Central Review of Cytogenetics Is Essential for Cooperative Group Clinical and Correlative Studies of Acute Leukemia: The Cancer and Leukemia Group B (CALGB) 8461 Experience.
Authors: Mrózek Krzysztof , Carroll Andrew J. , Maharry Kati , Rao Kathleen W. , Patil Shivanand R. , Pettenati Mark J. , Watson Michael S. , Arthur Diane C. , Tantravahi Ramana , Heerema Nyla A. , Koduru Prasad R.K. , Bigner Sandra H. , Stamberg Judith , Block AnneMarie W. , Edwards Colin G. , Sterling Lisa J. , Bloomfield Clara D. 
Published: October 2019

Cytogenetic analysis has become an integral part of diagnosis and prognostication of acute myeloid (AML) and acute lymphoblastic leukemia (ALL). Consequently, CALGB mandates cytogenetic analyses for adult AML and ALL first-line treatment trials and many correlative studies. It is thus imperative that cytogenetic data are accurate. To this end, CALGB has performed central review of karyotypes (CRK) submitted by CALGB approved institutional cytogenetics laboratories since 1985. In this study, we have evaluated the role of CRK in ensuring that high quality cytogenetic data are available to CALGB researchers using two criteria: 1) the proportion of specimens deemed on CRK to be of sufficient vs insufficient quality to be included in the CALGB database (ie, accepted vs rejected according to the criteria published by Byrd et al, Blood2002;100:4325–4336), and 2) among the accepted cases, the proportion of submitted karyotypes whose interpretation was changed during CRK. In our analyses, we excluded samples studied cytogenetically during complete remission, because they differ from pretreatment and relapse samples in that they rarely contain leukemic cells and usually are karyotypically normal. Overall, 18% of AML and 35% of ALL karyotypes submitted were not accepted (Table). The most common reason for rejecting a karyotype on CRK was inadequate banding quality, which accounted for rejection in 41% of AML and 34% of ALL inadequate cases.

Disease All Specimens 1986 CRK 2001-2003 CRK P-value* * A comparison of the rejection rates between the 1986 and 2001–2003 CRKs using Chi-square test; † % of the accepted specimens AML No. of specimens reviewed 4169 269 795 <0.0001 % rejected on CRK 18% 30% 12% % revised on CRK† 26% ALL No. of specimens reviewed 996 92 65 0.004 % rejected on CRK 35% 49% 26% % revised on CRK† 25%

The quality of the submitted karyotypes, measured by the proportion of rejected cases, has improved significantly in both AML and ALL since 1986. However, CRK in 2001–2003 still found 12% of AML and 26% of ALL samples inadequate. Among karyotypes deemed adequate, we analyzed in detail revisions made during the 2001–2003 CRK. Changes in karyotype interpretation were made in 26% of AML and 25% of ALL cases. The revisions included identification or reinterpretation, other than reassignment of breakpoints, of the chromosome abnormality (seen in 52% of samples with karyotype errors), a misidentified or upside down chromosome(s) (34%), reassignment of breakpoints in structural aberrations recognized by the submitting laboratory (28%) and correction of errors in the ISCN (1995) nomenclature (15%). Examples of clinically relevant changes in karyotype interpretation included revisions of a normal karyotype to an abnormal one that harbored inv(3)(q21q26), t(9;11)(p22;q23), t(11;19)(q23;p13.1), or inv(16)(p13q22), change from del(11)(q23) to t(6;11)(q27;q23), etc. Overall, 35% of AML and 45% of ALL samples submitted were either rejected or revised on CRK. We conclude that although we observed an improvement in quality of cytogenetic analyses over time, central review of karyotypes still plays a vital role in ensuring the success of the clinical trials and correlative studies conducted by cooperative groups.