%, ranking this as one of the major success stories of oncology. Improvements in adult ALL have lagged behind with overall survival of around 30- 40%.1 Biologic differences account for much of the discordant outcomes in adults compared to pediatric patients, as higher-risk types of ALL engender a greater proportion of adult ALL (eg, Philadelphia chromosome positive ALL). Diminished tolerance to therapy in adults may also hinder aggressive therapy. Even among adults diagnosed with ALL, older adults fare worse then younger adults. Whether biologic differences or tolerance problems account for the adverse prognosis of older age has not been well delineated.
Pullarkat and colleagues evaluated patients enrolled in the Southwest Oncology Group (SWOG)-9400 study, a phase 2 trial of adult ALL. Patients were required to have L1 or L2 FAB morphology and age between 15-65 years. Therapy entailed a standard induction regimen followed by consolidation and maintenance. There were 200 patients enrolled with a median age of 32 years. A subset of 19 patients who were 50 years or younger having an HLA identical sibling underwent allogeneic hematopoietic cell transplantation.
Conventional banded cytogenetic studies prior to treatment were available for 66%. FISH was employed for the t(9;22) and t(4;11) (MLL gene rearrangement) identifying cytogenetic abnormalities in additional subjects without results available from conventional cytogenetics. Thus, 140 subjects had evaluable cytogenetic data. Among these, 22% had a normal karyotype, 26% showed the t(9;22) defining Philadelphia chromosome positive disease (Ph +), 14% exhibited unfavorable karyotypic changes of t(4;11), trisomy 8, monosomy 7, or del 7(q22). Thirty-eight percent harbored miscellaneous karytoypic abnormalities. The t(1;19) was found in 7 patients: three were categorized as unfavorable based upon the presence of a trisomy 8 and the other four were considered miscellaneous. Not surprisingly, patients having Ph+ ALL tended to be older. The presenting WBC tended to be higher in the higher-risk cytogenetic groups.
Among the 200 enrolled subjects, 159 achieved complete remission. The estimated 5 year probably of survival was 33% for the entire cohort. The estimated probability of disease free survival for the 19 transplant patients was 37%. In univariate analysis, older age was associated with worse CR rate (P = 0.001) and lower survival (P = 0.008). Higher absolute blast count also translated into lower CR rate and survival. The CR rate did not differ among cytogenetic categories except for a trend for a reduced CR rate for Ph+ ALL at 67% (P = 0.051). However, after adjusting for the older age of these patients, the CR rate was not statistically worse for Ph+ ALL (P = 0.36). Overall survival was worse for Ph+ disease and other unfavorable abnormalities compared to subjects having a normal karyotype. The miscellaneous group had similar survival to those having a normal karyotype. In multivariate analysis of survival, cytogenetic risk group remained significant whereas older age, and presenting white blood cell count did not.
Commentary
ALL is an uncommon disease particularly among adults. The poor outcomes in patients harboring Philadelphia chromosome positive ALL, at least prior to tyrosine kinase inhibitors, has been long appreciated. Stratifying outcome in ALL by cytogenetic risk groups aside from Ph positive disease, as frequently done for AML, has not been as readily accepted. These data further validate the prognostic relevance of cytogenetic risk groups for adult ALL.2 Cytogenetic abnormalities in addition to the Philadelphia chromosome can identify high-risk patients compared to a normal karyotype. More interestingly, cytogenetic abnormalities essentially trumped other known risk factors such as older age, and leukocytosis. The emerging data on the prognostic importance of cytogenetic abnormalities requires the community oncologist to ensure a specimen is sent for cytogenetic analysis in cases suspected of ALL. Moreover, FISH probes for BCR/ABL can be applied when the cytogenetic samples are inadequate.
The conclusion that cytogenetics are more important then the traditional risk factors of age or presenting white blood cell count must be tempered somewhat. First, enrolled patients were 65 years or younger with a median age of 32 years and fit enough to undergo intensive therapy. Among adults, ALL increases in late life and thus many adult cases occur in individuals over 65 years of age. Thus, these results do not apply to older and/or frail patients often encountered in routine clinical practice where the prognosis is generally dismal. Further, aside from Ph+ ALL, the exact abnormalities that encompass unfavorable cytogenetics in adult ALL vary in different studies. For example, the unfavorable cytogenetic categories of monosomy 7 and trisomy 8 reported herein were not found to be adverse in another larger study.3 The authors rightly conclude a standardized cytogenetic and/or molecular classification system is needed for ALL.
The data raise questions about how to tailor therapy based upon cytogenetic risk. Allogeneic transplant is often considered for high risk disease; however, the benefits and risks of allogeneic transplant for ALL remain controversial. Even for Philadelphia positive ALL in a younger adult, the improved outcomes with tyrosine kinase inhibitors (eg, imatinib, nilotinib, dasatinib) both with and without allogeneic transplant have muddied even these previously clear waters. Because of the uncertainty, it behooves physicians to offer transplant referral for adults under 50-60 years of age who are otherwise fit to further discuss the risks and benefits of allogeneic transplant. Another issue not addressed but frequently encountered is the older adult (eg > 60-70 years of age) with ALL for whom intensive chemotherapy may not be tolerated. Generally, such older adults have a particularly poor prognosis although the high prevalence of Philadelphia chromosome positive disease provides a less intensive palliative option of oral tyrosine kinase inhibitors.
References
1. Pui CH, et al. Acute lymphoblastic leukemia. N Engl J Med. 2004;350:1535-1548.
2. Wetzler M, et al. Blood. 1999;93:3983-3993.
3. Moorman AV, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189-3197.
The prognostic importance of cytogenetics was evaluated in 200 adults between 15 and 65 years of age treated on a single ALL cooperative group protocol. Among the 140 having evaluable cytogenetic data, four risk categories were devised. Philadelphia chromosome positive t(9;22), unfavorable (monosomy 7, trisomy 8 or an 11q23 rearrangement), miscellaneous and normal. Overall survival of the miscellaneous group was similar to the normal karyotype patients whereas survival was considerably worse for both unfavorable and Ph + cytogenetic groups. The traditional adverse risk factors of older age and higher presenting white blood cell count were not associated with worse survival after adjusting for cytogenetics. In adult ALL, cytogenetics categories may be the strongest factor in predicting outcome.Subscribe Now for Access
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