Patients with Isolated Trisomy 8 in Acute Myeloid Leukemia Are Not Cured with Cytarabine-Based Chemotherapy: Results from Cancer and Leukemia Group B 84611

Vol. 4, 1235-1241, May 1998 Clinical Cancer Research 1235

Patients with Isolated Trisomy 8 in Acute Myeloid Leukemia Are Not Cured with Cytarabine-based Chemotherapy: Results from Cancer and Leukemia Group B 84611

John C. Byrd,2 David Lawrence, isfactory with a complete remission (CR) rate of 59%, me- Diane C. Arthur, Mark J. Pettenati, dian CR duration of 13.6 months, and median survival of 13.1 months. Older age adversely affected outcome; trisomy Ramana Tantravahi, Mazin Qumsiyeh, 8 patients 60 years had both an inferior CR rate (40% Judith Stamberg, Frederick R. Davey, versus 88%; P = 0.004) and overall survival (median, 4.8 Charles A. Schiffer, and Clara D. Bloomfield versus 17.5 months; P 0.01), as compared with those <60 Walter Reed Army Medical Center, Washington, DC 20307 [J. C. B.]; years of age. Of the patients <60 years of age, only four Roswell Park Cancer Institute, Buffalo, New York 14263 [D. L., remain alive, and all received noncytarabine-based intensive C. D. B.]; University of Minnesota, Minneapolis, Minnesota 55455 chemotherapy, followed in three cases by autologous (n 2) [D. C. A.]; Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157 [M. J. P.]; Dana-Farber Cancer Institute, Boston, or allogeneic (n = 1) stem cell transplant in CR!. Adults Massachusetts 021 15 [R. T.]; Duke University Medical Center, with AML and isolated trisomy 8 have a poor outcome that Durham, North Carolina 27710 [M. Q.]; University of Maryland is accentuated by increasing age and is rarely cured with Cancer Center, Baltimore, Maryland 21201 [J. S., C. A. S.]; and cytarabine-based therapy. Alternative investigational treat- SUNY Health Science Center at Syracuse, Syracuse, New York ments should be considered for individuals with this AML 13210 [F. R. D.] subset.

ABSTRACT INTRODUCTION To date, neither the clinical significance of isolated Cytogenetic studies in AML3 have become one of the most trisomy 8, the most frequent trisomy in acute myeloid leu- useful prognostic factors in predicting both initial response to kemia (AML), nor the effect of age within a single cytoge- induction chemotherapy, remission duration, and overall sur- netic group has been examined. We report a large cohort of vival. Adult patients presenting with the t(8;2 I )(q22;q22) and adult trisomy 8 patients and examine whether increasing age inv(16)(p13q22) chromosomal abnormalities can expect a within a homogeneous cytogenetic group alters clinical out- >90% chance of attaining a CR (1, 2) and a 78% cure rate with come. Characteristics and outcome of patients with isolated HDAC intensification therapy (3). Although patients with t(15; trisomy 8 enrolled in the prospective Cancer and Leukemia 17)(q22;q2l) initially were believed to have a slightly worse Group B (CALGB) cytogenetic study CALGB 8461 are prognosis than the t(8;21) and inv(16) patients, several recently described. Isolated trisomy 8 was identified in 42 (3.03%) of reported trials have noted up to a 95% CR rate using all-trans 1387 patients enrolled in five CALGB treatment protocols. retinoic acid with durable remissions when combined with These patients had a median age of 64 (range, 16-79) years, chemotherapy (4-8). Patients with normal karyotypes have an 50% female proportion, and a low frequency of hepatomeg- intermediate prognosis with a -70% (1, 2, 9, 10) chance of aly (10%) or splenomegaly (10%). Laboratory features in- attaining a CR and 38% likelihood of these individuals being cluded a median white blood count of 7.3 x iO9fL, nonspe- cured with HDAC intensification (8). Although karyotype- cific French-American-British distribution, with 36% of specific postremissiom therapy benefits patients with t(8;2l), patients having Auer rods. Treatment outcome was unsat- inv(16), and normal karyotypes (8, 1 1), no added effect has been demonstrated in patients with adverse karyotypic abnormalities (8). Because the poor prognostic group includes a variety of partial or whole deletions (chromosomes 5, 7, 1 1 , and others), Received 9/12/97; revised 12/31/97; accepted 1/21/98. translocations [t(9;22), t(6;9), and others], and trisomies (+4, The costs of publication of this article were defrayed in part by the +8, + 1 1, + 13, +21), it is possible that one or more of these payment of page charges. This article must therefore be hereby marked advertisement in accordance with I 8 U.S.C. Section 1734 solely to small specific karyotype groups have potentially an inherently indicate this fact. good prognosis when given intensive HDAC chemotherapy. t This work was supported by National Cancer Institute Grants 37027 Trisomy 8 is the most frequently noted abnormality in and 26806 and the Coleman Leukemia Research Fund and additional AML, occurring in -9% of patients with adequate pretreatment grants to individuals as follows: Grant CA26806 (to J. C. B.); Grant CA cytogemetics 1 ). Trisomy 8 is most often associated with other 59518 (to D. L. and C. D. B.); Grant CA16450 (to D. C. A.); Grant ( CA03927 (to M. J. P.); Grant CA32291 (to R. T.); Grant CA47577 (to M. Q.); Grant CA31983 (to J. S. and C. A. S.); and Grant CA2IO6O (to F. R. D.). Presented in part at the April 1996 meeting of the American Association for Cancer Research, Washington D.C.

2 To whom requests for reprints should be addressed, at 3 The abbreviations used are: AML, acute myeboid leukemia: CR, com- Hematology-Oncology Service, Ward 78, Walter Reed Army Medical plete remission: HDAC, high-dose cytarabine: CALGB, Cancer and Center, Washington, DC 20307. Phone: (202) 782-5746; Fax: (202) Leukemia Group B; FAB. French-American-British; EFS, event-free 782-3256. survival.

karyotypic abnormalities but also can occur as the sole abnor- the first three days of treatment. Patients >60 years were given mality. Isolated trisorny 8 was noted in 3% of AML patients 30 mg/m2/day of daunorubicin on some of the studies. Postre- with adequate pretreatment cytogenetics.4 Despite this relatively mission therapy for CALGB 8221 ( 16), 8525 (17), and 9022 high frequency, the largest reported series of isolated trisomy 8 ( 1 8) has been described previously. Postremission therapy on patients includes only 20 patients, and information regarding the CALGB 8923 (19) included four cycles of cytarabine (100 outcome of treatment is quite controversial. Furthermore, virtu- mg/m2/day) by continuous infusion for 5 days or two cycles of ally all of the report published previously have used cytogenetic cytarabine 500 mg/m2 and mitoxantrone 5 mg/m2 every I 2 h for prioritization schemes ( I 2) to compare different karyotype six doses. Postremission therapy on CALGB 9222 included 3 groups for prognostic value. In such schemas. patients with cycles of HDAC (3 g/m2 cytarabine over 3 h every I 2 h on days trisomy 8 are often combined with individuals who have other I , 3, and 5) or I cycle of HDAC, followed by one course each cytogenetic abnormalities. Such heterogeneity in reporting tn- of etoposide ( I 800 mg/m2 by CI on day 1) with cycbophos- somy 8 has produced widely conflicting conclusions, not nec- phamide (50 mg/kg iv. over 2 h on days 2 and 3) and diazi- essanily applicable to the patient with tnisomy 8 as a sole quone (24 mg/m2 by CI daily for 3 days), filgrastim (5 p.gfkg abnormality. Additionally. despite the higher frequency of tn- s.c. daily from day 4-28), and mitoxantrone (12 mg/m2 daily somy 8 observed in older patients. a previously well-defined bolus on days 1-3). prognostic factor in AML, none of the published cytogenetic Definition of Response. The definition of hematological series to date have examined age in the context of a single CR in this study adhered to the criteria established previously nonheterogeneous karyotypic group. In an attempt to better (20). This required normal bone marrow cellularity with normal characterize the clinical features and curability of both young erythropoiesis, megakaryocytopoiesis, and granulocytopoiesis and old patients with pretreatment. isolated tnisomy 8, we de- with <5% blasts. scribe 42 cases enrolled in the prospective CALGB cytogenetic Definition of Relapse, Remission Duration, and Sur- study 8461 who were treated with intensive chemotherapy and vival Duration. Relapse was defined by >5% leukemic cells review the limited literature on this topic. in bone marrow aspirates or new extramedullany leukemia in patients with a previously documented CR. PATIENTS AND METHODS EFS was measured using the failure end points of induction failure (with EFS of 0) and relapse or death in CR (with EFS Patients. Patients included in this analysis were enrolled equal to CR duration). Censoring of the EFS occurs if there is a in CALGB 8461, a prospective cytogenetic companion study to all CALGB treatment protocols since 1984 for adults with continuous CR (with EFS equal to CR duration). In patients who had a CR, CR duration was measured from the date of docu- untreated AML. All patients were I 6 years or older with de novo mented CR to AML relapse (bone marrow or extramedullary) or AML as defined morphologically by the FAB classification system ( I 3, 14). Patients with a prior history of myelodysplasia, death from any cause. Overall survival was measured from the other antecedent hematological malignancies. prior nonsteroidal time of entry on the treatment study to the time of death. Patients who are presently known to be alive were censored for remis- cytotox iC chemotherapy or radiation therapy, preexisting liver sion duration and survival at the date last known to be in disease. or uncontrolled infection were excluded. Central review remission, or alive, respectively. of the pathological diagnosis was performed. Statistical Analysis. The level of significance was eval- Cytogenetics. Chromosomal analyses of bone marrow uated at the 5% level, and two-sided tests were used. CR rate were performed in institutional CALGB cytogenetics Iaborato- nies, and karyotypes were centrally reviewed. Specimens were was compared with the Fisher exact test between age groups dichotomized at 60 years. The Kaplan-Meier method was used obtained at diagnosis from all patients. Specimens were pro- to evaluate the distribution of survival, CR duration, and EFS. cessed using direct methods and unstimulated short-term (24-, 48-, and 72-h) cultures. G-banding was usually done, although CR duration was compared for age groups and intensification Q banding was acceptable for inclusion in this series. A mini- groups using the log-rank test. Because survival curves for the two age groups crossed, the modified Kolmogorov-Smirnov test mum of 20 bone marrow metaphase cells was analyzed in each patient designated as having a normal karyotype. The criteria was used to test for a difference in survival distribution (21). Median follow-up of four patients censored for survival used to describe a cytogenetic clone and description of kanyo- type followed the recommendations of the International System was 44 months (minimum of I 1 months and maximum of 60 months). For CR duration, the median follow-up of four cen- for Human Cytogenetic Nomenclature (15). This study only included patients with +8 as their sole karyotypic abnormality. sored patients was 43 months (minimum of 10 months and maximum of 59 months). Three of these cases were transplanted Treatment. A total of 42 patients with isolated trisomy 8 in first CR. were treated on the prospective AML treatment studies CALGB Literature Review. All cytogenetic series were identi- 8221 (ii = I ), 8525 (‘z = 17), 8923 (ii = 12), 9022 (ii = 6), and fled by Medline, Cancer Lit. Blood supplement, and British 9222 (ii = 6). All patients received an induction regimen that consisted of 7 days of continuous infusion cytarabine (200 Journal of Hematology supplement review, and subsequent mg/m2/day with daily bolus daunorubicin (45 mg/m2/day) for cross-referencing of bibliographies was also performed. Series including 10 or more patients with tnisomy 8 as a sole abnormality were included in this review. Many of these series included heterogeneous groups of trisomy 8 patients based on categorization schemas. The focus of this review was isolated

4 CALGB, unpublished data. trisomy 8. Therefore, when possible, patient characteristics,

Table 1 Pretreatment characteristics of isolated trisomy 8 patients 1.0

No. of patients 42 Median age in years 64 0.8 Sex (% females) 50 Median leukocyte count ( X 1091L) 7.3 Median hemoglobin (g/dl) 9.2 0.6 Median platelet count (X l09/L) 52 .#{128} a % lymphadenopathy 22 0 Q. 0.4 % splenomegaly 10 % hepatomegaly 10 % gum involvement 17 Frequency of FAB classification (%) 0.2 MO 1 (2) Ml I I (26) M2 8 (19) 0.0 M3 0 (0) 0 12 24 36 48 60 72 M4 9 (21) Months MS 6(14) Fig. I Estimated CR duration and overall survival for trisomy 8 pa- M6 2(5) tients. -, survival (n = 42): ---. CR duration (ii = 24). M7 0 (0) Other 3 (7) Median % blasts in blood 47 Median % blasts in bone marrow 70 9222. Disseminated fungal infection (n = I ) or life-threatening % with Auer rods in myeloblasts 36 toxicity during induction with subsequent withdrawal of consent (n 2) were the reasons for patients not receiving further postremission therapy as directed by the respective CALGB treatment study. Short-term maintenance therapy followed for therapy, and outcome were summarized based on the presence three patients assigned to low-dose cytarabine and one assigned of isolated trisomy 8. to intermediate-dose cytarabine on protocol CALGB 8525. This therapy was refused by the other three patients receiving inten- RESULTS sification therapy on CALGB 8525. The CR rate. CR duration, Patient Characteristics. For the five CALGB treatment and overall survival did not vary among the different treatment studies examined, 1387 patients with de novo AML had ade- protocols or by virtue of sex (data not shown). Three additional quate pretreatment cytogemetics. Of these patients, 42 (3.03%) trisomy 8 patients received an autologous (ii = 2) or albogeneic had isolated trisomy 8 as their sole ciomal abnormality. The (n I ) bone marrow transplant in the first CR after completion pretreatment characteristics of these 42 patients are summarized of two or more cycles of protocol-directed. postremission in Table 1. Patients with trisomy 8 had a median age of 64; therapy. however, 81% were age 70 years or less. The frequency of Outcome of Induction and Postremission Therapy. hepatomegaly (10%) and splenomegaly (10%) was low in the Outcome for induction therapy was evaluable in 41 patients, of trisomy 8 patients. Five patients had biopsy-proven leukemia whom 24 (59%) attained a CR. Of these 24 patients attaining a cutis at diagnosis. The median WBC count was 7.3 X 1091L, CR, postremission outcome is depicted in Fig. 1 . Median CR with three (7.1%) of the patients having a presenting value duration was 13.6 (95% confidence interval, 8.5-31.8) months, greater than 100 x l09/L. The FAB classification for trisomy 8 with a 3-year Kaplan Meier estimate of continuous CR of 16%. patients included 2% MO, 26% Ml, 19% M2, 21% M4, 14% Of the 21 patients relapsing, 19 experienced bone marrow M5, and 5% M6, with 7% of patients being unclassifiable. No relapses, and two had central nervous system relapses (menin- patient with sole trisomy 8 was classified as FAB M3 or M7. geal leukemia), which was soon followed by medullary recur- There was a 36% frequency of Auer rods. All patients had rence. Treatment failure occurred late in only one patient (50 polysomy of chromosome 8 as the sole abnormality (38 patients months), but four other patients experienced relapse at 24, 32, with trisomy 8; 3 patients with trisomy 8 and tetrasomy 8 as 33, and 34 months. Combining CR and CR duration outcome secondary clone; and 1 patient with tetrasomy 8). together (i.e., EFS) yields an even shorter median outcome of Induction and Postremission Therapy. Induction treat- only 6.2 (95% confidence interval, 0.0-10.4) months. Fig. I ment for this large cohort of patients was virtually uniform with demonstrates the Kaplan Meier plot of overall survival for all receiving daumorubicin and cytarabime-based therapy. Fol- patients with trisomy 8. Median survival for the trisomy 8 lowing induction, 2 1 received various postremission intensifi- patients was 13.1 (95% confidence interval, 5.2-31.8) months cation therapies including low-dose (n = 4), intermediate-dose with a 3-year Kaplan-Meier estimated survival of only 17%.

(n 2), or high-dose (n = 1) cytarabime as part of CALGB Effect of Dose-Intensive Therapy on Treatment Out-

8525; low-dose cytarabine (n = 1) or intermediate-dose cytara- come. Because postremission therapy with HDAC has been bime and mitoxantrone (n = 5) as part of CALGB 8923; HDAC, demonstrated to significantly affect outcome in favorable AML high-dose cyciophosphamide/etoposide, and mitoxantrome/dia- cytogemetic groups, we examined the effect of one or more ziquome (n = 3) as part of CALGB 9022; and three cycles of cycles of HDAC on CR duration and overall survival for tn-

HDAC (n = 2) or HDAC, high-dose cyclophosphamide/etopo- somy 8 patients. CR duration stratified by the administration of side, and mitoxantrone/diaziquone (n = 3) as part of CALGB one or more cycles of HDAC intensification, as depicted in Fig.

P = .23 P=.93

0 0

C C

C C 0 0 t t 0 0 0. 0.4 0. 0 0 0. 0.

0.2

0.0 0 12 24 36 48 60 72 12 24 36 48 60 72 Months Months

Fig. 2 Estimated CR duration for trisomy 8 patients based on treatment Fig. 3 Estimated CR duration for trisomy 8 patients stratified for age with at least one cycle of HDAC therapy intensification. 60 versus <60.

1.0

2, yielded a CR duration of 19.5 months, which did not signif-

icantly differ (P = 0.23) from the 16.3-month interval observed 0.8 P=.o1 in the non-HDAC-treated patients. Notably, of the four patients 0) C who remain in continuous CR, three received consolidative bone > a marrow transplants in first CR. Of the 20 relapsing isolated CI) C trisomy 8 patients, all received cytarabine-based chemotherapy, 0 t including sequential cycles of HDAC in three. a 0.4 0 Therapy after relapse was ineffective. Although intensive 0.

therapy with stem cell transplant after first relapse of AML is 0.2 considered a standard salvage therapy, its applicability to this (n=25) cohort of patients was minimal. Many of the patients were 0.0 re-induced with a variety of intensive therapies, including 0 12 24 36 48 60 72 HDAC, with the intent of stem cell transplant salvage. However, Months only two (9.5%) ofthe relapsing patients were subsequently able Fig. 4 Estimated overall survival for trisomy 8 patients stratified for to undergo this therapy, and both died of recurrent AML at 1 and age 60 versus <60. 10 months after an autologous bone marrow transplant. Effect of Age on Treatment Outcome. Increasing age is a uniformly agreed upon poor prognostic factor in AML. How- remain alive. Three of these patients underwent autologous or ever, these comparisons have often included different propor- tions of favorable and unfavorable cytogenetic groups in each ailogeneic stem cell transplant in first CR. subset, making interpretation difficult. The effect of age on treatment outcome in this identical cytogenetic group of trisomy DISCUSSION 8 patients was marked. Patients 60 years and older with tnisomy This series constitutes the largest known reported group of 8 (n 25) had a CR rate of only 40% compared with an 88% prospectively studied patients with tnisomy 8 as the sole karyo-

response rate in evaluable individuals (n = I 6) <60 years of age typic abnormality. All of these patients had centrally reviewed

(P = 0.004). Although median CR duration was longer for pathology and cytogenetics. Furthermore, all of the patients patients 60 years and older (median, 20.6 versus 9.9 months), received standard induction chemotherapy, with a majority at- there was no statistical difference between the two age groups taming a CR and subsequently receiving postinduction cytara-

(P = 0.93), as depicted in Fig. 3. All 10 ofthe patients 60 years bine-based therapy. Disappointingly, 94% of the patients receiv- and older have relapsed as compared with 10 of 14 of the ing just short duration, cytarabine-based postremission therapy younger individuals. The survival of patients 60 years and older, relapsed and died of AML. These failures occurred both early as depicted in Fig. 4, was dismal (median, 4.8 months) as and beyond 23 months (24, 32, 33, 34, and 50 months), empha-

compared with that of younger patients ( 1 7.5 months; P = sizing the importance of follow-up beyond 2 years for this 0.01). This marked difference in survival for the 25 elderly cytogenetic group. It is notable that of the four patients who patients is reflective of both a high death rate during induction remain alive in CR with isolated trisomy 8, three received a stem and the absence of sustainable remission in this group. Indeed, cell transplant in first CR. Although autologous or aliogeneic all of the patients 60 years of age and older have died as a stem cell transplant was cited as a planned salvage in many of consequence of either AML or treatment-related toxicity for this these patients, only two underwent this therapy, and both died of underlying disease. Of the 16 patients <60, only four patients AML (I and 10 months after transplant). The poor outcome in

Table 2 Literature review and summary of patient serie s reporting trisomy 8 in AML

Reference 2. 24 22 1 23 25 This report Years studied 1975-1983 1977-1984 1981-1988 1987-1990 1989-1996 1984-1995 No. of +8 patients 3 1 10 27 17 20 42 No. of sole +8 patients I 7 10 20 1 1 20 42 Central review of cytogenetics No No No No No Yes Age NR” NR 57” NR 57’ 64 % CR rate 35 70 73 59 70 59 CR duration” 7.5 mo NR 24 mo 33% predicated CR at 5 yr NR 13.6 mo EFS” NR NR NR NR 5.6 mo 6.2 mo Overall survival” NR 16 mo NR 27% predicted alive at S yr 20.5 mo 13.1 mo Follow-up time” NR NR NR NR 49 44 No. of patients in continuous CR >3 yr NR NR NR NR 3 2 BMT in CR1 (% patients) No No No Yes (% NR) Yes (5%) Yes (7.1%)

a NR, not reported; BMT, bone marrow transplant.

b Median.

C Mean.

94% of this trisomy 8 cohort using cytarabine-based chemother- studies published previously, it is very possible that an overes- apy is problematic. In an attempt to confirm the findings of our timation of treatment success may have occurred. Finally, short, large patient series, a comprehensive review of the literature was intensive, cytarabine-based therapies used in our cohort of pa- performed. tients contrasts with either inclusion of intensive moncytarabime- A total of five series published previously with 10 or more based therapy or prolonged maintenance treatment used in other patients (range, 10-20) with trisomy 8 were identified from the small studies (I , 22-25), citing success in treating tnisomy 8. literature ( 1 , 22-25). Only two of these reports (20 and 10 Although CALGB has demonstrated previously that both inter- patients) included only isolated trisomy 8 patients. The patient mediate-dose cytarabine and HDAC were extremely beneficial characteristics and treatment outcome of these series, along with in patients with favorable or intermediate cytogenetic groups the CALGB experience, are summarized in Table 2. One addi- (8), no long-term survivors were observed in the 10 patients tional series not included in Table 2 is the experience of Potter with +8 as a sole abnormality receiving just this therapy. This and Watmore (26), who report a similar frequency (4%) and is consistent with the lack of benefit of cytarabine dose-escala- FAB distribution of 64 isolated trisomy 8 patients but do not tion in adverse cytogenetic groups demonstrated previously by characterize treatment outcome. Three of the series included in our group (8). Our data do suggest that cytarabime-based, pos- Table 2 included patients with trisomy 8 with other additional tremission therapy by itself is am inadequate therapy for trisomy cytogemetic abnormalities, thus giving a heterogeneous group of 8 patients. trisomy 8 patients that significantly confounds interpretation of Despite increasing age being a well-established poor prog- clinical outcome (1, 23, 24). Data on age distribution, CR rate, nostic factor in adult AML (16), little data exist on the effect of CR duration, and overall survival were lacking in several series, age in specific cytogemetic groups. Rowley et a!. (27) and others making interpretation of treatment outcome difficult for patients (1, 8, 10) have identified certain karyotypes, such as trisomy 8 with trisomy 8. Patients with trisomy 8 had a CR rate ranging and deletions of chromosomes 5 and 7, to be more frequent in from 35 to 73%. Remission duration was often incompletely elderly patients. To our knowledge, no studies published previ- characterized, with little follow-up beyond 3 years. Of the 134 ously have examined the prognostic significance of age in patients with trisomy 8 identified, in only 5 (3.6%) could it specific favorable or unfavorable cytogenetic groups. Our data absolutely be determined that they remained in CR beyond 3 demonstrate that patients with trisomy 8 who are >60 years of years. Thus, the current available literature does not support the age have a significantly lower CR rate and overall survival when contention of several groups (1, 23-25) that trisomy 8 is an compared with younger patients with this same abnormality. intermediate prognostic factor for patients with AML. Surprisingly, CR duration was similar between the younger and There are many reasons for discordance between some of older patients with trisomy 8; however, no elderly patients with the series published previously and our results. Four of these trisomy 8 were cured. Both increased resistance to therapy and series included a heterogeneous mixed cytogemetic group of susceptibility to treatment-related toxicity have been noted in trisomy 8 patients, which confounds interpretation of clinical elderly patients with AML, irrespective of karyotype. Unfortu- outcome. Furthermore, none of the five series had central review nately, the relatively small number of patients in this elderly of karyotype, a process that can identify primary translocations subtype prevent adequate dissection of outcome based upon and inversions that frequently have trisomy 8 as a secondary these factors. However, these data do suggest that factors other abnormality.4 Because these translocations and inversions in- than karyotype contribute to the poor outcome in some subsets dude t(8;21), t(9;l 1), t(15;17), and imv(16), which have a good of AML. or intermediate prognosis, absence of identification can con- In conclusion, our data and review of the literature suggest found interpretation of the prognostic significance of trisomy 8. that patients with AML and trisomy 8 have a poor outcome Additionally, our series has a median follow-up of 44 months when treated with short-term, cytarabine-based chemotherapy. for living patients. Given the short follow-up in many of the Elderly patients with trisomy 8 have a lower CR rate when

compared with younger patients with this karyotype and are not and Degos, L. All-trans retinoic acid followed by intensive chemother- cured with presently available therapy. Similarly, long-term apy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 outcome of younger patients with trisomy 8 is also poor, thus patients. Blood, 80: 2176-2181, 1992. mandating the need for studies examining the efficacy of stem 5. Lo Coco, F., Divenio, D., Avvisati, G., Luciano, A., londi, A., and cell transplant and new experimental agents in the treatment of Mandelli, F. High frequency of early molecular remission in acute all patients with trisomy 8. promyelocytic leukemia by combined all-trans retinoic acid and idaru- bicin. Blood, 86: 265a, 1995. ACKNOWLEDGMENTS 6. Chen, Z. X., Xue, Y. Q., Zhang, R., Tao, R. F., Xia, X. M., Li, C., Wang, W., Zu, W. Y., Yao, X. Z., and Ling, B. I. A clinical and We thank Dr. Steve George. Linda Regal, and Enin Tnikha for experimental study of all-trans retinoic acid-treated acute promyelocytic technical assistance in preparing the manuscript. leukemia patients. Blood, 78: 1413-1419, 1991. 7. Chim, C. S., Chu, Y. C., Kwong, Y. L., Liang, R.. Lee, C. K., Todd, APPENDIX D., and Chan, T. K. All-trans retinoic acid for acute promyelocytic leukemia. Blood, 86: 753, 1995. The following CALGB institutions, principal investigators, and cytogeneticists participated in this study: Bowman-Gray Medical Cen- 8. Tallman, M. S., Andersen, I., Schiffer, C. A., Appelbaum, F. R., ten. Winston-Salem. NC-M. Robert Cooper and Mark I. Pettenati Feusner, J. E., Woods, W. G., Ogden, A., Weinstein, H., Shepherd, L., Rowe, J. M., and Wiernik, P. H. Phase III randomized study of all-trans (CA03927); North Shore University Hospital, Manhasset, NY-Daniel retinoic acid (ATRA) versus daunorubicin and I --D-arabinofuranosyI- T. Budman (CA3S279); University of Chicago, Chicago, IL-Nicholas cytosine as induction therapy and ATRA versus observation as mainte- Vogelzang and Michelle Le Beau (CA41287); Dana-Farber Cancer nance therapy for patients with previously untreated acute promyelo- Institute, Boston, MA-George Canellos and Ramana Tantravahi cytic leukemia. Blood, 86: 80, 1995. (CA32291): Dartmouth-Hitchcock Medical Center-L. Herbert Maurer, 9. Weh, H. J., Kuse, R., Hoffman, R., Seeger, D., Suciu, S., Kabisch, and T. K. Mohandas (CA04236); Duke University, Durham, NC-Jef- H., Ritter, I., and Hossfeld, D. K. Prognostic significance of chromo- frey Crawford and Mazin Qumsiyeh (CA47577); University of Iowa, some analysis in de novo acute myeloid leukemia. Blut, 56: 19-26, Iowa City, IA-Gerald Clamon and Shivanand R. Patil (CA47642): Long 1988. Island Jewish Medical Center, New Hyde Park, NY-Marc Citron and 10. Schiffer, C. A., Lee, E. I., Tomiyasu, T., Wiernik, P. H., and Testa, Prasad R. K. Koduru (CAl 1028): Eastern Maine Medical Center-Tho- I. Prognostic impact of cytogenetic abnormalities in patients with de nov mas Ervin and Laurent Beauregard: University of Maryland Cancer acute nonlymphocytic leukemia. Blood, 73: 263-270, 1989.

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J C Byrd, D Lawrence, D C Arthur, et al.

Clin Cancer Res 1998;4:1235-1241.

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