Presence Of Additional Chromosomal Abnormalities Research Articles

Prognosis influence of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia with t(15;17)(q24;q21)

ABSTRACT Objectives In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs. Methods 268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs. Results APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable. Conclusions Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights.

The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.

Rare monosomy 7 and deletion 7p at diagnosis of chronic myeloid leukemia in accelerated phase

Clonal cytogenic evolution with the development of additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is a marker for disease progression and is known to impact therapy and survival. The presence of ACAs has been shown to affect the responses to tyrosine kinase inhibitors (TKI) in patients with newly diagnosed CML in accelerated phase (CML-AP). We report a rare case of a CML patient who presented in CML-AP and was found to have multiple ACAs including monosomy 7, deletion 7p, trisomy 8, and an extra Philadelphia chromosome (Ph) in separate Ph-positive cell line, respectively. Six months after combined chemotherapy with TKI, the patient achieved a major cytogenetic response with disappearance of monosomy 7/deletion 7p with no major molecular response.

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

PB1937 CHROMOSOMAL ABERRATIONS IN CHRONIC MYELOID LEUKEMIA AND THEIR IMPACT ON RESPONSE TO CONVENTIONAL TYROSINE KINASE INHIBITORS AND RISK OF BLASTIC TRANSFORMATION.

Background:Chronic Myeloid Leukemia(CML) is a common hematological malignancy with tyrosine kinase inhibitors(TKI) forming the main stay of treatment.Aims:The purpose of this project was to study the clinical presentation of patients with CML harboring additional chromosomal abnormalities at diagnosis and disease outcomes.Methods:This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at our institution.Results:Response to initial TKI A total of 283 patients were diagnosed with CML from January 2010 to January 2015. Thirty one patients were found to have ACAs at the time of diagnosis in addition to BCR‐ABL fusion gene.23 patients (74.2%) were males whereas 8(25.8%) were females. 13(41.9%) were in the age group of 31 to 50 years. 30 patients were started on Imatinib and one on Nilotinib. 16 patients (51.6%) achieved complete hematological response within 3 months. However a complete molecular and cytogenetic response was never achieved in 17 (54.8%) and 18 (58.1%) patients respectively.Cytogenetics Analysis and ACAs Conventional cytogenetic analysis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q.Risk of blastic transformation Eight patients (25.8%) transformed to acute myeloid leukemia(AML) whereas 3 (9.7%) patients had a transformation to acute lymphoblastic leukemia(ALL).Therapy and response in transformed patients Out of the 11 patients who transformed to AML and ALL, 6 patients underwent induction chemotherapy while 5 were not considered fit for it on account of poor performance score and lack of resources. Out of these 6 patients, none responded to induction chemo.Summary/Conclusion:In summary, this study aimed to look at the clinical presentation of patients with CML harboring additional chromosomal abnormalities at diagnosis, cytogenetic analysis, risk of blastic transformation and response to treatment in transformed patients. Despite an early hematological response, more than half of the patients failed to achieve complete molecular and cytogenetic response which clearly shows suboptimal response to the tyrosine kinase inhibitors in this particular set of CML patients. There was transformation to acute leukemia in 35.5% of patients. We were able to give induction chemotherapy to only 6 out of 11 patients and none of them responded to it. This study showed that presence of ACA at the time of diagnosis is a high risk feature for patients with CML and confers poor prognosis when treated with conventional TKI. Further studies are required in our population regarding alternative therapy for such patient population.

Association between the clinical stages of chronic myelogenous leukemia and presence of additional chromosomal abnormalities

Association between the clinical stages of chronic myelogenous leukemia and presence of additional chromosomal abnormalities

Prognostic importance of additional cytogenetic anomalies in chronic myeloid leukemia

Additional chromosomal abnormalities (ACAs) in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) are strongly associated with disease progression, but their prognostic impact and effect on treatment response are not clear. While the onset of ACAs in Ph-negative cells during treatment has been described, their origin and clinical significance remain to be clarified. Between January 2008 and January 2011, 105 patients with Ph-positive CML were analyzed. With a median follow-up of 25.5 months, 18 CML patients (17 %) with ACAs in either CP (n = 12) or advanced phases (n = 6) were identified. The median age of the patients was 53.5 years at diagnosis. ACAs were determined in Ph-positive metaphases of 12 patients and in Ph-negative metaphases of 5 patients. One patient showed trisomy 8 both in Ph-positive and in Ph-negative metaphases. The median follow-up after the detection of ACAs was 11.9 months. None of the patients carrying ACAs in their Ph-negative metaphases developed AP or BP; however, 7 out of 12 patients (58 %) having ACAs in their Ph-positive metaphases developed AP/BC at diagnosis or follow-up (p = 0.03). All the patients carrying ACAs in only Ph-negative metaphases achieved optimal response under tyrosine kinase inhibitor (TKI) therapy, whereas only 4 out of 12 patients (25 %) had optimal TKI response in patients with ACAs in Ph-positive metaphases (p = 0.009). The presence of ACAs in Ph-positive cells during TKI therapy may reflect genetic instability and therefore negatively affect OS. Conventional cytogenic analyses remain mandatory during follow-up of patients with CML under TKI therapy.

Characteristics of translocation (16;16)(p13;q22) acute myeloid leukemia

A subgroup of patients with core binding factor acute myeloid leukemias (AML) is characterized by the presence of the fusion gene CBFb-Myh11. At the cytogenetic level, most of these patients are identified by the presence of an inversion of chromosome 16 [inv(16)(p13q22)] and rarely by a translocation t(16;16)(p13;q22). The aim of this study is to describe the natural history of patients with t(16;16) [N = 6] treated at MD Anderson Cancer Center and compared them with a cohort of patients with inv(16)(p13q22) [n = 61]. In patients with t(16;16) the complete remission rate (CR) was 100% when treated with a combination of fludarabine and high-dose cytarabine. Median overall survival (OS) had not been achieved. There was no difference in response or OS or progression free survival between both groups. Presence of additional chromosomal abnormalities and molecular aberrations had no effect on prognosis. In conclusion, and consistent with previous reports, the natural history of patients with t(16:16)(p13;q22) is similar to that of classic patients with inv16 AML and therefore should be treated similarly.

Pathogenesis of MONOSOMY 7 In BONE MARROW FAILURE SYNDROMES

Abstract 2411One of the most serious complications of aplastic anemia (AA) is the clonal evolution to myelodysplastic syndrome (MDS). Monosomy 7 (del[7]) is the most common chromosomal aberration encountered in this setting, but it can also occur in primary MDS along with deletion 7q (del[7q]). In our whole cohort of AA, we detected del[7] in 24 cases of clonal evolution; however, unlike in MDS no cases of del[7q] were observed. In contrast, in MDS or myelodysplastic/myeloproliferative neoplasms, del[7]/[7q] were present in 12% and 11%, respectively. Based on an initial observation of an index AA case with a mutation of CBL, we speculated that certain molecular events such as point mutations can promote or are at least associated with the evolution of del[7]. Given the distinct distribution of del[7] and del[7q] in primary and secondary MDS (derived from AA), we stipulate that the associated mutational pattern will be distinct. This may be due to different driving mechanisms, such as immune escape or a growth factor-rich milieu in AA.Pursuant to this theory, we performed a screen for CBL, RUNX1, TET2, UTX, EZH2, DNMT3A, ASXL1 and IDH family mutations in patients who developed del[7] after AA (N=24). 14 cases were adults and 10 were pediatric cases. In addition, we analyzed 15 del[7], 13 del[7q] and 10 UPD[7q] abnormalities in patients with MDS without antecedent AA. We identified 3 CBL (13%), 5 RUNX1 (20%), 1 TET2 and 1 DNMT3A mutation in patients with del[7] after AA; all CBL mutations are observed in adult cases of AA (21%). However, 0, 1, and 2 CBL mutations were found in primary MDS with del[7], del[7q] and UPD[7q], respectively. In contrast, RUNX1 mutations were seen in both AA sub-groups (14% and 30% in adults and children, respectively). Also, no differences were seen with regard to the distribution of RUNX1 mutations in either post-AA MDS with del[7] or primary MDS with del[7], del[7q] and UPD[7q]. Most significantly, ASXL1 was found to be the most frequently mutated gene in the cohort without AA (37%), although no mutations were seen in patients with del[7] after AA. Additionally, UTX and EZH2, both involved in the trimethylation of histone H3 lysine 27, were found to be mutated only in cases of MDS with UPD[7q] and del[7q], but no mutations were seen in primary and AA-derived MDS with del[7]. When studied serially, none of the tested mutations was seen in the initial AA phase, but the mutated clone increased gradually during clonal evolution of del[7].We also investigated the presence of additional chromosomal abnormalities using single nucleotide polymorphism array (SNP-A)-based karyotyping in the cases with del[7] after AA. In addition to del[7], 22 gains, 20 losses and 4 regions of somatic uniparental disomy (UPD) were identified. These abnormalities, including microdeletions, were found in 50% and 60% of adult and pediatric cases, respectively. Recurrent lesions were detected on chromosome 6, 8 and 21. A microdeletion on chromosome X involved the tumor-associated gene PHF6 in a male case. In another patient, trisomy 21 was accompanied by a RUNX1 mutation. Regions of UPD included 6p resulted in loss of heterozygosity of MHC class I and 11q was associated with homozygous CBL mutations in 2 cases.In sum, our analysis supports the theory that distinct mechanisms of molecular progression during MDS evolution may be operative in AA and primary MDS. Moreover, del[7], del[7q] and UPD[7q] have distinct molecular profiles with frequent TET2 mutations in del[7q] and UPD[7q]. ASXL1 mutations appear to be most ubiquitous promoting event in MDS with LOH [7/7q], suggestive of their “type II' nature. In contrast, other mutations such as those in CBL may be selected for e.g., through cytokine-rich milieu and activation of CBL-regulated receptor tyrosine kinases. Disclosures:No relevant conflicts of interest to declare.

Outcome of Patients with Philadelphia Positive Chronic Myeloid Leukemia Post Imatinib Failure: Prognostic Significance of ABL Mutation and Additional Clonal Abnormality.

Abstract 4673Point mutation within the ABL kinase domain of the BCR-ABL gene has been associated with clinical resistance to imatinib in chronic myeloid leukemia (CML). However, several other mechanisms have been proposed to underlie the development of imatinib resistance such overexpression and amplification of the BCR-ABL gene locus; development of additional chromosomal abnormalities (ACA), activation of BCR-ABL independent mechanisms; increased drug efflux through multidrug resistance gene and binding of imatinib to serum alfa-1 acid glycoprotein. In this regard, we report the outcome of 54 patients Ph+ CML who were resistant to imatinibe and the association with point mutation, ACA and overexpression of BCR-ABL through in situ hybridization (FISH). Patients and MethodsOf 54 CML patients, 16 were in early chronic phase (ECP), 24 in late chronic phase (LCP) and 14 in accelerated phase (AP) before imatinib treatment. They were considered imatinib resistant for the following reasons: hematologic resistant or recurrence (7 patients), cytogenetic resistance or recurrence (30 patients) or progression to more advanced phase (17 patients). Mutational analysis was carrying out by direct sequencing and FISH analysis using commercial BCR/ABL t(9;22), dual color, dual fusion probe (Kreatech, Poseidon, The Netherlands). Subsequent therapy was also analyzed, as to whether they underwent to allogeneic SCT, chemotherapy, or received, dasatinib or nilotinib. ResultsA total of 24 BCR-ABL kinase domain mutations were detected in 54 patients. Two patients had more than 1 mutation. The most frequent mutations were F359V (6/24), T315I (5/24) and F317L (3/24). P-loop mutations accounted for 60% of the remaining amino acid substitutions. Twelve patients were treated with nilotinib 400 mg bid, 50% presented mutation at resistance (3 F359V, 1 Q252H, 1 E355G, and 1 T315I), and all alive but one with T315I mutation died after 1 month. Dasatinib, 100-140 mg daily, was dispensed for 37 patients, mutations were identified in 40%, where 10 patients are still alive (2 T315I, 2 F317L, and 6 others). Allogeneic SCT was performed in 2 patients (1 G250E), and both died. Two patients died (1 F359V) after systemic chemotherapy and 1 patient who received 800 mg of IM is in CCyR after 40 months. There was no difference in overall survival when mutation was present or not at the moment of resistance (log rank, p=0.9). We also compared the karyotype tacked before imatinib treatment with the karyotype performed at the time of resistance; 17 patients developed ACA and were associated with worse overall survival (log rank, p=0,046) when compared with those patients without ACA. FISH analysis did not identify overexpression of BCR-ABL, but 4 cases presented 3 signals for BCR-ABL indeed had an extra Ph chromosome. ConclusionsSecond-generation TK inhibitors improve overall survival of those patients who presented mutations at resistance. The presence of ACA during imatinib treatment was related with a higher mortality despite the treatment applied and the presence or not of mutations. We also conclude that overexpression of BCR-ABL was not responsible for resistance to imatinib in our study population. Disclosures:No relevant conflicts of interest to declare.

Monitoring chronic myeloid leukemia (CML) response to tyrosine kinase inhibitors (TKI) and homoharringtonine (HHT) using peripheral blood (PB) fluorescence in situ hybridization (FISH) and quantitative RT-PCR (Q-PCR): Are bone marrow biopsies still needed?

7064 Background: The purpose of this study is to compare simultaneously obtained PB and bone marrow (BM) BCR-ABL FISH and Q-PCR to monitor response to TKI and HHT in CML. Methods: Between January 2005 and December 2008, 52 patients (pts) with chronic (n = 37, 80%), accelerated (n = 6, 7%), and blast phase (n = 9, 14%) CML had 112 simultaneous PB and BM FISH and Q-PCR before and/or after start of imatinib (IM, n = 27), dasatinib (n = 9), nilotinib (n = 1), bosutinib (n = 13), or HHT (n = 2) for newly diagnosed (n = 27), IM resistant (n = 20), or IM intolerant (n = 5) CML. 13 (26%) had chromosomal abnormalities in addition to the Philadelphia chromosome, and 10 (20%) had a detectable BCR-ABL mutation including the T315I in 2 pts. Results: 24 (46%) had simultaneous PB and BM FISH and/or Q-PCR measurements obtained at 1 time point, 9 (17%) at 2; 9 (17%) at 3; 10 (20%) at > 4 time points before and/or post-initiation of TKI or HHT. Excellent concordance was observed between PB and BM at all time points for both FISH (r = 0.96; p = 0.0003) and Q-PCR (r = 0.88; p= 0.0015). Correlation was not affected by the presence of additional chromosomal abnormalities, phase of the disease, treatment (TKI or HHT), or the number of prior therapies. Conclusions: FISH and Q-PCR are reliable methods to monitor CML response to TKI and HHT in patients with CML and may render the need for BM biopsy monitoring obsolete. No significant financial relationships to disclose.

Prognostic value of low platelets in MDS patients with del(5q)

7078 The most common (10–15%) chromosomal abnormality found in myelodysplastic syndromes (MDS) is an interstitial deletion of the long arm of chromosome 5 (del(5q)). The recent finding that lenalidomide is efficacious for MDS patients with del(5q) as either the sole abnormality or as part of a complex karyotype has focused renewed interest in the prognostic characteristics of these patients. We analyzed 189 patients with del(5q), 70 having isolated and 119 having additional chromosomal abnormalities. The median survival for the isolated del(5q) patient was 2.45 years and for those with complex abnormalities was 0.63 years (p=0.001). Each of these groups was then divided by IPSS category; median survival for Low/Int1 (n=56) was 2.46 years and 0.49 years for Int2/High (n=10, p=0.019).Thus our median survival times match previously published results and we have a representative dataset. Since 5q- syndrome patients with normal to high platelets have the best survival, platelet count may be of prognostic significance. We determined the median platelet count for our dataset to be 115,000 and analyzed median survival for patients with greater (n=89) or less (n=88) than the median value. Survival for those with higher platelet counts was 2.6 years, but dropped to 0.54 years with lower counts (p=0.0001). We then analyzed each of these two groups independently for survival based on IPSS, blast % and karyotype. Median survival for patients with >115,000 platelets and either Low/Int1-risk (n=62), <5% blasts (n=46) or an isolated del(5q) (n=46) was 2.95–3.0 years. The survival of these patients dramatically decreased (0.63 years) if they had Int2/High IPSS (n=19) or >10% blasts (=11). The presence of additional chromosomal abnormalities decreased survival to 1.85 years (n=28). A different range of survival times occurred with patients that had <115,000 platelets. Their median survival based on Low/Int1 IPSS (n=20), <5% blasts (n=18) or isolated del(5q)(n=20) was only 0.68–0.84 years. Int2/High IPSS (n=64), >5% blasts (n=50) or additional chromosomal abnormalities (n=68) lowered survival to 0.44–0.49 years. Thus lower platelet counts in del(5q) MDS patients with favorable IPSS (median survival 0.84 years), <5% blasts (median survival 0.68 years) or isolated del(5q) (median survival 0.74 years) appear to have poor prognosis. No significant financial relationships to disclose.

Additional Cytogenetic Abnormalities and/or Philadelphia Chromosome Metaphase Mosaicism Might Adversely Influence Survival and Imatinib Response in Chronic Myeloid Leukemia.

Background: Chronic myeloid leukemia (CML) is invariably associated with the reciprocal translocation of BCR and ABL to form the Philadelphia chromosome (Ph), t(9;22)(q34;q11). At diagnosis, a small proportion of patients display additional cytogenetic abnormalities and/or a variable proportion of cytogenetically normal metaphases that coexist with Ph-positive metaphases. The objective of the current study was to examine the prognostic relevance of these two scenarios.Methods: The study population consisted of 65 (47.7% female) consecutive, newly diagnosed CML patients seen at the Mayo Clinic with a median age of 59 years. 44.5 percent were initially treated with interferon alpha (IFN) resulting in complete cytogenetic remission in 10.7 percent for a median length of 5.83 years, partial cytogenetic remission in 3.57 percent for a median length of 2 years. 55.5 percent were treated with imatinib (Gleevec) resulting in complete cytogenetic remission in 54.1 percent for a median length of 3.08 years, partial cytogenetic remission in 13.5% for a median length of 1.08 years.Results: Survival at five years through Kaplan-Meier analysis was approximately 92 percent in patients demonstrating only the Ph chromosome (n = 53), versus 60 percent in patients with additional chromosomal abnormalities (n = 12; p < 0.0001 by both Logrank and Breslow-Gehan-Wilcox analysis). Furthermore, patients with additional chromosomal abnormalities demonstrated lower rates of either complete or partial cytogenetic remission with imatinib therapy. Similarly, five year survival of patients with less than 90% Ph-positive metaphases at diagnosis (n = 4) was approximately 60% compared to 92% in patients with greater than 90% Ph-positive metaphases (n = 61; p = 0.01 by Logrank and p = 0.001 by Breslow-Gehan-Wilcox analysis). Additionally, the former group of patients was significantly less responsive to imatinib. Finally, there was significant correlation between Ph-positive metaphase mosaicism and the presence of additional chromosomal abnormalities (p = 0.05).Conclusion: Although it is tempting to speculate the possibility that Ph-chromosome mosaicism and/or additional cytogenetic abnormalities at presentation of CML is a surrogate for the presence of Ph-negative imatinib-resistant clones, the preliminary results from the current study require validation from a larger study. [Display omitted] [Display omitted]

The clinical spectrum of adult acute myeloid leukemia (AML) associated with core binding factor (CBF) translocations

6513 Background: Although adults with AML containing CBF translocations [t(8;21) or inv(16)/t(16;16)] have a high complete response (CR) rate and improved overall survival (OS) compared to other AML patients (pts), not everyone does well. Methods: In order to better understand the spectrum of CBF-associated AML, we analyzed 373 pts with newly diagnosed CBF-related AML treated on SWOG, ECOG or MDA protocols. Results: Pts ranged in age from 16–83 (median 39) with a slight male predominance (56%). Overall, 53% of pts had inv(16) or t(16;16) while 47% had t(8;21); 58% had chromosomal abnormalities in addition to the CBF translocation. Pts with t(8;21) tended to be younger (p=0.03), have lower white counts (p<0.0001) and more often have additional chromosomal abnormalities (p<0.0001). CR was achieved in 86% of pts (95% confidence interval [CI] 82–89%) and the estimated resistant disease (RD) rate was 8% (CI 5–12%). Increasing age was the major factor associated with a decreased CR rate (p=0.0029) and increased incidence of RD (p=0.0014). OS at 10 years was 43% (CI 38–49%), and was significantly lower in older pts (p<0.0001) and those with higher peripheral blast percentage (p=0.0001). Relapse-free survival (RFS) was 40% (CI 34–46%) at 10 years and likewise was associated with age and peripheral blast percent. The treatment results did not differ significantly between pts with t(8:21) versus inv(16) and were not significantly influenced by the presence of additional chromosomal abnormalities. Conclusions: Although pts with CBF-associated AML do relatively well with 43% 10-year OS, considerable improvement is needed, particularly in older patients and those presenting with a higher percent of blasts in their peripheral blood. No significant financial relationships to disclose.

No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities

This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.

Cytogenetic studies on Burkitt's lymphoma-leukemia

Chromosome studies on 26 cases of Burkitt's cell malignancy are reported, including 7 lymphomas and 19 acute lymphocytic leukemias. A specific translocation was found in 26 of the patients: 20 t(8;14), 4 t(8;22), and 1 t(2;8). In one other case only 2 mitoses out of 59 were found to have a probable t(8;22) translocation. Additional chromosomal abnormalities were found in 15 of the patients, irrespective of whether they had or had not been treated before cytogenetic investigation. The most remarkable was a partial duplication of chromosome 1q. The presence of additional chromosomal abnormalities together with a specific translocation allows a distinction to be made between specific and secondary chromosome anomalies. The implications of the two types of aberrations for research into the molecular mechanisms of malignancy are discussed.