Introduction Imatinib (IMAT) made possible complete marrow remissions of CML beginning in 1998. By 2001, relapses in non-marrow sites (CNS and many other organs) were reported in IMAT patients in marrow remission, which proved resistant to RT and systemic or intrathecal chemotherapy routinely used over 70 years. Sequelae include blindness, paralysis, spread of resistance to marrow, and death. Since the debut of dasatinib (DAS), a dual BCR::ABL1/SRC kinase inhibitor, in 2004, clearing of extramedullary leukemia (EML) by DAS in IMAT-resistant patients has been reported in numerous individual cases. As DAS is the first agent to produce complete remissions of resistant EML, we undertook to ascertain the durability of responses to DAS and to explore differences in DAS and IMAT. Methods All reports of patients with EML in any organ published 2004-2025 given DAS alone or added to routine approaches were reviewed. Response durations were elicited from authors. Results of our prior RNAseq study of specimens of EML in breast in AML and ALL patients were reviewed. Results 165 patients with EML in any site who received DAS were identified in the literature, 70% presented after IMAT failure and 35 after transplants. Diagnoses were BCR::ABL1 (Ph‘+): 99 CML, 39 ALL, 4 AML, 3 biphenotypic leukemia, 7 lymphoblastic lymphoma; 13 had Ph‘- diseases. Age range was 2-80 years, 24 were under 21. DAS dose was usually 140 mg/d. Complete remission (CR) of EML was reported in 159 patients, confirmed by MRI, CSF, PET/CT in 11, autopsy in 2. CR sites include meninges, brain, bones, skin, ovary, heart, pancreas. In 6 patients, EML CR was not documented: in 3, disease progressed, in 2, visual and motor impairment was unchanged, and 1 died on DAS. Follow-up was obtainable from 56 authors. Response duration was knowable for 144 patients. 91 obtained CR lasting a few months to 11+ years, 38 for 2+-11+ years, (17 for >4 years). 12 of the 38 2-year survivors had undergone transplants after CR. 20 patients died in CR (2 myocardial infarctions, 10 infections, 2 transplant complications, 1 cancer, 1 accident, 1 hemorrhage, and 3 cause unknown). Relapse occurred in 34 patients:6 in same and 6 in other sites, 14 in marrow(M), 4 in EM +M, and 4 in unknown sites. Maintaining adequate dose appeared to be a factor in EML relapse. BCR::ABL1 mutations were reported in 12 relapses, 8 were T3151. Among genes significantly overexpressed in EML tissue compared to normal tissue in our prior RNAseq study were SRC family kinase (SFK) LCK and PECAM-1 (CD31). Discussion Leukemia growth in non-marrow sites is an under-investigated lethal aspect of leukemias, known over 200 years but never a focus of specific treatment development. EML is an important cause of treatment failure and estimated to occur in 10-30% of leukemia patients; survival is typically <1 year. We report that DAS has produced lengthy CRs of EML, many in IMAT-resistant patients, and that LCK and PECAM-1 are upregulated in EML tissues. Overexpression of SFKs like LCK, and of PECAM-1 has previously been reported to be associated with IMAT resistance and with inhibition of IMAT-induced apoptosis in murine CML cells, respectively. We hypothesize that overexpression of LCK and PECAM-1 may contribute to IMAT resistance of EML and to the susceptibility of EML to DAS treatment. LCK is an oncogenic SFK found in choroid plexus, nerves, some cancers, and some Ph'-negative AML marrows. PECAM-1 has roles as a regulator of apoptosis, and in transendothelial migration and extramedullary dissemination of AML. PECAM-1 is phosphorylated in an SFK-dependent manner and both LCK and PECAM-1 are tyrosine phosphorylated by BCR::ABL1. DAS was developed as a LCK inhibitor (and BCR::ABL1 inhibitor) and DAS treatment completely prevents PECAM-1 phosphorylation. Therefore, it is not unreasonable to speculate that IMAT-driven overexpression of LCK and PECAM-1 may lead to enhanced LCK-mediated PECAM-1 tyrosine phosphorylation which promotes leukemia survival and migration to extramedullary sites, both of which deleterious outcomes can be inhibited by DAS. Trials designed to identify EML in all leukemia patients by PET/CT and the use of EML-targeted DAS therapy for documented involvement, could improve patient survival and open new avenues of research.

Abstract Purpose: To review outcomes of pts with extramedullary leukemic tumors (EMLT) treated with the second-generation tryrosine kinase inhibitor (TKI) dasatinib. Procedures: Reported cases of extramedullary leukemic tumors in patients treated with TKIs were reviewed and survivals elicited from authors. RNA seq and RT-PCR for lymphocyte-specific kinase (LCK) mRNA were performed on cases of EMLT in breast. Summary: Leukemic cells growing as tumors in any organ lead to treatment failure and death, even if marrow is in remission. Median survival of patients with EMLT is 5 months, unchanged for the last 50 years. Like solid cancers, EMLT are invasive and metastatic, showing desmoplastic fibrosis and invasion of adipose tissue. Traditional anti-leukemia chemo has not reliably cured EMLT in any site, but excision of primary tumors followed by adjuvant chemo has achieved remissions of > 20 yrs. This suggests the benefit of removing tumor microenvironment (TME) containing cytokines and immune cells influencing tumor growth and resistance. TME is a logical target to ablate EMLT; TME is not affected by agents that kill replicating leukemia cells. RNAseq of very long-stored samples of EMLT in breast found upregulation of LCK compared to normal breast, confirmed by LCK RT-PCR analysis in 3 of 5 ALL tumors (2 Ph+ALL, 1 B-ALL) and 1 of 8 AML tumors. LCK is a target of DAS, a second-generation TKI that, like first-generation imatinab (IM), effectively controls BCR-ABL+ (Ph+) chronic myeloid leukemia (CML) marrow. However, IM cannot prevent or treat EM relapse, documented in 90 reported cases, mostly in CNS sites, with or without blastic marrow. CNS leukemia can lead to blindness, deafness, and paralysis. Responses to routine CNS therapy with RT and intrathecal or high-dose chemo +/- transplant, occur but lengthy DFS is rare. Since 2004, DAS +/- routine therapy has cleared CNS sites (meninges, brain, optic nerve) for up to 7+ yrs in Ph+ and T lymphoid leukemias. LCK is expressed diffusely in the CNS within neurons and ependymal cells. Tumors in non-CNS sites have also been cleared by DAS +/- routine therapy in pts with CML, Ph+ALL, T-ALL, and Ph+ B lymphoblastic lymphoma. Sites include skin, pancreas, stomach, testis, and epidural space, with DFS up to 9+ yrs. Among 137 of 153 DAS-treated pts with EMLT with followup after response, 23 have had progression in EM sites, while 47 were disease-free for 1 to 10 yrs (29 pts > 2 yrs). Conclusions: DAS appears to be an effective agent for treatment of EMLT. LCK is a potential DAS target in both Ph+ and non-Ph+ hematologic malignancies (HM), as EM tumors occur in leukemias, lymphomas, and myeloma. DAS combined with other therapies may benefit some HM patients and improve survival. Prospective clinical studies are needed to define which patients might benefit from DAS and the role of LCK. Routine scanning by PET/CT should be conducted in HM to find clinically unrecognized EMLT and to document response. Citation Format: Isabel Cunningham, Jianqi Yang, Herbert B Newton, Rory A Fisher. Dasatinib targets an upregulated SRC family kinase gene in extramedullary leukemia, improving prognosis in these patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C156.

We investigated whether the proposed role of adipocytes in driving solid cancers could apply to breast tumors formed of leukemia cells. This could explain the desmoplastic collagen deposition, metastasis, resistance, and lethality of these tumors that we previously reported. All 290 published cases of breast tumors composed of acute myeloid leukemia (AML) cells were reviewed and extended survivals were solicited from authors. RNA sequencing compared 11 AML breast samples to normal breast. Histology revealed invasion of adipose tissue by AML cells, many of which resided at the adipocyte periphery, accompanied by a shrinkage of adipocytes and the accumulation of collagen and elongated fibroblastic-like cells. Both lymphocytes and macrophages accompanied the infiltration. RNA sequencing showed deregulation of numerous adipose genes, including adiponectin, leptin, FABP4, COL6A3, CD36, and PPARγ, as reported in co-culture studies of breast and other solid cancer cells with adipocytes. Analysis of 210 clinical cases with available followup data revealed a survival benefit of tumor excision and/or irradiation in combination with systemic leukemic agents compared to systemic treatment alone. Two-year survival was achieved with excision +/- RT + systemic agents in 35/88 (40%), with RT + systemic agents in 12/38 (32%) and in 12/84 (14%) given systemic treatment alone. Five-year survival was achieved in 19%, 11%, and 2%, respectively. Eleven patients given surgery +/- RT with systemic treatments survived 10+ to 19+ years. This study reveals for the first time that removal/ablation of leukemic tumors and microenvironment can result in prolonged survival and potentially cure. Agents designed to treat marrow leukemia are ineffective in eradicating cells that have adopted solid tumor phenotype. The observed histologic features and clinical behavior of leukemic breast tumors could result from leukemic cell crosstalk with adipocytes, as reported in solid breast and other cancers. Invasion of fat is correlated with poor prognosis in many cancers. It is very likely that our findings also apply to hematologic tumors in other organs, as most contain or are near adipose tissue. Treating to cure extramedullary leukemia using combined excision/RT and systemic therapy requires confirming that the tumor is isolated and no occult tumors are present. This was not documented in most published cases. Only 10% of reported patients had PET/CT scans, so greater success is expected when body scans are routinely used in staging leukemia, as has been routine in every other cancer for decades. Until pharmacologic agents to interrupt malignant cell-adipocyte crosstalk are available, direct treatment of hematologic tumor after total body scan should be a new standard of care. Citation Format: Isabel Cunningham, James E. Goldman. Focus on adipocytes in the growth, resistance, and lethality of extramedullary leukemic tumors could transform our approach to curing leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3196.

To explore whether the growth and treatment resistance of lymphoma and myeloma tumors is similar to that previously observed in leukemic and solid tumors growing in the same organ microenvironment.

Resistance of extramedullary leukemia growth post-transplant prevents cure. Review of its behavior detailed in 585 published cases should lead to better treatment. Leukemic tumors were found up to 13 years after transplant, most in sites inaccessible to physical exam. In 83%, marrow was not in morphologic relapse; next relapse was most often extramedullary. Induction protocols alone produced few durable responses in acute leukemias and fatal marrow aplasia in 17 %. Overall, 120 patients survived over 2 years, 43 relapse-free up to 18 years, the majority after combined tumor-directed and systemic therapy. Overall median survival was 9 months. This review highlights how results can improve: by defining extent of leukemia involvement with scans before transplant, and emergently when leukemic tumor is found after, ablating tumor directly to abort metastasis, and determining dosing of systemic chemotherapy that protects, without ablating, donor marrow. Monitoring total body remission with body scans should increase transplant cures.

Recent studies of leukemic tumors in individual extramedullary sites showed they adopt the clinical and metastatic behavior of solid cancers originating in those sites. To elucidate features of leukemic tumors that render them resistant to agents effective against marrow leukemia, we analyzed a series of AML breast tumors by histology, immunohistochemistry, and RNA sequencing. Striking histologic similarities to solid cancers were found: a single-filing architectural pattern virtually identical to that of invasive lobular breast carcinoma and dense desmoplastic keloid-like fibrosis similar to colon, gallbladder, and pancreas carcinomas. Sequencing found 2157 genes significantly downregulated in AML breast tumors compared to normal breast. Comparison to triple-negative breast cancer found 859 genes similarly downregulated. At least 30 of these genes have been associated with poor prognosis in breast cancers. Five were reported in AML marrow studies to correlate with poor prognosis. The findings of this pilot study suggest the seed-and-soil interaction recognized in solid cancer growth may help explain how leukemic cells, in some patients, adopt solid tumor behavior in non-marrow sites. Transformed cells that metastasize from tumor to marrow can impart chemoresistance and be an unrecognized cause of treatment failure and death. Further studies comparing leukemic tumor to simultaneous marrow could potentially identify biomarkers that predict extramedullary resistance and lead to new therapeutic targets. Recognizing the potential for leukemia to adopt solid tumor phenotype, and implementation of body scanning and ablative tumor treatment, could decrease the persistently high rates of marrow resistance and treatment failure.

Leukemia growing as tumors in gastrointestinal organs is an under-investigated cause of treatment failure and death. These present with symptoms often mistaken for common toxicities but may grow large before symptoms. To synthesize experience available only in case reports, 378 were analyzed. Invasive and metastatic behavior typical of solid GI tumors was revealed even when marrow was uninvolved. Within 3 months of diagnosis, 33% had died, 47% within 1 year. Survivals of 4 to 18 years after involvement suggest cure is possible. Evidence is presented that combined local and systemic therapy has successfully treated GI leukemic tumors when identified early.

Abstract We previously reported our observation that tumors composed of leukemic cells found in breast mimic solid breast cancers in gross and histologic appearance (single-filing of cells and distinctive keloid-like fibrosis), invasiveness, metastatic pathway, and high mortality. They are resistant to anti-leukemia drugs; only 4% treated without excision lived 4 years but survivals over 20 yrs resulted when tumor and its microenvironment were excised. The incidence of occult leukemic tumors, still unknown as scans are not yet routine, was estimated near 20% in 1970s autopsy studies. We hypothesized there may be similarly altered genes in leukemic and epithelial breast tumors directing clinical behavior and resistance that could provide targets for curative treatment. We performed RNA sequencing on 11 FFPE breast tumors from annotated AML cases, all IHC-negative for hormones and E-cadherin, compared to normal breast samples. Differential expression analysis identified 3647 genes that were significantly downregulated (adjusted p < 0.05 and log2 fold change < -2). Among the 100 genes downregulated 8-10 fold in leukemic breast, FOXA1, CA12, CXCL14, SFRP1, SFRP4, DCN, LUM, PHLDA1, NTN4, GABRP, TAGLN, AZGP1, and ARRDC3 have been associated with poor prognosis in breast cancer, mainly triple-negative (TNBC)/basal types. Compared to TNBC cases in the TCGA database, 851 genes were similarly deregulated; significantly enriched KEGG pathways include neuroactive ligand-receptor interaction, focal adhesion, ECM-receptor interaction, and regulation of lipolysis in adipocytes. A role for altered stroma is suggested as many of the similarly downregulated genes were reported in dissected breast cancer stroma and silenced SFRP1 and CXCL14 were found in keloid fibroblasts. Silencing of SFRP1 and E-cadherin in AML marrows was reported in 30-50% and each was correlated with poor survival. Reversal of SFRP1 silencing has been achieved by epigenetic-modifying drugs in cancers and keloid fibroblasts. We validated loss of SFRP1 and RGS6 in leukemic breasts by RT-PCR. Loss of RGS6 in breast and other cancers promotes doxorubicin resistance and DNMT1 upregulation leading to silencing of tumor suppressor genes. These data open a new view of resistance of AML cells to marrow-directed drugs through interaction with aberrant microenvironment. Solid tumors of epithelial and leukemic cells may share unrecognized treatable targets. Adding drugs directed at tumor, including available epigenetic-modifying agents, to marrow-effective protocols, may finally decrease the persistently high rate of AML treatment failure. Citation Format: Isabel Cunningham, Diane Hamele-Bena, Audrey Papp, Yan Guo, Antony B. Holmes, Yu Shyr, Rory A. Fisher. Organ-specific epigenetic reprogramming of leukemia cells: Clues to chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1748. doi:10.1158/1538-7445.AM2017-1748

Extramedullary tumors remain an obstacle to curing more acute leukemia patients. Their incidence is unknown because the presence of occult tumors that contribute to relapse is not routinely sought as in other cancers. No standard approach exists for treating tumors at most sites, apparent clinical response is typically followed by further tumors, and achievement of lengthy remission is uncommon. Body scanning with 18 FDG PET/CT now provides a means to identify the extent of occult tumors that enables directed tumor eradication and a way to evaluate tumor response. To evaluate its potential benefits, analysis was undertaken of 124 published cases scanned after apparent tumors were diagnosed. Clinical and radiologic exams underestimated extent of disease in over half of 100 cases. Among 70 cases that reported scans after various treatments, 70% achieved negative scans. Half relapsed subsequently but disease‐free survivals up to 6 years were documented. These reported cases add to our knowledge of extramedullary leukemia in showing that further tumors are more likely than marrow relapse, clinical and radiologic evaluation of response is inadequate, intensive chemotherapy alone generally does not prevent progression and is associated with significant mortality, and tumor‐directed plus systemic therapies appears the most effective approach, particularly to AML tumors. This analysis suggests this technology could increase our ability to eradicate all foci of leukemia, and identify tumors responsible for refractory, residual, and relapsed disease. Am. J. Hematol. 91:379–384, 2016. © 2015 Wiley Periodicals, Inc.

Abstract Chemoresistance is responsible for death in up to 60% of acute leukemia patients despite high initial responses to therapy; a new approach to residual disease is crucial. Leukemia is considered a liquid cancer that circulates through organs and homes to the marrow niche. It sometimes adopts, however, a solid tumor phenotype in an extramedullary organ, an under-investigated means of developing resistance. Solid masses grow and progress to invade other organs regardless of marrow involvement. Occult, sub-clinical, resistant foci may occur more often than is recognized, and lead to marrow relapse and death. Scans and autopsies are rarely performed and only obvious tumors are reported, so the incidence of resistant masses is unknown. We observed that leukemic tumors in breast assume the aggressive phenotype of invasive lobular breast cancer, with similar morphologic features (single-filing and targetoid pattern), and metastasize to the same organs. AML and ALL tumors bear leukemic markers and are cytokeratin-, hormone receptor-, and e-cadherin negative. Only 4 of 106 reported cases treated with only chemotherapy survived 4 years, but when tumor excision was added, leukemia-free survival over 20 years has occurred (Am J Hem, 2012). Based on these observations, we postulate that understanding the molecular mechanisms that regulate these solid masses would be a potential means to overcome the chemoresistance that prevents cure in AML and ALL. Gene expression profile studies were performed on paraffin-fixed leukemic breast tumors (2 ALL, 1 AML) found 8 to 22 months after diagnosis while marrows remained in remission. Many of the same genes were significantly upregulated in leukemic tumors (30 to 2877-fold) and breast cancer (9 to 108-fold). The most enriched clusters by DAVID analysis were actin cytoskeleton organization, cell cycle, and regulation of apoptosis. RhoGTPases were significantly upregulated in both types, as was PI3Kδ. Among genes related to metastasis in breast (and other) cancers, some (PTTG1, ELMO1, VAV1, PAK1, NEK2) were upregulated 5 to 224 times in leukemic tumors. Profilin, KLF6, and CXCL14 were significantly downregulated in both leukemic and epithelial tumors, as were cell cycle regulators CDKN1A, CDKN1B, and cyclin D2. Wiskott-Aldrich Syndrome gene, known to correlate with resistance in AML and ALL, was significantly upregulated in leukemic tumors and carcinomas. Overall, the results indicate a remodeling of the cytoskeleton, promotion of metastasis, and a decrease in cell cycle regulation in the leukemic tumors. Studies with 25 leukemic breast tumors are ongoing to identify key aberrant gene targets. Characterizing the dysregulation responsible for transformation to a tumor phenotype has the potential to lead to specific agents. These could be used in conjunction with marrow-effective leukemia drugs to eradicate resistant foci to cure more acute leukemias. Citation Format: Isabel Cunningham, Diane Hamele-Bena, Takayuki Shiomi, Stephen Emerson, Jose M. Silva, Jeanine M. D'Armiento, Ashani T. Weeraratna. Liquid to solid: Leukemic breast tumors assume the morphologic and genetic characteristics of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3996. doi:10.1158/1538-7445.AM2014-3996

Abstract Tumors composed of leukemia cells grow in non-marrow sites in some acute leukemia patients, often without apparent marrow involvement. The majority cannot be eradicated by anti-leukemia agents and lengthy survival is rare. Exceptions are testis and meninges treated by local therapy, with systemic treatment to prevent marrow relapse. Tumor resistance to marrow-directed therapy has not been investigated nor prospective trials done. Only clinically obvious tumors are reported, as scans and autopsies are not routine in acute leukemia, so occult tumor incidence is unknown. It is possible that occult leukemic tumors are common. Finding tumors and targets on them could prevent the high rate of relapse (>50%) and increase cures. To characterize the course of leukemic tumors in one site, 235 cases in breast were analyzed and their subsequent behavior elicited from authors (Cunningham, Am J Hem, 2012). A pattern of leukemic tumor progression was revealed that mimics invasive lobular breast cancer (ILC): to other breast, then abdomen/pelvis, then CSF. We examined 25 paraffin-embedded specimens of leukemic breast tumors. H+E staining showed single-filing and targetoid pattern of leukemic cells in all AML and ALL cases - the classic pattern for ILC, not reported in leukemia. All showed areas of dense keloid-like fibrosis positive for Collagen Type 1 and frequent expression of αSMA-positive cancer cell-adjacent fibroblasts, as seen in advanced breast, rectal, pancreatic, and basal cell cancers. We postulated that altered microenvironment of organs such as breast, a site of fetal hematopoiesis, may foster leukemic cell-stroma interaction leading to tumor growth and migration paralleling epithelial cancers. With immunohistochemistry the leukemia cells were CK18-negative and CD45-positive, negative for hormonal markers (ER, PR, PRLR, Her 2/neu) and E-cadherin and positive for CD44, pSTAT5, TGFβ, FGFR, and SDF-1α. Leukemic cells in breast showed minimal to no CXCR4 staining but in one unusual case with concurrent ER-negative AML tumor and ER-positive ILC, CXCR4 was positive in cancer cells but not AML cells. This may reflect rapid internalization of CXCR4. The present study is the first work documenting many common features of leukemic and epithelial tumors. Our results suggest that pathways of tumorigenesis, and therapeutic targets, may be shared by solid and ‘liquid’ tumors. An innovative approach to relapse caused by tumor formation is long overdue, and could significantly improve survival and chance of curing acute leukemias. Abnormally activated pathways key to retention of stem cells in the marrow niche may be operative in extramedullary niches, where leukemic cells adhere to stroma and are protected from chemotherapy. Our unique collection of leukemic tumors allows us to further elucidate possibly common resistance mechanisms of malignant neoplasms provided by stromal microenvironment. Citation Format: Isabel Cunningham, Takayuki Shiomi, Jeanine M. D'Armiento, Hallgeir Rui, Carlos Cordon-Cardo, Diane Hamele-Bena. Hiding from chemo: Leukemic cells forming tumors to survive. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1096. doi:10.1158/1538-7445.AM2013-1096

The clinical behavior of acute leukemic tumors at each organ site must be recognized if relapse is to be prevented. The courses of 124 cases of leukemic ovarian tumors were analyzed with survival durations obtained from authors. Local expansive growth and invasion of contiguous organs similar to epithelial ovarian cancer was seen in both acute myeloid (AML) and lymphoid (ALL) leukemias. Overall, 56% survived 1 year. Tumors at other sites were clinically apparent on presentation in over half the cases without simultaneous marrow relapse, and next relapse was as common in extramedullary sites as in marrow. Leukemic ovarian tumors were generally resistant to chemotherapy, and lengthy survivals were seen most often after complete excision together with systemic therapy. This study documents similar behavior in AML and ALL tumors and that they are rarely isolated to a single ovary. It suggests that scanning could improve our ability to find and eradicate occult tumors which, because of chemoresistance, prevent the cure of leukemia for most patients who develop them.

No studies exist documenting that chemotherapy alone eradicates tumors composed of leukemic cells in a large group of patients with tumors at any one site. Yet, its use has continued over 40 years in the absence of data. Consensus protocols exist only for testis and meningeal tumors, relying on local therapy. To constitute a body of knowledge about tumors at one site, the breast was chosen and all published cases were analyzed, with follow-up obtained, to document the behavior of acute leukemia tumors and survival after presentation. Among 235 cases (52% published since 2000), overall survival was poor, particularly for the 43% with concurrent morphologic marrow relapse, with 66-73% one-year mortality. Only 4 of 106 patients treated with chemotherapy alone survived 4 years. The majority of AML and ALL tumors were only transiently 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 lobular breast cancer was revealed. When relapse occurred in marrow, durable remission was only rarely obtained. These data suggest a potential benefit of incorporating extent of disease workup at diagnosis and relapse into prospective trials. This could yield an accurate incidence of extramedullary tumors and a means to identify occult residual disease which could lead to marrow relapse. This approach could potentially result in greater success in curing acute leukemias.

Abstract 1014 Poster Board I-36 A database was created of 305 women with leukemic breast (Br) or ovarian (Ov) tumors, reported 1970-2009 (35% since 2000), to analyze their clinical behavior and reasons why survival remains poor. Follow-up was elicited from 96 authors. Distribution of cases and 2-year DFS are shown. Breast Ovary Breast+Ovary Presentation of Br or Ov tumor AMLn=129 ALLn= 59 AMLn=53 ALLn=56 AMLn=6 ALLn=2 GS 11 of 35 0 3 of 22 0 0 of 2 0 At marrow dx 2 of 30 2 of 17 4 of 18 0 of 3 0 1 of 2 After chemo 0 of 34 2 of 23 1 of 8 11 of 50 1 of 3 0 After SCT 1 of 30 4 of 19 1 of 5 1 of 3 1 of 1 0 There is no common feature (FAB, karyotype, wbc) except age; 90% were under 51 (range:3mo-67yr). Br and Ov tumors were generally the first site of extramedullary (EM) leukemia, but 21 had prior or concurrent CNS involvement. The median time of Br and Ov relapse after diagnosis was 11-13 mo in AML and in Br cases with ALL, but for ALL Ov cases, the median was 44 mo. Late relapse at 5 to 13 yrs was reported in 24 cases (7 Br, 17 Ov). Median survival of 59 cases of granulocytic sarcoma (GS), before marrow leukemia, was 30mo for Br and 13mo for Ov cases. For the 71 Br or Ov relapses after chemo without marrow relapse, median survivals were 12mo (AML) and 17mo (ALL). When marrow was simultaneously involved in 115, median survivals were <8mo (AML) and <12mo (ALL). Of 60 cases of Br or Ov relapse after SCT, marrow had not relapsed in 36 cases with median survival of 16-22mo; when marrow was involved in 24, median survival was 4mo. Failure to control primary and subsequent EM disease was the principal obstacle to cure, as tumor response to chemotherapy was asynchronous with marrow response, and rarely complete or documented serially. Br tumors were single or multiple, axillary nodes were often involved, and recurrence in ipsi- or contralateral breasts was seen in at least 14%. Ovarian tumors grew rapidly to large size (median 10cm) before symptoms and tended to invade contiguous organs and to involve the contralateral ovary, so excision was difficult and recurrence common. After treatment of Br and Ov tumors, further relapse in EM soft tissue sites was almost twice as common as marrow relapse. The most common subsequent site was CNS in both AML (14 cases) and ALL (23 cases), despite universal prophylaxis in ALL. The 46 cases disease-free at 2 yrs provide a focus for analyzing successful initial treatment. In addition to systemic chemo, the majority received local therapy (tumor excision and/or RT); in at least 7 cases, local followed systemic therapy. Nine underwent SCT. Only 12 long survivors had been in simultaneous marrow relapse (5 Br, 6 Ov, 1Br/Ov); 2 with ALL subsequently relapsed in CNS with marrow. Of the 34 pts with isolated Br or Ov tumors disease-free at 2yr, 13 subsequently relapsed, predominantly in EM sites (8 EM, 1 EM+BM, 4BM). Twenty-six pts (11ALL, 15AML) have been documented disease-free at 5 to 31 yr. Six additional patients who relapsed and responded to salvage therapies survived 5 to 26 yr. Neither age nor karyotype predicted DFS; survivors were ages 5mo to 55yr at dx, and 13 had abnormal karyotypes, only 2 were 'favorable'. This study documents the behavior and drug resistance of leukemic tumors in breast and ovary, the greater risk for subsequent extramedullary than marrow relapse, an association with resistant CNS disease, and short survival, but also that lengthy survival and cure are possible. Current systemic agents alone are inadequate to cure most EM tumors. Local and aggressive systemic therapy, promptly initiated, with reliable, probably intraventricular, CNS treatment and long-term monitoring for further extramedullary involvement should improve prognosis until more effective agents are available. Disclosures: No relevant conflicts of interest to declare.