Document G5kkMrQrn25r1bwJd6V9GMD1n

Acute Leukemia in Multiple Myeloma FRANCISCO GONZALEZ, M.D.; JOSE M. TRUJILLO, M.D.; and RAYMOND ALEXANIAN, M.D.; Houston, Texas Of 476 patients with multiple myeloma treated during a 9-year period, 11developed acute myelogenous leukemia or sideroblastlc anemia. I n all, the myeloma was In remission from chemotherapy with melphalan-prednisone combinations that had been continued for a median duration of 3 years. The incidence of acute leukemia or sideroblastic anemia was about 100 times higher than found in normal individuals of the same age. I n all patients studied, major cytogenetic abnormalities were present, with hypodiploidy and evidence of chromosomal damage being noted most frequently. The frequency and nature of the chromosome changes were attributed to effects resulting from the prolonged drug therapy. These findings supported the long-term follow-up of selected patients with myeloma without any chemotherapy when marked degrees of remission followed the initial treatment courses. IMPROVED TREATMENTS have prolonged the survival of many patients with multiple myeloma (1, 2 ) . However, acute leukemia has caused the death of some (3-5) and a refractory sideroblastic anemia has sonietimes preceded the development of leukemia (6, 7). This report defines b From the Departments of Medicine and Laboratory Medicine, The University of Texas M. D. Anderson Hospital and Tumor Institute; Houston, Texas. the incidence of these complications in a large n u n r h r 01 patients with multiple myeloma who received melphalan Of 476 patients treated during a 9-year span, six devetopec: acute leukemia and five others had a sideroblastic anemia without leukemia. T h e second marrow diseases were alwayf associated with major cytogenetic changes and occurred about 100 times more frequently than was observed in normal subjects of similar age. Materials and Methods Between January 1965 and December 1973, 476 consecutive patients with multiple myeloma received chemotherapy at six Southwest Oncology Group institutions according to specific treatment protocols. All received intermittent courses of mel. 'phalan and prednisone with or without added vincrktine, or procarbazine, or both (I,2). The clinical response waF evaluated from criteria previously defined and based on niarkcd, sustained declines in myeloma protein production rate to les than 25% of the pretreatment value ( 2 ) . Except for 34 patients followed without chemotherapy during remission, all patients received intermittent courses of a melphalan-prednisone or carmustine prednisone combination until relapse or death (Z)J The diagnosis of acute leukemia required the presence ofj more than 20% myeloblasts in the bone marrow. Sideroblastici anemia was defined by the presence in the marrow of marked erythroid hyperplasia and dysplasia with ringed siderobiarlt! constituting more than 40% of the erythrocyte precursors. All! had markedly elevated, but ineffective, erythropoiesis ( 8 ) ) Cytogenetic studies were done on bone marrow specimens on1 after the onset of unexplained leukemia m anemia using pr Table 1. Patients with Myeloma and Acute Leukemia or Slderoblartic Anemia. Patient Acute Leukemia 3 ! 12 3 4 5 61 Age, yrs Sex Protein Type Treatment Survival from diagnosis, modis Myeloma Anemia Cytogenetics Bone marrow t 58 F L only MPPr Radiotherapy 32 2 ND 65 M L only MP 73 2 ND 18 F IgGl MP 45 8 6OOj,44 I045 15% Polyploid 25% Normal Diploid 59 M L only MP Radiotherapy 58 4 85% 43 to 45 15% Polyploid Chromosomal damage 52 M IgG? MPPr 27 2 ND Metaphases analyzed, 110. . -* M = melphalan; P = prednisone; centrlcci, and so forth; ND not done. t Chromosome no. as indicated. 440 Pr' = procarbazine; V = vincristine; .a 25 BCNU = bischloroethylnitrosurea; Chromosomal damsee = breaks. di. 1Annals of Internal Mediclne 86:440-443. 1977 ...i ,,,' r,l,,een ........ _ . . O L.. 1969 and 1974 were used to define the predicted ;.knil' of acute leukemia and sideroblastic anemia in our cnl, \,ilh multiple myeloma*. The frequency of leukemia :;."',.~"-,;rhC.c,llrI.nnls patient-years of life at each age decade for awintohrmmaylelopmopaulwataisonc.omFpoarreedxawmitphlet,heamanonnugal our 3i0n0- nl.\O:IrS of life for 164 patients aged 60 to 69, three pa- .!( .' .., loped acute leukemia in comparison with the preI , l l m ~oefr 0.02 derived from the Connecticut frequency. :,.. - ~,.~,l;ltionwas made separately for each age decade and ,c,ll\,s added in reaching the total predicted incidence for ",~IiCfllS. HIUllS ,,l,,,llg476 patients with myeloma who were evaluated, , oped acute leukemia and five had a sideroblastic , 1"111~1 without evidence of leukemia. T h e clinical and -.,r.l~,)ry findings for these patients are summarized on ,hlc 1 . All had achieved a remission by virtue of a greater .lt 7 5 % reduction in myeloma protein production rate. I h c age distribution (median, 65 years) and duration Ircatnient were similar to that of other responding ~ ,icnts who had not developed acute leukemia o r sidero1~~~~ anemia. Eight of the patients were male; none had .-In~nlrinoglobulinA myeloma protein and the light-chain , ?\!as lambda in all five with only Bence Jones proteins. \ .lc'n the second marrow disorder was recognized, chemo+.;.~pyfor myeloma had been given for 3 t o 68 months -zdi;in. 38 months) ; localized radiotherapy for the relief ' hmc pain due to pathologic compression fractures in .i' spine had been given to three patients. The first -<wtory abnormality suggesting a new bone marrow . , d e r always consisted of a decline in hemoglobin to \\ lhnn 8 g/dl from a level of greater than 10 g/dl ring remission; seven patients also had a decline in plate* count to less than 80 OOO/plR. When it developed, . 1 1 l~eukemia was myelocytic o r monocytic in type and ' l'crwnnl communication on the incidence of acute leukemia from ihrnriph 1974 from the Connecticut Tumor Registry, J . T. Flannery, ' ,r irwn tne occurrence ot severe anemia was 7 months for all patients. In none of the four patients with sideroblastic anemia who had died was a repeat marrow sample examined during the 4 to 12 months of life subsequent t o development of the disorder. All six patients with adequate chromosome studies showed major abnormalities (Table 1). Hypodiploidy was always present with a chromosome number varying between 43 and 45; hyperdiploidy was found in two patients; polyploidy and chromosomal damage (breaks, dicentrics, and so forth) were noted frequently. There was usually marked variability in the nature of the cytogenetic abnormalities among different cells from the same patient. Marker chromosomes resembling long D and long A chromosomes were noted in three patients. There was no distinction in the cytogenetic pattern between the patients with acute leukemia and those with sideroblastic anemia. T h e frequency of leukemia o r sideroblastic anemia in our patients was compared with the predicted rate reported from normal human beings of the same age. Accrued were 991 patient-years of survival with six occurrences of acute leukemia and five of sideroblastic anemia. T h e frequency of these diseases in our patients was compared with the predicted incidence derived from the frequency in normal individuals reported by the Connecticut Tumor Registry. Because the detection of one patient with acute leukemia or sideroblastic anemia required about 10 times the number of patient-years that we observed, the presence of 1 1 patients in our population indicated an incidence of about 100 times higher than predicted. Discussion Six patients with acute leukemia and five with a refractory sideroblastic anemia were identified among a group of 476 consecutive patients with myeloma treated at six cooperating institutions. Except for one patient, all had received chemotherapy for myeloma for at least 2 years ' m e 1. (Continued) __ f ._. 62 49 8 -c' 1 ' ; ; 4N5o, rXmYa,l [liploid +-- I...\\' 21 Sideroblastic Anemia 8 '9 85 42 xa SOY. MPPrV 55 12 50% 42 to 45 3070 47 to st 10% Pseudodiploid 10% Polyploid Chromosomal damage 25 /. 48 6 25% 45 to 46 70% 46 to 47 5% Normal Diploid Chromosomal damage 25 10 74 M lgG1 MPPrV BCNU 36 7 ND 11 43 M L only MPPrV too% 45, XY,-c Chromosomal damage 25 Gonrslez e t al. * Leukemia and Myeloma 441 c before the second bone marrow disease became evident. age. Even. this frequency may have been underestinlatd The occurrence of unexplained pancytopenia, particularly because bone marrow examinations were not con&tclcdin n fall in hemoglobin to less than 8 g/dl, provided the first all myeloma patients who developed an UnexpIainetI pap. clue to a new bone marrow disorder. After isolated re- cytopenia. ports of acute leukemia in myeloma patients ( 3 ) , Kyle The survival of patients with myeloma who nCrcin ( 4 ) first described the relation between the alkylating- remission and were then followed without chentoii,crapy agent treatment and the occurrence of acute leukemia as was similar to that of patients receiving indefinite Tollrid a clinical entity. Subsequently, acute myelogenous leuke- of melphalan-prednisone ( 2 ) . There was an increa\ctl in. mia or a refractory sideroblastic anemia has been de- cidence of certain infections in patients maintait,ctl on scribed in more than 60 patients with multiple myeloma chemotherapy for prolonged periods (21, and secolld re. (5-7, 10). Most patients had received many months of missions usually occurred with the resumption or nlei. chemotherapy for myeloma, and an oncogenic effect from phalan-prednisone during relapse. Two percent of :III pa- this treatment has usually been suggested as a cause. Yet, tients and 6 % of those responding patients alive alter 2 three patients have been described with a myelomonocytic years developed acute leukemia or sideroblastic iincttti~, leukemia occurring simultaneously with multiple myeloma Despite the low incidence, this complication providcd .id&. and without any previous drug exposure (11, 12). As in tional justification for the long-term follow-up \\iihoet one of our patients, in whom acute leukemia was recog- any chemotherapy of selected patients with myelont:t. The nized 3 months atter the diagnosis of myeloma, chemo- applied mainly to those responding patients with long tlura- therapy was clearly not a prerequisite for this complica- tions of unmaintained remission, such as those with dit. tion. The rare occurrence of both diseases may have appearance of their monoclonal component after cllcltio- represented a coincidence, or else one disorder may have therapy. predisposed some patients to the second disease. All six of our patients with adequate cytogenetic studies had hypodiploidy with major chromosome alterations. Hyperdiploidy. marker chromosomes, and evidence of chromosome damage were also present. Most chromosome groups showed abnormalities but there was considerable variability in the nature of the deviation even among cells from the same patient. The unusual degree of aneuploidy and other changes noted in our patients was similar to that reported in other patients with acute leukemia (13) or sideroblastic anemia (7, 14) after chemotherapy for ACKNOWLEDGMENTS: The authors thank Dr. James 11rw1~11 of the Cleveland Clinic (Cleveland, Ohio). Dr. Raymond Winto of the Henry Ford Hospital (Detroit, Michigan), and Dr. \iwk! Balcerzak of the Ohio State University Hospital (Columbu\. b o t for allowing us to describe their patients. Additional patictit. uith myeloma who did not develop leukemia or sideroblastic .tiwit were included from the University of Arkansas Medic:il ( mtrr (Little Rock, Arkannaa) and the ScoU and White Clinic 1 lciiipk. Texas). Ms.Ann Cork provided the cytoeenetic studies. Grant support: Grants CA-03195, CA-05811, and CA-12W fnm the National Cancer Institute, National Institutes of Ilcdlh. Rethesda. Maryland. Received 26 August 1976;revision accepted 12 January 197' multiple myeloma. Similar cytogenetic findings have been described in other patients with cancer who developed t Requests for reprints should be oddressed to Raymond Alt \ lihn. M.D.; 6723 Bertncr Avenue: Houston, TX 77030. acute myeloid leukemia after prolonged treatment with alkylating agents (15). In contrast, spontaneous acute leukemia in adults has been associated with normal cytogenetics in about 60% of patients (16) and a hypodiploid karyotype has been confirmed in about 25% of another group ( 9 ) . Thus, the frequency and extent of the chromosome changes in our series and that of others (6, 13, 14) were most unusual for patients with acute leukemia or idiopathic sideroblastic anemia: for example, marker chromosomes were found in three of our six patients in com- References 1. ALEXANIANR. HAUTA, KMANAU, et al: Treatment fni I w l e r I ~ myelornu. Combination chemotherapy with dikrent ii.elt-h:lkin ,dose regimens. JAMA 208:1680-16RS, 1969 2. ALEXANIAN R, BALCERZASK. HAur A, et ai: Remisriwi 1*1;1111. tcnnnce therapy for multiple myeloma. Arch Irtrrirr M A 115:147-!S2. 1975 I. OSSERMANEF, I.AWI.DOP:RSerum and cirinory I!.l'Cm fmuramldaae) in monocytic and monomyclocytic leulcmir. J E.rp Mrd 124:921-952,1966 4. KYLE RA, PIERRE RV, BAYRDED: Multiple myeloma :id .icl1lf myelomonocytic leukernin. N Ettnl J Mrd 2Rl:1121-I 125. W o parison with a 20% incidence in patients with spontaneous acute leukemia. Thus, the chromosome annme!ics in patients with acute leukemia or sideroblastic anemia that followed treatment for myeloma most likely resulted from the alkylating-agent chemotherapy. Acute leukemia has been described many years after the institution of radiotherapy or chemotherapy, or both, for other solid tumors (10, 17). Yet, the precise incidence S. ROSNERF, GRUNWALOH: Multiple myeloma terminilting in acute leukemia. Am I Mrd 57:927-919,1974 '6. CATovsKY D. SHAWMT. HOFFBRANAOV. et al: Sidrrl'l'kirtic anaemio and Its association with leukemia and myelom:ll~l~is: report of five caws. Br J Horntaro/ 20:3AS-393,1971 7. KHALEELIM, KEANEWM, LEE OR: Sideroblnstic anclllia ni 'multiple myeloma: a preleukemic change. Blood 41:17-2!. 19'!, 1. ALEXANIAN R, AI.FREY CP JR: Erythmkinetics and androW' bone marrow cancer. Cancrr lR:8ll-R40,1976 9. TRUJILLO JM, CORK A, }(ART JS,et a ~ :Clinical impljcali~~n~d aneuploid cytogenetic profilea in adult acute leukemtn. l"icer of this complication has not been ascertained because the number of patients at risk in the various series was unknown. Among a clearly defined group of patients with multiple myeloma, 1 1 patients were identified with acute leukemia or sideroblastic anemia among 476 patients with 991 patienbyears of exposure. The incidence of acute 33:R24-834. 1974 10. RO~NEFR: Acute leukemia ns a delayed consequence nf c:I'lcrl chemolhernpy. Caucrr 37:1033-1036,1976 I t . PAnu.n AC: ' A case of acute myelomonocytic leulaemit es!dPted with myelomatosis. Scand J Harmofol 11:257-2m* 12. Tunst T, FLANDRIN0, BROUETJ-C,et el: Simultnneous rcnce of acute myeloblaslic leukaemia and multiple m!pltlmr without previous chemothernpy. Br Med J 2:642-643,19" leukemia and sideroblastic anemia was about 100 times higher than that observed in normal subjects of similar 13. HOSPEI.DDK, HOI.I.ANDJF, COOPER RG, et ai: Chramou!nx studies in acuk leukemias developing in patients with mltlllpl( myeloma. Cancrr Res 3S:2808-2813,197s 442 Aprll 1977 Annals el Internal Medlclne Velum. 86 Numbrr 41 b o n d e r et d. Leukernla and Myeloma 443