A basis for updating our approach to resistant acute leukemia

A basis for updating our approach to resistant acute leukemiaIsabel Cunningham*

No studies exist documenting that chemotherapy alone eradicates tumors composed of leukemic cells in alarge group of patients with tumors at any one site. Yet, its use has continued over 40 years in the absenceof data. Consensus protocols exist only for testis and meningeal tumors, relying on local therapy. To con-stitute a body of knowledge about tumors at one site, the breast was chosen and all published cases wereanalyzed, with follow-up obtained, to document the behavior of acute leukemia tumors and survival afterpresentation. Among 235 cases (52% published since 2000), overall survival was poor, particularly for the43% with concurrent morphologic marrow relapse, with 66-73% one-year mortality. Only 4 of 106 patientstreated with chemotherapy alone survived 4 years. The majority of AML and ALL tumors were only transi-ently responsive to anti-leukemia treatments, including transplant, and next relapses were as, or more,common in further tumors than in marrow. A pattern of tumors similar to the metastases of invasive lobu-lar breast cancer was revealed. When relapse occurred in marrow, durable remission was only rarelyobtained. These data suggest a potential benefit of incorporating extent of disease workup at diagnosisand relapse into prospective trials. This could yield an accurate incidence of extramedullary tumors and ameans to identify occult residual disease which could lead to marrow relapse. This approach could poten-tially result in greater success in curing acute leukemias. Am. J. Hematol. 87:251–257, 2012. VVC 2011 WileyPeriodicals, Inc.

IntroductionResistant leukemia remains the main cause of treatment

failure and mortality for acute leukemia patients. Despitehigh initial remission rates, leukemia relapses in the major-ity of adults with AML and ALL [1,2], at least 20% of chil-dren with ALL, and up to 40% with AML [3,4]. Mostrelapsed patients die of the disease. Among the meanswhereby leukemic cells resist chemotherapy is their forma-tion into extramedullary tumors. These may occur in anyorgan and may be an occult source of systemic relapsemore often than is clinically recognized, as body scans andautopsies are not routine. Leukemic tumors in testis andmeninges are the only ones for which there are consensusapproaches, centered on local tumor-directed therapy, butfor extramedullary tumors at all other sites there has beenno knowledge base on which to make therapeutic deci-sions. As a result, treatment with chemotherapy alone hascontinued over 40 years with no studies confirming its valuein eradicating tumors at any one site. Knowledge is limitedto individual case reports, but there are now enoughreports of leukemic tumors to enable analysis of behaviorin each organ. A study was designed to track the course ofleukemic breast tumors, enlarging on one which identified153 cases in 2006 [5], combining those with 50% morecases published in the intervening years, with follow-upobtained from authors. The goal of this study was to trackthe clinical behavior of these tumors and their patterns ofresistance. Recognition of these patterns should lead tonew approaches, as marrow-directed leukemia treatmentalone has been generally ineffective against leukemictumors and the mortality for patients who develop thesetumors remains very high.

MethodsAll cases of leukemic breast tumors were identified in published

articles found in Medline1, Scopus1, bibliographies, and meetingabstracts, and authors were contacted for full survival duration. Morethan two-thirds of authors, from 34 countries, responded and an addi-tional 16 unpublished cases were contributed. Cases not referenced inthe text are listed in Supporting Information. The cases were publishedbetween 1969 and 2010, 52% since 2000. Data collected from thereports were age, gender, temporal relation of breast tumor to marrowleukemia, other extramedullary site involvement, marrow remission sta-tus, types of therapeutic approach, consequences of treatment, and

total survival. Obtaining exact treatment doses, details, and timing wasneither possible nor the goal of this retrospective study.

‘‘Clinical response’’ in breast tumor, as determined by the treatingphysician, was used to denote clinical resolution, instead of ‘‘completeremission’’, because radiologic confirmation was rare.

For analysis, the cases are divided into the four time periods inwhich breast tumors present: (1) prior to diagnosis of marrow leukemia,(2) simultaneously with marrow leukemia diagnosis, (3) subsequent totherapy for marrow leukemia, and (4) subsequent to stem cell trans-plant (autologous or allogeneic). In the latter two groups, the marrowmay or may not have been in relapse.

Results

Patient characteristicsTwo hundred thirty-five cases were identified. There were

163 cases of AML and 72 of ALL; 13 patients were men.The age of AML patients ranged from 1 to 75 years; 24%were younger than 22. Among ALL patients, ages were 8to 69; 43% were under 22. All FAB subtypes were repre-sented, none was predominant. Karyotyping was availablefor only 55 cases of AML (36%) and 18 of ALL (26%). InAML, 16 (29%) were normal, 10 had inv (16), 9 t(8;21), 3t(15;17), and 6 had 18; 11 other translocations, additions,or deletions were reported in one or two cases each. InALL, seven (39%) were normal, four had t(9;22), 1 hadt(4;11), and six others had various other abnormalities.

PresentationMost leukemic breast tumors were reported to grow rap-

idly over days, but many grew over months. Most were

Conflict of interest: Nothing to report.

*Correspondence to: Isabel Cunningham, MD, 310 West 72nd St. New York,NY 10023, USA. E-mail: [email protected]

Additional Supporting Information may be found in the online version of thisarticle

Division of Hematology Oncology, Columbia University College of Physiciansand Surgeons

Received for publication 8 September 2011; Revised 17 October 2011;Accepted 10 November 2011

Am. J. Hematol. 87:251–257, 2012.

Published online 16 November 2011 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.22256

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VVC 2011 Wiley Periodicals, Inc.

American Journal of Hematology 251 http://wileyonlinelibrary.com/cgi-bin/jhome/35105

symptomatic, but some were found incidentally on self- orphysician exam or routine mammograms or scans per-formed after tumors were found at other sites. The majorityof breast tumors were clinically unilateral, as single or mul-tiple nodules or diffuse enlargement; 40% of both AML andALL cases were clinically bilateral on presentation. Thesetumors may appear indistinguishable from epithelial breastcancers on mammography and at surgery. Tumor massesvaried in size up to 12 cm. In one case, fungating tumoreroded through breast in four sites (Ruiz-Arguelles GJ.Unpublished case. 2010). Axillary lymphadenopathy wasfound in 64% of 28 AML and 79% of 28 ALL cases whereaxillary examination was recorded.For cases of breast tumors presenting subsequent to

treatment for marrow leukemia, there was considerablerange in the time of onset after diagnosis. In both AML andALL cases, the median time was 12 months after diagnosis,but some relapses occurred late. Nine AML breast relapsesoccurred between 3 and 10 years [6–14] and four cases inALL occurred 3–7 years after diagnosis [15,16, Milpied N.Unpublished case. 2010, Dutra AP. Unpublished case.2009]. After transplant for AML (all but four of which wereallogeneic), the median time of breast relapse was 16months, and seven cases were noted after 3–8 years [17–23], including two after autologous transplants. One patienthad a leukemic breast tumor 6 years after an allogeneictransplant for severe aplastic anemia [24]. Among ALLpatients with breast tumors after transplants (all but two allo-geneic), all occurred within 2 years, at a median of 1 year.Involvement of other extramedullary sites had been clini-

cally evident prior to occurrence of the breast tumor in 12%of AML and 7% of ALL cases. Simultaneous with presenta-

tion of the breast tumor, 29% of both AML and ALL caseshad clinical involvement of other extramedullary sites,almost exclusively in soft tissues.

Diagnostic studiesThe diagnosis of leukemia was made on excisional bi-

opsy or tumor removal in a minority of cases. In the major-ity, diagnosis was made on core biopsies or needle aspi-rates. Myeloperoxidase, lysozyme, and PAS staining werecommonly used to differentiate leukemic tumors from epi-thelial breast cancer. Leukemia cell surface markers wererecorded in some cases and combined results are shownin Table I.

SurvivalTable II illustrates the overall patient survival at each

year after diagnosis of the breast tumors. Survival ofpatients without simultaneous marrow leukemia is superiorto those who had concurrent marrow relapse in every pre-sentation time. Apart from those patients with breasttumors before marrow leukemia, only 36% of the total AMLpatients survived 1 year, and only 14% survived 5 years.ALL patients had better one-year survival but, like AML,only 15% were alive at 5 years. More than half of thosewho survived 5 years had relapsed after their initial post-breast tumor responses.

Response to treatment

Acute myeloid leukemiaTable III details the types of treatment given to AML

cases of breast tumor without morphologic marrow relapsefor which there was evaluable relapse data. Among the 80cases without simultaneous marrow relapse, local therapyalone was employed most commonly to treat breast tumorsfound prior to marrow leukemia (known as ‘granulocyticsarcoma’). In 71% of these cases, tumor was removed bymastectomy or excision. With no further therapy, the major-ity relapsed within 2 years, in marrow with or without anextramedullary site. However, it is noteworthy that threecases remained disease-free 3–6 years before relapse [25–27], having had no chemotherapy, and another, who refusedchemotherapy after excision and radiation, was still disease-free at 8 years [28]. Three of nine patients with marrowrelapses subsequently received salvage chemotherapy fornumerous cycles, and obtained lengthy remissions ongoingat 5, 18, and 26 years [29–31]. Local therapy alone pro-duced no long responses among patients presenting afterchemotherapy or transplant and further extramedullary

TABLE I. Markers on Leukemic Breast Tumors (Number Positive of Number

Tested)

AML ALL

CD33 11 of 11CD34 17 of 21 CD34 6 of 7CD43 16 of 16 CD43 2 of 3HLA-DR 7 of 7 HLA-DR 5 of 5CD13 8 of 9 CD3 4 of 4CD43 16 of 16 CD10 4 of 5CD45 14 of 14 CD19 4 of 5CD56 5 of 9 CD20 4 of 6CD68 13 of 16CD117 8 of 11TdT 4 of 7 TdT 4 of 4

TABLE II. Survival by Year after Leukemic Breast Tumor

Cases Evaluable Alive 1 yr Alive 2 yr Alive 3 yr Alive 4 yr Alive 5 yr

AML survivalPrior to BM 39 35 28 (80%) 22 (63%) 17 (49%) 14 (37%) 11 (31%)At dx 37 32 11 (34%) 4 (13%) 4 (13%) 3 (9%) 2 (6%)After chemo 45 40-BMr �1 m 19 4 (24%) 1 (5%) 0 0 0-No BMr 21 9 (43%) 6 (29%) 5 (24%) 3 (14%) 2 (10%)After SCT 43 41-BMr �1 m 9 1 (11%) 0 0 0 0-No BMr 32 17 (53%) 13 (41%) 9 (28%) 8 (25%) 5 (16%)

ALL survivalPrior to BM 1 1 1 1 1 1 0At dx 21 16 6 (38%) 3 (19%) 3 (19%) 2 (13%) 2 (13%)After chemo 26 20-BMr �1 m 8 1 (13%) 0 0 0 0-No BMr 12 9 (75%) 5 (42%) 3 (25%) 3 (25%) 3 (25%)After SCT 24 22-BMr �1 m 5 3 (60%) 1 (20%) 1 (20%) 0 0-No BMr 17 12 (71%) 8 (47%) 6 (35%) 6 (35%) 4 (24%)

Evaluable, survival data available; SCT, stem cell transplant; BMr, bone marrow relapse.

252 American Journal of Hematology

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relapse was more common than marrow relapse. There isone extraordinary response to total hysterectomy andoophorectomies in an 18-year-old woman, whose large bilat-eral ovarian tumors were noted 2 months after bilateralbreast tumors. With no chemotherapy, there was a surpris-ing disappearance of the breast tumors, confirmed by mam-mography at 18 months. Her disease-free survival wasreported by her physician to be ‘‘many years’’, becauserecords are no longer available [32].Chemotherapy alone was given to a total of 20 cases in

the three groups in Table III, with only one response lastingover 25 months. This was a young woman whose breast tu-mor expressed high levels of WT-1 mRNA, found also inthe otherwise normal-appearing marrow. She received 6months of intensive chemotherapy with resolution of breasttumors, confirmed by PET scan, with disease-free survivalongoing at 10 years [33].Combination local and systemic therapy was given to a

total of 34 patients in the three groups, of whom 11obtained disease control for periods from 2 to 26 years[25,34–43]. Seven of these responses were in patients withgranulocytic sarcomas, where there was a relapse in mar-row as late as 8 years [38]. After combined therapy, amongthe 18 cases that relapsed, the first site of relapse was asoften in extramedullary sites as in marrow, and half thepatients relapsed in ipsi- and/or contralateral breasts.Table III shows the poor response of the 57 evaluable

cases whose breast tumors presented with simultaneousmarrow relapse. The majority did not respond to treatment.Most cases were refractory to chemotherapy alone, givento 48; complete responses were seen in only 10 patients,and all but one relapsed within 16 months. One was stilldisease-free over 4 years [44]. The asynchrony of responseto chemotherapy between bone marrow and breast tumorsis illustrated by two cases in particular. One presented withbilateral breast tumors and 7% marrow blasts. Intensivechemotherapy produced complete marrow remission afterone course, with transient clinical disappearance of tumorsin both breasts, but the left breast tumor recurred after oneconsolidation course, and grew from 5 cm 3 4 cm to 10

cm prior to the next consolidation. Resolution of the rightbreast tumor was confirmed by mammogram and ultra-sound, while the left one grew, despite continued chemo-therapy. Full bone marrow relapse occurred after 6 months[45]. In another case, bilateral breast tumors and marrowrelapse occurred 5 months after diagnosis of AML, after a2-month marrow remission. Chemotherapy produced mar-row remission and clinical resolution of the right breasttumors, which did not recur, but the tumor in the left breastremained and continued to grow. Marrow relapse recurredand remission was again achieved, while the left breast tu-mor grew. It was ultimately removed 16 months after pre-sentation, at which time abdominal tumors were obvious.Shortly thereafter, marrow relapse and death occurred [46].Stem cell transplants were part of treatment for 34 AML

patients with breast tumors, of which six were autologous. Allbut four had periods of apparent response. Nineteenrelapsed: five first in marrow, 12 in extramedullary sites (eightin breast), and two in both. Five died of transplant-relatedcauses, one was lost to follow-up, and six continued disease-free from 1 to 9 years [39,43,47–49, Jakubowski A. Unpub-lished case. 2005], including one well 2 years after autolo-gous graft [43]. Donor lymphocyte infusions were part oftreatment for nine cases whose breast tumors occurred aftertransplants; there were no lengthy responses.In summary, follow-up data on the 80 evaluable AML

patients with breast tumors without concurrent marrowrelapse showed only a few prolonged responses, reflectingthe high percentage of further relapses in extramedullarysites as often as in marrow, typically within one year of thebreast tumor, despite chemotherapy. A principal site of nextrelapse was the ipsi- or contralateral breast, in at least 21cases. For the 57 evaluable cases with concurrent breastand marrow leukemia, the majority of cases were resistantto induction chemotherapy, with less than one-third obtain-ing responses, and all but two relapsing within 22 months.

Acute lymphoblastic leukemiaThe response to treatment of 37 ALL patients with breast

tumors without simultaneous marrow relapse is shown in

TABLE III. AML: Response in 137 Evaluable Breast Tumors Presenting With or Without Marrow Relapse

80 Cases Without Marrow Relapse 57 Cases With Marrow Relapse

Prior to BM After chemo After SCT At Dx After chemo After SCT

Total cases 39 21 29 37 19 9Evaluable 35 19 26 29 19 9

Local Rx only 17 3 5 0 0 0Clinical response 17 3 5EMr (mo) 2 (12, 72) 2 (2,5) 4 (12,14,23,56)BMr (mo) 9 (2,2,2,2,3,20,23,36,42) 1 (2) 1 (4)EMr/BMr 4 (6,6,8,18)DF (yrs) 2 ( 1, 8 YRS)

Local 1 chemo 15 6 13 2 5 2Clinical response 15 6 12 2 3 2Lost in CR 2 1 1 (5)Dead in CR (mo) 1 (6) 1 (16) 1 (6)EMr (mo) 3 (1,16,45) 5 (4,12,12,12,51) 1 (16)BMr (mo) 4 (3,5,19,96) 1 (13) 1 (18) 1 (1.5) 1 (22)EMr/BMr 1 (4) 3 (8,14,20)DF (yrs) 5 (2,2,4,22,26 yrs) 3 (<1, 1.4, 4.5 yrs) 2 (6.5, 12 yrs) 1 (9 yr)

Chemo alone 3 9 8 27 14 7Partial response 6 1 0Lost 5Br NR/BM CR 1 BMr (8) 1 EMr (16)

Clinical response 3 7 1 8 2 0EMr (mo) 3 (2,4,10) 1 (25) 2 (6,16) 2 (6,6)BMr (mo) 2 (2,6) 3 (all <9) 3 (2,6,8)EMr/BMr (mo) 2 (6,8)DF (yrs) 1 (10 yrs) 1 (0.7 yrs) 1 (4 yrs)

Br, breast; BMr, bone marrow relapse; DF, disease-free; EMr, extramedullary relapse.

American Journal of Hematology 253

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Table IV. For 32, there was evaluable information aboutresponse. Only one case presented before marrow involve-ment. After chemotherapy alone produced clinical breastresponse, there was relapse in femur in 18 months [25]. In12 evaluable cases of breast tumors occurring subsequentto chemotherapy, all but one had clinical responses. Twowere treated with irradiation only; one was reported to bedisease-free at 30 years [50] and the other relapsed inmarrow at 13 months [51]. Of five treated with combinationtherapy, one had no breast response and relapsed in CSFin 12 months [52]. Three had short responses ending inextramedullary relapses [53–55] and one patient continueddisease-free at 10 years, after busulfan/cyclophosphamideand autologous transplant followed by breast irradiation[15]. All five treated with chemotherapy alone had clinicalresponses; three relapsed in extramedullary sites within 8months [51,54,56], one relapsed in breast and marrow at24 months [57], and one was disease-free at 161 months[16]. Similar, almost universal, response to therapy wasseen among the 19 post-transplant cases (17 allogeneic,two autologous), which were short-lived in most cases. Ofthe six treated with local therapy alone, one had no obtain-able follow-up after radiation [58], one relapsed in marrowwhile undergoing radiation [59], and four had early extrame-dullary relapses [60–62, Selleri C. Unpublished case.2002]. Of the eight patients treated with combination ther-apy, seven had extramedullary relapses [63–67] and onehad no disease recurrence at death from an unrelatedcause after 51 months [Nichols G. Unpublished case.2002]. One of the four responses to chemotherapy alonelasted 4 years [68,69, Mensah-Glanowska P. Unpublishedcase. 2005]. In summary, in ALL patients whose breastrelapses occurred without marrow relapse, initial responsewas common, at least 75% relapsed, and extramedullarytissue was the most common site of next relapse, in 21cases, whereas marrow was the next site in only four.Treatment of breast tumors in ALL patients that occurred

with morphologic marrow relapse had very poor outcomes,documented among 32 evaluable cases. As seen in TableIV, the rare durable responses were seen among the 17evaluable patients whose breast tumors were noted at thetime of ALL diagnosis, treated with chemotherapy alone.

Marrow remission and clinical breast response was attainedin all but one. Although there were four relapses in extra-medullary sites and one in bone marrow, there are threecases disease-free for 1 to 121 years [70–72]. Chemother-apy alone was not as successful among patients whosebreast tumors occurred after a remission induced by chem-otherapy; only five of the nine obtained responses, nonelasting over 13 months. Among eight patients with breastand marrow relapse after transplant, the only responseswere after combination chemotherapy and radiation in twoof the post-allogeneic patients, both died in remission withGVHD at 13.7 and 37 months [73,74].Other treatments for breast relapse included stem cell

transplant, given to 12 patients (10 allogeneic, 2 autologous)and donor lymphocyte infusions given to nine for post-trans-plant breast relapses. Of those transplanted, one had noresponse to autologous graft [50] and another, whoset(9;22) leukemia and breast tumors responded to pre-trans-plant imatinib, died of graft failure [75]. Six relapsed in extra-medullary sites, one also in marrow [52,61,63,76, Selleri C.Unpublished case. 2002, Mensah-Glanowska P. Unpub-lished case. 2005] and four were disease-free at 8 and 16months and 10 and 12 years after breast relapse [15,16,70,Milpied N. Unpublished case. 2010]. Four of the ninepatients who received DLI as part of combination treatmentin the post-transplant group obtained responses of 13 to 51months [73,74, Nichols G. Unpublished case. 2002, Men-sah-Glanowska P. Unpublished case. 2002], three of whomdied with severe GVHD without relapse.

Relapse sitesThe first site of relapse after leukemic breast tumor was

available for 84 AML and 34 ALL cases. In AML, it wasbone marrow in 41 (including eight with concurrent extra-medullary relapses), ipsi- or contralateral breast (includingtwo with marrow) in 21, and 20 relapsed in various non-breast sites (including one also in marrow). In six patients,the central nervous system was the first relapse site andfour others had subsequent CNS relapses. Among ALLcases, the first site of relapse after the breast tumor wasCNS in 11 patients (three of whom had concurrent skin,breast, or marrow relapses) and five others had CNS relap-

TABLE IV. ALL: Response of 64 Evaluable Breast Tumors With and Without Marrow Relapse

32 Cases without Marrow Relapse 32 Cases with Marrow Relapse

Prior to BM After chemo After SCT At dx After chemo After SCT

Total cases 1 17 19 21 9 4Evaluable 1 12 19 19 9 4

Local Rx only 1 2 6 0 0 0Clinical response 1 2 6Lost 1EMr (mo) 1 (18) 4 (1,1,5,6)BMr (mo) 1 (13) 1 (1)DF (yrs) 1 (301 yrs)

Local Rx 1 Chemo 0 5 8 2 0 2Clinical Response 4 8 2 2Lost 1Died in CR 1 (51) 2 (13.7, 37)EMr (mo) 3 < 6m 7 (2,5,5,5,31,48,50)BMr (mo) 1 (1)DF (yrs) 1 (101 yrs)

Chemo alone 0 5 5 17 9 2Clinical Response 5 4 16 5 0Lost 1 5Died 3 1EMr (mo) 3 (2, 2, 8 ) 2 (10,48) 4 (2,2,12,23 ) 1 (13)EMr/BMr 1 (24 ) 1 (4)BMr (mo) 1 (2) 1 (7) 1 (3)DF (yrs) 1 (1.5 yrs) 3 (1, 7, 121 yrs) 1 (91 mo)


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ses subsequently. The ipsi- or contralateral breast was thenext site in nine (two were concurrent with CNS). In onlyeight cases was the next site the marrow (two each withconcurrent breast or CNS relapses). Five cases had othernon-marrow first relapse sites after the breast: two insinuses [64, Mensah-Glanowska P. Unpublished case.2005], and one each in heart [62], femur [25], and retroper-itoneum [69]. It is noteworthy that two of the 13 malepatients had testicular involvement: an ALL patient with latetesticular relapse after several breast recurrences [55], andone AML patient with bilateral testis and breast tumors atdiagnosis [77].Without routine scans, and with autopsies reported for

fewer than 5% of the deceased patients, the clinically appa-rent sites enumerated in the cases in this report are cer-tainly an underrepresentation of organ involvement. None-theless, the data suggest that leukemic breast tumors areassociated with clinical involvement of CNS (mainlymeninges), skin, pelvic, gastrointestinal, and retroperitonealsites, in both AML and ALL.

DiscussionImportant points about the biology of acute leukemia

when it forms tumors become apparent from this study of235 cases, the largest analysis of leukemic tumors at anindividual site ever published. They provide a basis for anew perspective on resistant residual disease that couldimprove prognosis for acute leukemia patients. Theyinclude the critical value of local therapy, the elucidation ofan independent extramedullary path of tumor progression,the inadequacy of chemotherapy alone, and the similarbehavior of AML and ALL.Local therapy appears to have an important role in eradi-

cating leukemic breast tumors, as it does in breast carci-noma. However, it was used in less than one-third of pub-lished cases, principally for de novo breast tumors beforemorphologic marrow leukemia. Among these are severalcases of 3 to 8 year responses without any chemotherapy.This long period of leukemia quiescence raises the ques-tion of whether ‘‘local myelopoiesis’’ could occur in sometissues, hypothesized 7 decades ago [78]. These leukemictumors have typically not been approached by clinicians assolid cancers, but as collections of sensitive cells, whichthey do not appear to be. Focus has been on the risk ofmarrow relapse when a leukemic tumor is diagnosed andclinicians may hasten to employ systemic chemotherapyalone, unaware that such tumors are resistant to marrow-directed therapy, that response will likely be transient, andthat there is a significant chance of ipsi- and contralateralrelapse, followed by further tumor spread. Even when localradiation is given, it has typically been directed only to asingle breast. This is in contrast to the approach to unilat-eral leukemic testis tumors, where bilateral radiation,acknowledging the high risk of contralateral tumors, isstandard and effective. The omission of local therapy hasbeen even more common in cases of breast tumors wherethe marrow is in relapse on presentation, when marrow-directed treatment is urgent. Post-chemotherapy irradiationmay be an attractive option in such cases. It was given tofive AML and two ALL patients, with responses lasting 2 to121 years thereafter [15,22,35,38,40,43,73]; two of thesewere given radiation after autologous transplants [15,43].This study documents that after one extramedullary tumor,there is a high chance that the next site of leukemia will beanother tumor in another site, not the bone marrow.Chemotherapy alone, a commonly reported approach to

leukemic breast tumors, has produced few long-termresponses in either AML or ALL. There appears to be tran-sient clinical response in most cases, except among the 15

AML cases with breast relapses presenting after stem celltransplants where only one responded. There are only fourcases among 106 AML and ALL patients treated withchemotherapy alone with disease-free survivals from 4 to12 years. They include one AML and two ALL cases whoreceived chemotherapy for newly diagnosed marrow andbreast leukemias [44,70,72], and the de novo case treatedfor WT-1 expression in both sites[33]. With these observa-tions, there is little data to justify relying on chemotherapyalone when extramedullary breast tumors, or probably anysoft tissue leukemic tumors, are found. The majority of the46 cases given stem cell transplants after chemotherapyrelapsed, but there are seven reports of 2 to 9 year dis-ease-free survivals in both AML and ALL patients after allo-geneic or autologous transplants [15,39,43,47,49,70 Jaku-bowski A. Unpublished case. 2005]. Transplant thus offersone of the best current options, provided there are nooccult tumors in the patient before initiating conditioningtreatment, and that their absence is confirmed after trans-plant.Though chemotherapy protocols for AML and ALL are

composed of different agents, the results observed suggesttheir leukemic tumors have similar behavior. After thebreast, relapse in another extramedullary site was common,four times more common than marrow relapse among theALL patients, and equally common in the AML cases. It isnoteworthy that in both leukemias, meningeal leukemiadeveloped, in at least 22% of ALL and 6% of AML cases.Although individual prophylaxis details were unobtainable,most ALL protocols include CSF prophylaxis. This supportsthe value of prolonged CSF monitoring in cases of leuke-mia in non-marrow sites.These data suggest that leukemic tumors in extramedul-

lary sites behave more like invasive solid tumors than acuteleukemia. The asynchrony of response when anti-leukemiaagents are given has been amply documented in this largestudy. The cases with lengthy responses to local therapy,without chemotherapy, imply that in at least some, the tu-mor burden may be initially confined to a non-marrow site.The clinical behavior of breast tumors suggests they havethe ability to metastasize, independent of marrow relapse,with a proclivity for spread to the contralateral breast, in apattern paralleling the natural history of invasive lobularbreast cancer, which is likewise known to spread to abdo-men/pelvis and eventually to meninges [79]. A morphologicsimilarity of leukemic breast tumors to invasive lobular car-cinoma has been noted by some authors [27,30,80–82].The breast, like many organs, is a site of normal hemato-poiesis in the embryo through a few weeks after birth[83,84] and of extramedullary hematopoiesis in myelofibro-sis [85], and is occasionally seen in normal infants [86] andcancerous or contralateral breasts after chemotherapy andsurgery [87]. Therefore, one could postulate that after anunknown leukemogenic stimulus, the breast (or any othersite) could revert to the embryonic state where hematopoi-etic cells, in this instance malignant ones, could proliferate.Factors in the breast microenvironment may interact withleukemic cells and render them resistant to anti-leukemiaagents. It may be that cells trafficking between breast andmarrow contribute to the marrow’s acquiring resistance toagents to which it should be sensitive, as is illustrated inmany of the cases detailed here.Though fewer than 39% of cases had available FAB or

karyotype data, it appears that leukemic breast tumors mayoccur in patients of any age, FAB, and karyotype. If resistantleukemic tumors cannot be predicted and the prognosis inavailable cases is so poor, attempting to find tumors earlymay help us improve results. The potential benefit of extent-of-disease workup for new and relapsed leukemia patients,


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as is done in every other cancer, could be considered. Incor-porating this into prospective trials could help determine thetrue incidence of extramedullary tumors and their role in theresidual disease found in some patients after protocolswhich eradicate leukemia in others. A large autopsy studysuggested that at least 50% of myeloblastic tumors wereasymptomatic during life [88], providing reason to suspectthat many relapsed patients harbor occult tumors whichcould be responsible for recurrent marrow disease. As PET,CT, and gallium scans have been useful in finding occulttumors [89–92], we now have the opportunity to alter theslow pace of progress in acute leukemia by identifying sitesof resistance and potential relapse before they are clinicallymanifest, and monitoring patients with leukemic tumors toassure their eradication. Leukemic tumors should never bedeemed ‘‘isolated’’ without radiologic documentation, as thisstudy has shown that the majority of patients with one tumorwill have multiple site involvement at some time. Improve-ment in prognosis for acute leukemia patients is long over-due, and an updating of our standard approach to treatmentcould decrease the high mortality from resistant leukemia insites outside the marrow documented in this analysis.

AcknowledgmentsThe contributions and collegial spirit of the dedicated

physicians who made this work possible are gratefullyacknowledged, as are the invaluable suggestions of Drs.Gwen Nichols and David Straus

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A basis for updating our approach to resistant acute leukemia