Whole-Genome Sequencing of Acute Myeloid Leukemia

We used massively parallel sequencing technology to sequence the genomic DNA of tumor cells (leukemic bone marrow) and normal cells (skin biopsy) obtained from patients with Acute Myeloid Leukemia (AML). Patients had either de novo AML (AML with no prior diagnosis of a hematologic disease or exposure to chemotherapy), secondary AML (occurring after a prior diagnosis of myelodysplastic syndromes (MDS)), or therapy-related AML (occurring after exposure to prior chemotherapy). We identified somatic mutations in the tumor genomes, including single nucleotide variants, insertions, deletions, and structural variants.

• Study Weblinks:
  • Genome Sequencing Center
• Study Design:
  • Tumor vs. Matched-Normal
• Study Type:
  • Single Patient
  • Tumor vs. Matched-Normal
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 170
• Subject Sample Telemetry Report (SSTR)

• BioSample

Case presentation of UPN 933124. A previously healthy Caucasian female in her late 50s presented with a sudden onset of sore throat and easy bruisability. There was no antecedent history of prior cancer, or administration of cytotoxic drugs and/or radiation therapy. The patient's family history was obtained by a trained genetic counselor and was positive for late onset cancers in her mother and several of her mother's siblings, including a maternal uncle with a reported case of AML that was confirmed by death certificate. The patient's sister has Essential Thrombocythemia (JAK2 V617F negative). None of the patient's children had a history of cancer. The patient's pedigree is being withheld from this report to protect the privacy of the family. The patient was found to have a peripheral blood white blood cell count of 105,000 cells per microliter with 85% blasts on presentation. The hemoglobin was 12.1 grams per deciliter, and platelet count was 20,000 per microliter. A bone marrow biopsy and aspirate revealed 100% blasts, and confirmed the diagnosis of AML, FAB M1 subtype. Flow cytometry revealed a single population of myeloblasts with cell surface expression of CD-13, -33 and -117, and absent expression of CD-34 and HLA-DR. Cytogenetic analysis of tumor cells revealed a normal 46 XX karyotype. After informed consent was obtained, she was enrolled in a cooperative group protocol for treatment of AML in adults less than age 60 (Cancer and Leukemia Group B (CALGB) #19808), and a Washington University Human Studies Committee-approved protocol for tissue banking in patients with MDS and AML (HSC #01-1014). Specimens of bone marrow, peripheral blood, and skin were collected and cryopreserved for genomic studies. After emergent leukopheresis, she underwent induction chemotherapy with cytarabine, daunorubicin, and etoposide. A bone marrow biopsy repeated 2 weeks later demonstrated chemoablation. After myeloid recovery, a repeat bone marrow biopsy demonstrated first complete remission. On the basis of her intermediate risk cytogenetics, she was assigned to undergo consolidation chemotherapy with high dose cytarabine and etoposide, followed by filgrastim to facilitate autologous hematopoietic stem cell mobilization and collection. She subsequently underwent dose-intensive busulfan and etoposide conditioning, followed by autologous hematopoietic stem cell rescue. Upon recovery from autologous stem cell transplantation, she was assigned to receive maintenance immunotherapy with IL-2. Despite these multiple therapies, she relapsed 11 months after her initial diagnosis. After failing to respond to a salvage regimen of mitoxantrone, etoposide, and cytarabine, she received fludarabine, high dose Ara-C, idarubicin and gemtuzumab ozogamicin. 10 days later she received high dose cyclophosphamide conditioning (60 mg/kg daily x 2) and then single dose total body irradiation (550 cGy; 30 cGy/min) followed by allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor. A bone marrow biopsy performed one month after transplantation confirmed second complete remission. Unfortunately, her disease relapsed four months later. Gemtuzumab ozogamicin was again administered, followed by two donor lymphocyte infusions, without clearance of circulating blasts. She was then successively treated with azacytidine, low dose cytarabine, and decitabine, again without appreciable response, and expired 24 months after her initial diagnosis. Informed consent for whole genome sequencing was subsequently obtained from her next of kin and family members, using a revised Washington University Human Studies Committee-approved protocol that specifically addresses privacy and confidentiality issues associated with whole genome sequencing (HSC #01-1014, Amendment #17).

Case presentation of UPN 807970. A 38-year-old Caucasian male who was previously in good health presented with fatigue and a cough. The white blood cell count was 39,800/ul with 97% blasts, the hemoglobin was 8.9 g/dl, and the platelet count was 35,000/ul. A bone marrow examination revealed 90% cellularity and 86% myeloperoxidase positive blasts. Flow cytometric analysis of the bone marrow sample revealed a uniform population of cells in the blast gate that stained for CD33 and CD117, but not CD13, CD14, CD34, or HLA-DR. Routine cytogenetics of the bone marrow samples revealed a normal 46 XY karyotype. The bone marrow and skin samples were banked with informed consent for whole genome sequencing on a protocol approved by the Washington University Institutional Review Board. The patient's Unique Patient Number (UPN) on the protocol was 807970. There was no family history of leukemia. The patient's mother developed breast cancer at age 60, and non-Hodgkins lymphoma at age 63; her half sister developed breast cancer at age 50. The patient was treated initially with a 7-day course of infusional cytarabine, and three days of daunorubicin. He obtained a morphologic complete remission and count recovery within 5 weeks. The patient was consolidated with high-dose cytarabine for four cycles, and has had no further therapy. He remains in complete remission 3 years later.

Case presentation of UPN 189941. A 37 year-old female presented with Stage 2 estrogen receptor-positive, progesterone receptor-positive, Her2-positive breast cancer and was treated with surgery, local radiotherapy and chemotherapy (cyclophosphamide, etoposide, and doxorubicin). At age 39, she was diagnosed with Stage IIIC ovarian serous cystadenocarcinoma (FIGO grade III), and she was treated with surgery and chemotherapy (carboplatin and paclitaxel). Her ovarian cancer recurred at age 42, and she received additional chemotherapy. Six months later, she presented with t-AML. Analysis of her bone marrow revealed 76% blasts with monocytic features and a complex karyotype involving monosomy 7, del(5q), and two marker chromosomes that could not be resolved by standard cytogenetic analysis. She developed respiratory failure and died 8 days after presentation. Of note, her family history did not suggest an inherited cancer susceptibility syndrome. Specifically, no cancers were reported in 6 first degree relatives (parents, brother, and 3 children) and only a single case of cancer (leg sarcoma at age 62 in a maternal grandfather) was reported in 10 second degree relatives. Nonetheless, the early onset of both breast and ovarian cancer prompted commercial testing for BRCA1 and BRCA2 mutations, which was negative.

Case presentation of UPN 757128. We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical clinical presentation of acute promyelocytic leukemia, who had no evidence of the classic t(15;17) translocation, but presented with pancytopenia, hypofibrinogenemia, disseminated intravascular coagulopathy and increased bone marrow promyelocytes. She was treated with standard induction therapy using cytarabine and idarubicin, but had persistent bone marrow leukemia at day 14. She entered a complete remission following reinduction with cytarabine, idarubicin and etoposide. She was empirically consolidated with arsenic trioxide. As a result of the whole genome sequencing results, she was further treated with all-trans retinoic acid maintenance therapy and remains in remission 15 months after presentation.

Case presentation of UPN 461282. A 65 year old male with refractory anemia with excess blasts (RAEB) received supportive care only (erythropoietin, RBC transfusion) until MDS banking on day 1077 after initial diagnosis. He had a complex karyotype at MDS banking consisting of: -17,del(20)(q11.2),r[5]/idem,del(5)(q31q33)[10]/idem,del(5)(q13q33)[3]/ idem,-X,add(X)(q22),der(12)t(12;?)del(12)(q22)[2]. He then received 11 cycles of decitabine, followed by 3 cycles of lenalidomide. On day 1755 (day 660 after MDS banking) he progressed to sAML. At sAML banking his karyotype showed: del(5)(q22q33),-17,del(20(q11.2)[14]. He then underwent standard induction ("7+3"), followed by salvage chemotherapy (fludarabine, high dose cytarabine, and filgrastim) for induction failure. He then proceeded to a matched, unrelated stem cell transplant with fludarabine/busulfan/thymoglobulin conditioning. He had evidence of persistent disease at day+30 following transplant, received two cycles of decitabine, and died of progressive leukemia on day 2009 (day 932 after MDS banking). The patient's past medical history was notable for basal cell carcinoma, localized prostate cancer, a pancreatic neuroendocrine tumor, and bronchioloalveolar carcinoma, all treated surgically without adjuvant chemoradiotherapy. A sister and two nieces had early onset breast cancer (age<40). One niece also had a neuroendocrine tumor and clinical testing revealed an inherited deleterious TP53 variant.

Case presentation of UPN 667720. A 66 year old female with refractory anemia with excess blasts (RAEB) was treated initially with supportive care (erythropoietin and RBC transfusions) until MDS banking on day 8, followed by four cycles of decitabine. She was then observed until sAML progression at day 667 (day 659 after MDS banking). Her karyotype was normal at MDS and sAML banking. She received one further cycle of decitabine, followed by supportive care until her death on day 724 (day 716 after MDS banking).

Case presentation of UPN 610184. A 45 year old female with refractory anemia (RA) was observed for one year, then received 3 cycles of lenalidomide prior to MDS banking on day 162 after diagnosis. She had a complex karyotype at MDS banking consisting of: add(1)(p36.3),del(5)(q13q33),-13,dic(16;21)(p13.3;q11.2),add(17)(p13),-18,-22. She received no further therapy until progression to sAML on day 314 (day 152 after MDS banking). Her karyotype at sAML banking showed: add(1)(p36.3),del(5)(q13q33),-7,-13,dic(16;21)(p13.3;p11.2),add(17)(p13),-18,-22,+mar[cp17]. She then underwent standard induction chemotherapy ("7+3"), followed by salvage chemotherapy (mitoxantrone, etoposide, cytarabine) for induction failure. On day 398 (day 236 after MDS banking), she underwent a matched, unrelated donor transplant, relapsed, and died of progressive disease on day 589 (day 427 after MDS banking).

Case presentation of UPN 182896. A 75 year old male with refractory anemia (RA) was observed until MDS banking on day 69 after diagnosis. His karyotype at MDS banking showed: +8 [6]. He then received supportive care only (RBC transfusion) until sAML progression on day 1047 (day 978 after MDS banking). His karyotype at sAML banking showed: +3, +8, +9, -12, +15, +19, +22 [cp11]. He then received 5 cycles of decitabine and intermittent hydroxyurea until he died from progressive disease on day 1205 (day 1136 after MDS banking).

Case presentation of UPN 266395. A 65 year old male with refractory anemia with excess blasts (RAEB) treated with supportive care (erythropoietin, RBC transfusion) until MDS banking on day 46 after initial diagnosis. He received one month of hydroxyurea before sAML progression on day 76 (day 30 after MDS banking). His karyotype was normal at MDS and sAML banking. He required emergency leukopheresis, followed by 5-azacytidine for 6 cycles. He then developed CNS leukemia and received supportive care only until his death on day 321 after diagnosis (day 275 after MDS banking).

Case presentation of UPN 288033. A 31 year old female with refractory anemia with excess blasts (RAEB) at diagnosis and MDS banking was observed until sAML progression on day 28. Her karyotype was normal at MDS and sAML banking. She underwent induction chemotherapy (cytarabine, daunorubicin, and etoposide), followed by reinduction and salvage chemotherapy Page 2 of 100 before proceeding to a matched, unrelated donor transplant. She died of graft-versus-host disease on day 367 (day 367 after MDS diagnosis).

Case presentation of UPN 298273. A 27 year old male with refractory anemia with excess blasts (RAEB) at diagnosis and MDS banking received 3 cycles of an oral angiogenesis inhibitor (Vatalanib) on a clinical trial until sAML progression on day 131. His karyotype was normal at MDS and sAML banking. He then received one cycle of 5-azacytidine, followed by a matched, unrelated donor transplant. He relapsed on day 257 and received salvage chemotherapy, but died of graft-versus-host disease on day 540 (day 514 after MDS banking).

Case presentation of UPN 400220. A 34 year old Caucasian female with a prior history of cervical carcinoma in situ (treated with LEEP procedure), mitral valve prolapse, and endometriosis, presented with fatigue, allergy symptoms and chest pain. A CBC demonstrated WBC 14,500 cells/mcl, hemoglobin 11.5 g/dl, platelets 139,000 cells/mcl, with 58% circulating blasts. A bone marrow biopsy demonstrated 90% cellularity, with 71% myeloblasts (MPX +, NSE -, CD13/33/34/117/HLA-DR+), consistent with a diagnosis of AML M4. Cytogenetics showed a 46 XX karyotype. Molecular diagnostic studies demonstrated a FLT3 internal tandem duplication. Initial therapy consisted of 7 +3 induction regimen with infusional cytarabine and idarubicin. A mid-cycle bone marrow biopsy revealed ablation, and a subsequent biopsy documented first complete remission. Post-remission therapy consisted of 3 cycles of high dose cytarabine. Relapse was documented 8 months after initial diagnosis. The patient underwent salvage chemotherapy with mitoxantrone, etoposide, and high dose cytarabine (MEC) with concurrent plerixafor, but did not achieve remission. She was subsequently treated with fludarabine, high dose cytarabine, idarubicin, and gemtuzumab with concurrent filgrastim, and subsequently underwent matched unrelated donor stem cell transplantation with active disease. She expired at day +7 post transplant, 10 months from initial diagnosis.

Case presentation of UPN 426980. A 69 year old Caucasian male, with a prior history of hypothyroidism, hyperlipidemia, and pneumonia, presented with low grade fever and cough. A CBC demonstrated WBC 6000 cells/mcl, hemoglobin 7.4 g/dl, platelets 102,000 cells/mcl, with 29% circulating blasts. A bone marrow biopsy demonstrated 50% cellularity, with 64% myeloblasts (MPX +, NSE -, CD13/33/117+), consistent with a diagnosis of AML M2. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent oblimersen (Genasense, a BCL2 antisense molecule). A mid-cycle bone marrow biopsy revealed ablation, and a subsequent biopsy documented first complete remission. Post-remission therapy consisted of 2 cycles of high dose cytarabine with concurrent oblimersin. Relapse was documented 26 months from diagnosis. Salvage chemotherapy regimens were administered sequentially with no or minimal response including decitabine, high dose cytarabine, mitoxantrone and etoposide, azacytidine, and palliative hydroxyurea. He expired from progressive disease 48 months following his initial diagnosis.

Case presentation of UPN 452198. A 55 year old Caucasian male, previously healthy, presented with fatigue, subjective fevers, and sinus congestion. A CBC demonstrated: WBC 72,600 cells/mcl, hemoglobin 8.2 g/dl, platelets 17,000 cells/mcl, with 8% circulating blasts and 50% monocytes. A bone marrow biopsy was inevaluable for cellularity. The aspirate demonstrated 97 % monoblasts (MPX -, NSE +, CD13/33/64+), consistent with a diagnosis of AML M5. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of hydroxyurea for two days, followed by 7 + 3 induction with infusional cytarabine and idarubicin. A mid-cycle bone marrow biopsy revealed ablation, and a subsequent biopsy documented first complete remission. Post-remission therapy consisted of 4 cycles of high dose cytarabine. Relapse was documented 16 months from diagnosis, and treated with mitoxantrone, etoposide, and high dose cytarabine (MEC) with concurrent plerixafor; the patient achieved a second complete remission. He underwent matched sibling donor stem cell transplantation following busulfan/cyclophosphamide conditioning, and remains alive and in complete remission 56 months from initial diagnosis.

Case presentation of UPN 573988. A 67 year old Caucasian female with a prior history of hyperthroidism (treated with radioactive iodine), hypertension, pancreatitis, and breast intraductal carcinoma in situ (treated with excision), presented with syncope. A CBC demonstrated WBC 15,200 cells/mcl, hemoglobin 8.2 g/dl, platelets 79 cells/mcl, with 10% circulating blasts and 30% monocytes. A bone marrow biopsy demonstrated hypercellularity, with 17% myeloblasts an (MPX +, NSE -, CD13/33/117+), and 58 % monoblasts (MPX -, NSE +, CD13/33/64+) consistent with a diagnosis of AML M4. Cerebrospinal fluid was negative for malignant cells. Cytogenetics showed a 46 XX karyotype. Initial therapy consisted of 7 + 3 induction with infusional cytarabine and idarubicin. A mid-cycle bone marrow biopsy revealed ablation, and a subsequent biopsy following marrow recovery documented first complete remission. Post-remission therapy consisted of a single cycle of 5 + 2 infusional cytarabine and idarubicin. Relapse (skin and bone marrow) was documented 12 months from diagnosis and was treated with decitabine without response. She expired from progressive disease 20 months from initial diagnosis.

Case presentation of UPN 869586. A previously healthy 23 year old Caucasian male presented with abdominal pain and was found to have a ruptured appendix. A CBC demonstrated WBC 27,100 cells/mcl, hemoglobin 12.0 g/dl, platelets 23,000 cells/mcl, with 63% circulating blasts. A bone marrow biopsy demonstrated was inevaluable for cellularity. The aspirate demonstrated 51% myeloblasts (sparse MPX+, NSE low, CD13/33/34/56/117+), consistent with a diagnosis of AML M4. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following marrow recovery documented first complete remission. Post-remission therapy consisted of high dose cytarabine and etoposide, followed by autologous stem cell transplantation with busulfan/cyclophosphamide conditioning. Relapse was documented seven months from diagnosis, and treated with fludarabine, high dose cytarabine, idarubicin, and gemtuzumab with concurrent filgrastim, resulting in second complete remission. He subsequently underwent matched sibling donor allogeneic stem cell transplant 12 months from initial diagnosis, but relapsed two months later. Subsequent treatment included: clofarabine and high dose cytarabine; decitabine; and cladribine, high dose cytarabine, and imatinib, as well as serial donor lymphocyte infusions, without achieving remission. He expired from progressive disease 19 months from initial diagnosis.

Case presentation of UPN 758168. A previously healthy 25 year old Caucasian female presented with fatigue, nausea, vomiting, and decreased visual acuity in her left eye. A CBC demonstrated WBC 3,500 cells/mcl, hemoglobin 5.9 g/dl, platelets 24,000 cells/mcl, with circulating promyelocytes. Diffuse intravascular coagulation (DIC) was present (INR of 3.2 and fibrinogen 88 mg/dl). A bone marrow biopsy demonstrated hypercellularity, with 93% promyelocytes (MPX +, NSE -, CD13/33+), consistent with a diagnosis of AML M3. Cytogenetics showed a t(15;17) translocation. Ophthalmologic evaluation demonstrated retinal hemorrhage, detachment, and acute glaucoma, resulting in irreversible loss of vision and eventual enucleation. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, idarubicin, and concurrent ATRA, complicated by headaches attributed to pseudotumor cerebri (CSF negative for malignancy). A bone marrow biopsy following marrow recovery documented first complete remission. Following induction, additional ATRA was withheld because it was presumed to be the cause of her pseudotumor cerebri. Post-remission therapy consisted of 3 cycles of "anthracycline" administered by the referring oncologist, followed by planned arsenic trioxide maintenance (prematurely aborted due to noncompliance). Relapse was documented 32 months from diagnosis, and was treated with arsenic trioxide, resulting in second complete remission. She subsequently underwent matched unrelated donor stem cell transplantation 4 months later, complicated by acute and chronic graft vs host disease and recurrent infection. She expired while in remission 50 months from initial diagnosis (14 months post transplant) from infectious complications of her transplant.

Case presentation of UPN 804168. A 53 year old Caucasian male with a history of hyperlipidemia, hypertension, and coronary artery disease (treated with stent), presented with a syncopal episode. A CBC demonstrated WBC 88,100 cells/mcl, hemoglobin 8.8 g/dl, platelets 30,000 cells/mcl, with 52% circulating blasts. A bone marrow biopsy demonstrated >90% cellularity, with 86% myeloblasts (MPX+, NSE -, CD13/33/117+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide. A mid-cycle bone marrow biopsy revealed ablation, and a subsequent biopsy following marrow recovery documented first complete remission. Post-remission therapy consisted of 2 cycles of high dose cytarabine. Relapse was documented 8 months from diagnosis, and was treated with mitoxantrone, etoposide, and high dose cytarabine with concurrent plerixafor, following which residual disease was documented (5-7% blasts). He subsequently underwent matched sibling donor allogeneic stem cell transplant following conditioning with single dose total body irradiation and high dose cyclophosphamide, but relapsed 1 month post transplant. Subsequent salvage therapy included decitabine, which yielded a third remission. He subsequently developed extramedullary relapse that was treated with radiation, and died of progressive disease 30 months from initial diagnosis.

Case presentation of UPN 123172 (AML3). 56 year old Caucasian male with a remote history of rheumatic heart disease and aortic valve replacement, presented with a one month history of unexplained fever, night sweats, and 12 pound weight loss. A CBC demonstrated: WBC 30,500 cells/mcl, hemoglobin 9.6 g/dl, platelets 88,000 cells/mcl, with 45% circulating blasts. A bone marrow biopsy demonstrated 90% cellularity, with 90% myeloblasts (MPX +, NSE -, CD13+, CD33+, CD41+, CD61+, CD117+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide with concurrent PSC833. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following marrow recovery documented first complete remission. Post-remission therapy consisted of 3 courses of high dose cytarabine consolidation, complicated by persistent pancytopenia. While in CR1, 11 months following his initial diagnosis, he underwent a matched unrelated donor transplant following conditioning with single dose dose (550cGy) and cyclophosphamide. He died 42 months later from complications of chronic GVHD while still in CR1.

Case presentation of UPN 831711 (AML4). 58 year old Caucasian female with a history of hypertension, peptic ulcer disease, and panic attacks, presented with fatigue and gum bleeding. A CBC demonstrated: WBC 2,500 cells/mcl, hemoglobin 6.3 g/dl, platelets 35,000 cells/mcl, with 61% circulating blasts. A bone marrow biopsy demonstrated 80% cellularity, with 64% myeloblasts (MPX +, NSE -, CD33/117+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XX karyotype. Initial therapy consisted of 7 + 3 with infusional cytarabine and idarubicin. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following marrow recovery documented first complete remission. Post-remission therapy consisted of 3 courses of high dose cytarabine consolidation. She remains alive and in remission 58 months from initial diagnosis.

Case presentation of UPN 849660 (AML5). 22 year old Caucasian male, previously healthy, presented with a 2 month history of unintentional 15 pound weight loss, night sweats, and soft tissue infections (skin/gingival). A CBC demonstrated: WBC 167,500 cells/mcl, hemoglobin 7.1 g/dl, platelets 41,000 cells/mcl, with 88% circulating blasts. Diffuse intravascular coagulation (DIC) was present with an INR of 3.2 and fibrinogen 88 mg/dl. A bone marrow biopsy demonstrated 90 % cellularity, with 71 % myeloblasts (MPX +, NSE -, CD13/33/34/117+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide. A mid-cycle bone marrow biopsy showed <10% cellularity, but was suggestive of persistent leukemia with 18% residual blasts. A subsequent biopsy following marrow recovery clearly documented persistent disease, and he was treated with a salvage regimen of mitoxantrone, etoposide, and high dose cytarabine, following which complete remission was achieved. He subsequently underwent matched unrelated donor stem cell transplantation in CR1 following fractionated total body irradiation/cyclophosphamide conditioning, five months after initial diagnosis. Relapse was documented at three months post transplant, and he underwent salvage chemotherapy with fludarabine, high dose cytarabine, and idarubicin, following which a second complete remission was achieved. He subsequently three serial donor lymphocyte infusions, and remained in remission for over a year before relapsing again, 24 months from his initial diagnosis. He was treated with a salvage regimen of clofarabine and high dose cytarabine, following which a third complete remission was achieved. He subsequently underwent a second matched unrelated donor transplant (from a different donor), but died from infectious complications prior to count recovery, 27 months from initial diagnosis.

Case presentation of UPN 529205 (AML49). 59 year old Caucasian male, with a history of diabetes mellitus, hypertension, and depression, presented with a three week history of fatigue, and was found to be pancytopenic. A CBC demonstrated: WBC 700 cells/mcl, hemoglobin 8.3 g/dl, platelets 23,000 cells/mcl, with 15% circulating blasts. A bone marrow biopsy demonstrated hypercellularity, with 79% myeloblasts and promyelocytes (MPX +, NSE -, CD13/33/117+, HLA DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XY karyotype with a t(15;17) translocation. FISH and RT-PCR confirmed the presence of a PML/RAR fusion. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, idarubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with RT-PCR negative for PML-RAR. Post-remission therapy consisted of two cycles of arsenic with concurrent ATRA, two cycles of daunorubicin with concurrent ATRA, and 2 years of ATRA, methotrexate, and 6-mercaptopurine maintenance. He remains alive and in remission 34 months from initial diagnosis.

Case presentation of UPN 501944 (AML50). 40 year old Caucasian female, previously healthy, presented with a history of excessive bleeding following tooth extraction for a dental abscess. A CBC demonstrated: WBC 400 cells/mcl, hemoglobin 7.8 g/dl, platelets 34,000 cells/mcl, without circulating blasts. A bone marrow biopsy demonstrated hypercellularity, with >90% promyelocytes (MPX +, NSE -, CD33/34/117+), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XX karyotype, with a t(15;17) translocation. FISH and RT-PCR confirmed the presence of a PML/RAR fusion. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with RT-PCR negative for PML/RAR. Post-remission therapy consisted of two cycles of idarubicin, followed by two years of maintenance therapy with ATRA. She remains alive and in remission 81 months from initial diagnosis.

Case presentation of UPN 943309 (AML51). 35 year old Caucasian male, with a history of hypertension and gastroesophageal reflux, presented with increased bruising. A CBC demonstrated: WBC 1500 cells/mcl, hemoglobin 12.3 g/dl, platelets 12,000 cells/mcl, with 8% circulating promyelocytes and blasts. A bone marrow biopsy demonstrated >90% cellularity, with 80% promyelocytes and myeloblasts (MPX +, NSE -, CD13/33+, CD34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 47 XY karyotype, with a t(15;17) translocation, trisomy 8, and del 7q. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH studies negative but RT-PCR positive for PML/RAR. Post-remission therapy consisted of two cycles of idarubicin and one cycle of etoposide, each with concurrent ATRA, followed by two years of ATRA, methotrexate, and 6-mercaptopurine maintenance. He remains alive and in remission 67 months from initial diagnosis.

Case presentation of UPN 709968 (AML9). 25 year old Caucasian male, with a history of depression, presented with a one week history of fatigue, nausea, vomiting, cough, and a new diagnosis of diabetic ketoacidosis. A CBC demonstrated: WBC 8200 cells/mcl, hemoglobin 9.9 g/dl, platelets 18,000 cells/mcl, with 63% circulating promyelocytes and blasts. Diffuse intravascular coagulation (DIC) was present with an INR of 1.68 and fibrinogen 130 mg/dl. A bone marrow biopsy demonstrated 100% cellularity, with 91% promyelocytes and myeloblasts (MPX +, NSE -, CD13/117+, CD33/34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XY karyotype, with a t(15;17) translocation. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery showed a hypercellular marrow with 6% blasts and 59% PML/RAR positivity by FISH. He was continued on ATRA for an additional 4 weeks, and repeat bone marrow demonstrated hematologic, cytogenetic, and molecular remission. Post-remission therapy consisted of three cycles of daunorubicin with concurrent ATRA, followed by a planned two year course of ATRA, methotrexate, and 6-mercaptopurine. Autologous stem cells were harvested after 12 months on maintenance therapy, and relapse was documented six months later (24 months from initial diagnosis). He was reinduced to complete remission with arsenic and gemtuzumab ozogamicin, and subsequently underwent matched unrelated donor stem cell transplantation following busulfan/cyclophosphamide conditioning. His transplant was complicated by steroid-refractory grade 4 acute GI graft vs host disease (GVHD), for which autologous stem cells were reinfused ultimately following reconditioning with fludarabine and low dose total body irradiation, following which his GVHD resolved and he reverted to 100% recipient engraftment. He did well with no further therapy for 22 months until relapsing a second time (55 months from initial diagnosis), and was treated with arsenic and ATRA, again achieving a third complete remission prior to proceeding to a second matched unrelated donor transplant from a different donor following single dose total body irradiation/cyclophosphamide condiditoning. He remains alive and in remission with full donor engraftment 75 months from his initial diagnosis.

Case presentation of UPN 478908 (AML11). 50 year old Caucasian male, with prior history of ankylosing spondylitis, hypertension, nephrolithiasis, and non-alcoholic steatosis, presented with fatigue, epistaxis, and syncopal episodes. A CBC demonstrated: WBC 500 cells/mcl, hemoglobin 10.0 g/dl, platelets 58,000 cells/mcl, with 10% circulating blasts. A bone marrow biopsy demonstrated >90% cellularity, with 74% promyelocytes and myeloblasts (MPX +, NSE -, CD13/33/117+, CD34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XY karyotype, with a t(15;17) translocation. A PML/RAR fusion was documented by FISH and RT-PCR. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. Initial therapy consisted of 7 + 4 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH and RT-PCR studies negative for PML/RAR. Post-remission therapy consisted of two cycles of arsenic, followed by two cycles of daunorubicin with concurrent ATRA, followed by 12 months of ATRA, methotrexate, and 6-mercatopurine maintenance. He remains alive and in remission 38 months from initial diagnosis.

Case presentation of UPN 344551 (AML12). 48 year old Hispanic male, previously healthy, presented with fatigue, bruising, and gum bleeding. A CBC demonstrated: WBC 600 cells/mcl, hemoglobin 8.7 g/dl, platelets 52,000 cells/mcl, with 28% circulating promyelocytes. A bone marrow biopsy demonstrated 100% cellularity, with 65% promyelocytes and myeloblasts (MPX +, NSE -, CD33/117+, CD13/34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XY karyotype, with a t(15;17) translocation. FISH studies documented a PML/RAR fusion. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH and RT-PCR studies negative for PML/RAR. Post-remission therapy consisted of a repeat cycle of 7+3, followed by one cycle of idarubicin and one cycle of mitoxantrone, each with concurrent ATRA, followed by two years of ATRA maintenance. He remains alive and in remission 75 months from initial diagnosis.

Case presentation of UPN 673778 (AML13). 53 year old Caucasian male, previously healthy, presented with dyspnea on exertion. A CBC demonstrated: WBC 1000 cells/mcl, hemoglobin 9.4 g/dl, platelets 46 cells/mcl, with 34% circulating promyelocytes and blasts. A bone marrow biopsy demonstrated >90% cellularity, with 42% promyeloccytes and myeloblasts (MPX +, NSE -, CD13/33/117+, CD34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XY karyotype, with a t(15;17) translocation. FISH studies documented a PML/RAR fusion. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. Initial therapy consisted of 7 + 4 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH studies negative for PML/RAR. Post-remission therapy consisted of two cycles of daunorubicin and concurrent ATRA, followed by two years of ATRA maintenance. He remains alive and in remission 80 months from initial diagnosis.

Case presentation of UPN 321258 (AML14). 31 year old Caucasian female, previously healthy, presented with pancytopenia noted incidentally during workup for back surgery. A CBC demonstrated: WBC 1600 cells/mcl, hemoglobin 11.1 g/dl, platelets 208,000 cells/mcl, with no circulating promyelocytes or blasts. Diffuse intravascular coagulation (DIC) was present with an INR of 1.45 and fibrinogen 89 mg/dl. A bone marrow biopsy demonstrated 65% cellularity, with 40% promyelocytes and myeloblasts (MPX +, NSE focally +, CD13/33/117+, CD34/64/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XX karyotype, with a t(15;17) translocation. FISH studies documented a PML/RAR fusion. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH studies negative for PML/RAR. Post-remission therapy consisted of three cycles of idarubicin with concurrent ATRA, followed by two years of ATRA maintenance. She remains alive and in remission 68 months from initial diagnosis.

Case presentation of UPN 455499 (AML16). 29 year old Hispanic female, previously healthy, presented with pancytopenia during pregnancy at 31 weeks gestation. A CBC demonstrated: WBC 1200 cells/mcl, hemoglobin 8.9 g/dl, platelets 29,000 cells/mcl, with 1% circulating promyelocytes. Diffuse intravascular coagulation (DIC) was present with fibrinogen 149 mg/dl. A bone marrow biopsy demonstrated 90% cellularity, with 85% promyelocytes and myeloblasts (MPX +, NSE -, CD13/33/117+, CD34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XX karyotype, with a t(15;17) translocation. FISH studies documented a PML/RAR fusion. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, idarubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH studies negative for PML/RAR. Post-remission therapy consisted of two cycles of idarubicin with concurrent ATRA, a single cycle of arsenic consolidation. She was lost to follow-up nine months after initial diagnosis, at which time she was in molecular complete remission.

Case presentation of UPN 808642 (AML6). 61 year old Caucasian male, with a prior history of nephrolithiasis, hypertension, hyperlipidemia, benign prostatic hypertrophy, gastroesophageal reflux, and essential tremor, presented with fatigue and unexplained fever. A CBC demonstrated: WBC 2900 cells/mcl, hemoglobin 13.5 g/dl, platelets 61,000 cells/mcl, with 14% circulating blasts. A bone marrow biopsy demonstrated 60% cellularity, with 49% myeloblasts (MPX +, NSE -, CD13/33/117+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XY karyotype. Initial therapy consisted of four cycles of decitabine. Bone marrow biopsies after two cycles and four cycles showed no response. He was subsequently treated with SAHA on a clinical trial, but taken off the study due to gastrointestinal side effects. He subsequently underwent 7 + 3 induction chemotherapy with infusional cytarabine and idarubicin. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following marrow recovery documented first complete remission. Post-remission therapy consisted of two cycles of high dose cytarabine. Relapse was documented 12 months from diagnosis, and treated with fludarabine, high dose cytarabine, idarubicin, and gemtuzumab ozogamicin without response. He expired from progressive disease 16 months from initial diagnosis.

Case presentation of UPN 509754 (AML7). 21 year old Caucasian female, previously healthy, presented with fever, cough, and sore throat. A CBC demonstrated: WBC 8200 cells/mcl, hemoglobin 7.9 g/dl, platelets 52,000 cells/mcl, with 83% circulating blasts. A bone marrow biopsy demonstrated 95% cellularity, with 91% myeloblasts (MPX +, NSE -, CD13/33/117+, CD34/HLA-DR-), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XY karyotype; FISH studies for a PML/RAR fusion were negative. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide. A mid-cycle bone marrow biopsy 9% blasts with <10% cellularity. A subsequent biopsy following count recovery documented first complete remission, however relapse was documented 3 weeks later, prior to consolidation therapy. She was treated with a salvage regimen of mitoxantrone, etoposide, and high dose cytarabine, following which complete remission was achieved. She subsequently underwent allogeneic matched sibling donor stem cell transplantation following fractionated total body irradiation/cyclophosphamide conditioning. She remains alive and in remission 78 months from initial diagnosis.

Case presentation of UPN 327733 (AML8). 32 year old Caucasian female, previously healthy, presented with fever, sore throat, and fatigue during pregnancy (11 weeks gestation). A CBC demonstrated: WBC 5100 cells/mcl, hemoglobin 8.7 g/dl, platelets 39,000 cells/mcl, with 70% circulating blasts. A bone marrow biopsy demonstrated 95% cellularity, with 94% myeloblasts (MPX +, NSE -, CD33/117+, CD13/34/HLA-DR-), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XX karyotype. Initial therapy consisted of 7 + 3 induction with infusional cytarabine and daunorubicin. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following count recovery documented first complete remission. Post-remission therapy consisted of 3 cycles of high dose cytarabine. Relapse was documented 11 months from diagnosis and treated with fludarabine, high dose cytarabine, idarubicin, and gemtuzumab with concurrent filgrastim, resulting in second complete remission. She underwent matched unrelated donor stem cell transplantation following single dose total body irradiation/high dose cyclophosphamide conditioning. She subsequently developed isolated extramedullary relapse (breast) 18 months post-transplant (32 months after diagnosis) and was treated with external beam radiation followed by donor lymphocyte infusion. She again relapsed in her breast and subsequently in her skull and was treated with additional radiation, followed by cladribine, high dose cytarabine, and mitoxantrone, with intrathecal methotrexate and cytarabine, following which she again achieved complete remission. She subsequently underwent a second matched unrelated donor stem cell transplant, 52 months from initial diagnosis, following busulfan/cyclophosphamide conditioning. She relapsed in her marrow 4 months following her transplant, and expired one week later, 56 months from initial diagnosis.

Case presentation of UPN 863018 (AML10). 62 year old Caucasian male, with a prior history of hypertension, hyperlipidemia, coronary artery disease (ventricular fibrillation arrest, coronary artery bypass grafting), atrial fibrillation, deep venous thrombosis (IVC filter), and stroke, presented with a two week history of fatigue and dyspnea on exertion. A CBC demonstrated: WBC 900 cells/mcl, hemoglobin 8.6 g/dl, platelets 15,000 cells/mcl, with 11% circulating blasts. There was no evidence of diffuse intravascular coagulopathy (DIC) at presentation. A bone marrow biopsy demonstrated 90% cellularity, with 82% promyelocytes and myeloblasts (MPX +, NSE -, CD13/33/117+, CD34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XY karyotype, with a t(15;17) translocation. FISH studies documented a PML/RAR fusion. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. A bone marrow biopsy following count recovery documented first complete remission, with FISH studies negative for PML/RAR. Post-remission therapy consisted of two cycles of idarubicin, followed by two years of ATRA maintenance. He remains alive and in remission 78 months from initial diagnosis.

Case presentation of UPN 224143 (AML21). 67 year old Caucasian female, with a prior history of hypertension, hypothyroidism post thyroidectomy, and coronary artery disease, presented with malaise. A CBC demonstrated: WBC 45,600 cells/mcl, hemoglobin 12.6 g/dl, platelets 71,000 cells/mcl, with 49% circulating blasts. A bone marrow biopsy demonstrated 10-20% cellularity, with 76% myeloblasts (MPX +, NSE -, CD13/33/34 partial/117+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XX karyotype. Initial therapy consisted of hydroxyurea, subsequent to which she developed subdural hematoma requiring surgical evacuation. She subsequently developed multi-organ failure and expired with active disease 3 weeks from initial diagnosis.

Case presentation of UPN 545259 (AML33). 31 year old Caucasian female, with a prior history of hypothyroidism and hypertension, presented during pregnancy at 10 weeks gestation with abnormal blood counts noted incidentally during routine pre-natal evaluation. A CBC demonstrated: WBC 22,900 cells/mcl, hemoglobin 10.0 g/dl, platelets 29,000 cells/mcl, with 88% circulating blasts. A bone marrow biopsy demonstrated 70% cellularity, with 86% myeloblasts (MPX +, NSE -, CD33/34/117/HLA-DR+), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XX karyotype. Her pregnancy was electively terminated. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following count recovery documented first complete remission. Post-remission therapy consisted of high dose cytarabine and etoposide consolidation and chemomobilization, with subsequent autologous stem cell transplantation following busulfan/cyclophosphamide conditioning. Following transplant she received eight courses of maintenance decitabine over 10 months. She remains alive and in remission 38 months from initial diagnosis.

Case presentation of UPN 548327 (AML34). 51 year old Caucasian male, with a prior history of unexplained pericarditis, presented with fever, sweats and a sore throat. A CBC demonstrated: WBC 63,700 cells/mcl, hemoglobin 9.6 g/dl, platelets 45,000 cells/mcl, with 85% circulating blasts. A bone marrow biopsy demonstrated 90% cellularity, with 85% myeloblasts (MPX +, NSE -, CD33/117+, CD13/34/64/HLA-DR-), consistent with a diagnosis of AML M1. Cytogenetics showed a 46 XY karyotype; FISH studies for a PML/RAR fusion were negative. Initial therapy consisted of 7 + 3 + 3 induction with infusional cytarabine, daunorubicin, and etoposide. A mid-cycle bone marrow biopsy was ablated, and a subsequent biopsy following count recovery documented first complete remission. Post-remission therapy consisted of high dose cytarabine and etoposide consolidation and chemomobilization, with subsequent autologous stem cell transplantation following busulfan/cyclophosphamide conditioning. Relapse was documented 35 months from initial diagnosis, treated with mitoxantrone, etoposide, and high dose cytarabine with concurrent plerixafor.

Case presentation of UPN 202127 (AML48). 68 year old Caucasian female, with a prior history of hypertension, hyperlipidemia, peptic ulcer disease, and gastroesophageal reflux disease, presented with a worsening headache. A CBC demonstrated: WBC 29,000 cells/mcl, hemoglobin 9.5 g/dl, platelets 73,000 cells/mcl, with 40% circulating promyelocytes and blasts. Diffuse intravascular coagulation (DIC) was present with an INR of 1.7 and fibrinogen 81 mg/dl. A bone marrow biopsy demonstrated 100% cellularity, with 85% promyeleocytes and myeloblasts (MPX +, NSE -, CD13/33/117+, CD34/HLA-DR-), consistent with a diagnosis of AML M3. Cytogenetics showed a 46 XX karyotype, with a t(15;17) translocation. Initial therapy consisted of 7 + 3 induction with infusional cytarabine, daunorubicin, and concurrent ATRA. During her induction course she developed progressive mental status changes and multi-organ failure requiring intubation and mechanical ventilation. Radiographic imaging studies demonstrated no evidence of intracranial hemorrhage. FISH studies repeated on peripheral blood 4 weeks after beginning chemotherapy demonstrated 97% cells positive for PML/RAR. She expired from complications of therapy 32 days from initial diagnosis.

UPN 859640. A 64 year old female with de novo MDS (RA) and normal karyotype at MDS banking. She was transfusion-dependent at diagnosis and received supportive care initially (hydroxyurea, erythropoietin). At 252 days post-MDS diagnosis (sAML banking), a bone marrow examination demonstrated progression to sAML (M4) with 55% blasts and trisomy 13 in 3/20 metaphases. She received 7 cycles of decitabine, but then had progressive disease. On day 594 after MDS diagnosis, she was enrolled on a clinical trial and received vorinostat, but was hospitalized with pneumonia during cycle 1 and died of progressive disease on day 609 after MDS diagnosis.

UPN 891669. A 65 year old male with de novo MDS (RA). Cytogenetics were unsuccessful at initial diagnosis. He received 1 cycle of azacytidine. At day 323 after MDS diagnosis (sAML banking), he evolved to sAML (75% blasts) with cytogenetics revealing inv(3)(q21q26.2) in 14/20 metaphases. He was enrolled on a phase II clinical trial of high dose lenalidomide, but was removed after 1 cycle due to intolerance. He was then enrolled on a clinical trial of decitabine + panobinostat, but came off study and died of progressive disease on day 509 after MDS diagnosis.

UPN 838538. A 65 year old male with de novo MDS (RAEB-2) and complex karyotype (+8, del 5q, del 7q). He was treated initially with 10 cycles of decitabine. He progressed to sAML on day 437 after diagnosis and had skin and bone marrow samples banked for analysis. At this time, his karyotype showed persistence of the original findings and acquisition of new clonal abnormalities (monosomy 2, 12, and 16). Results of mutational profiling for FLT3 and NPM1 were wildtype. He received no further therapy and died on day 565 after MDS diagnosis.

UPN 689147. A 68 year old female with de novo MDS (RAEB-1). Karyotype at diagnosis revealed: +1, del(5)(q15;q33), +11, i(22)(q10) in 20/20 metaphases. She received 5 cycles of azacytidine followed by lenalidomide. She progressed to sAML (90% cellularity, 25% blasts) on day 437 after diagnosis and had skin and bone marrow samples banked for analysis. She was enrolled on a clinical trial of arsenic trioxide + decitabine + ascorbic acid which was discontinued because of alveolar hemorrhage. She developed respiratory failure requiring ventilation support and died on day 453 after MDS diagnosis.

UPN 169510. A 56 year old male with de novo MDS (RAEB-1) and normal karyotype. He received supportive care initially (erythropoietin, filgrastim) followed by 5 cycles of azacytidine. He had disease progression and began treatment with lenalidomide. He then progressed to sAML 796 days after MDS diagnosis (28% blasts and normal cytogenetics) and had skin and bone marrow samples banked for analysis. He underwent induction chemotherapy and obtained a complete remission. His disease then relapsed and he underwent an allogeneic stem cell transplant from a haploidentical donor 982 days after MDS diagnosis. At last follow up (1544 days after MDS diagnosis) he remains in remission with chronic skin graft-versus-host disease.

UPN 989382. A 69 year old male with de novo MDS (RA) was managed initially with supportive care. He progressed to sAML (89% blasts) on day 1332 after MDS diagnosis and had skin and bone marrow samples banked for analysis. His disease was refractory to induction chemotherapy and he died on day 1440 after MDS diagnosis.

UPN 178647. A 61 year old male with de novo MDS (RCMD) and normal karyotype. He was treated initially with supportive care only. He transformed to sAML (23% blasts, normal karyotype) 368 days after MDS diagnosis and had skin and bone marrow samples banked for analysis. He was enrolled on a clinical trial of oblimersen + induction chemotherapy, but did not enter remission and died at day 705 after MDS diagnosis.

UPN 759134. A 66 year old male with de novo MDS (RA) and normal karyotype. He received 4 cycles of azacytidine. His disease evolved to sAML (21% blasts) on day 400 after MDS diagnosis and had skin and bone marrow samples banked for analysis. He received induction chemotherapy, entered remission, and was enrolled on a clinical trial of clofarabine maintenance and completed 1 cycle. Relapsed sAML was identified on day 575 after MDS diagnosis and he died of progressive disease on day 579 after MDS diagnosis.

Case presentation of UPN 126620. 51 year old male diagnosed with AML M4. Blood counts at presentation were WBC 42,400/mm3, hemoglobin 9.2 g/dl, platelets 25,000/mm3 with 5% circulating blasts/promonocytes. The bone marrow cellularity was >95%, with 30-40% blasts/promonocytes. Cytogenetics showed a 46,XY karyotype. Molecular diagnostic studies: NPM1 negative, FLT3 ITD positive, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at day 41 confirmed first complete remission. Subsequent chemotherapy consisted of one cycle of intermediate dose cytarabine consolidation; he relapsed one month later. Salvage chemotherapy consisted of mitoxantrone, cytarabine, and etoposide, following which a repeat marrow biopsy showed persistent disease at day 83. He subsequently underwent a myeloablative 10/10 matched unrelated donor stem cell transplant with refractory disease, following clofarabine/busulfan conditioning. Repeat marrow biopsies at approximately one, three, six, and twelve months post-transplant have demonstrated complete remission with full donor engraftment. His post-transplant course has been complicated by acute (skin) and chronic (skin/mouth/eyes) GVHD, and as of 26 months post-transplant he remains on immunosuppression (tacrolimus/low dose corticosteroids) in ongoing remission.

Case presentation of UPN 135035. 72 year old female diagnosed with AML M5a. Blood counts at presentation were WBC 91,100/mm3, hemoglobin 8.4 g/dl, and platelets 124,000/mm3 with 1% circulating blasts and 58% monocytes. The bone marrow cellularity was 80% with 76% blasts/promonocytes. Cytogenetics showed a 46,XX karyotype. Molecular diagnostic studies: NPM1 positive, FLT3 ITD positive, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction with concurrent sorafenib. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission. Subsequent chemotherapy regimens included 2 cycles of high dose cytarabine consolidation, with concurrent sorafenib maintenance for continued for 12 months. She remains in remission with normal blood counts as of 20 months after diagnosis.

Case presentation of UPN 174556. 65 year old male diagnosed with AML M1. Blood counts at presentation were WBC 51,200/mm3, hemoglobin 7.4 g/dl, platelets 45,000/mm3, with 46% circulating blasts. The bone marrow cellularity was >90%, with 52% blasts. Cytogenetics revealed a 49,XY (+6, +8, +11) karyotype. Molecular diagnostic studies: NPM1 negative, FLT3 ITD positive, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction, and was complicated by myocardial infarction, pneumonia, and C. difficile colitis. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at day 28 confirmed remission, although platelet counts did not recover and FISH studies suggested low level residual disease (7.5% +8). He received no subsequent chemotherapy due to declining performance status, and a bone marrow biopsy three months after his initial diagnosis demonstrated relapsed disease. He expired approximately four months after his initial diagnosis.

Case presentation of UPN 183696. 62 year old male diagnosed with AML M2. Blood counts at presentation were WBC 1,500/mm3, hemoglobin 11.0 g/dl, platelets 140,000/mm3, with 1% circulating blasts. The bone marrow cellularity was 50%, with 27% blasts. Cytogenetics showed a 46,XY karyotype. Molecular diagnostic studies included NPM1 negative, FLT3 ITD negative, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction (ECOG 2906). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy regimens included 2 cycles of high dose cytarabine consolidation. Ten months after initial diagnosis, his disease relapsed and was treated with fludarabine, cytarabine, and idarubicin (FLAG-Ida). A subsequent marrow showed second complete remission, and he underwent 10/10 matched unrelated donor stem cell transplantation following reduced intensity fludarabine, busulfan, thymoglobulin conditioning. His disease again relapsed 7 months post-transplant, and he received mitoxantrone, cytarabine, and etoposide salvage chemotherapy. A subsequent bone marrow showed persistent disease, and he underwent second (haploidentical) allogeneic stem cell transplant following myeloablative cyclophosphamide/total body irradiation (Cy/TBI) conditioning. He is alive 1 month post second transplant, 24 months following initial diagnosis.

Case presentation of UPN 192545. 47 year old female diagnosed with AML M4 with eosinophilia. Blood counts at presentation were WBC 247,400/mm3, hemoglobin 7.1 g/dl, platelets 22,000/mm3, with 25% circulating blasts. The bone marrow cellularity was >90%, with 71% blasts and increased eosinophils. Cytogenetics showed no metaphases; FISH was notable for a CBFB rearrangement (inversion 16). Molecular diagnostic studies included c-Kit, which was negative. Initial therapy consisted of idarubicin, cytarabine, and vorinostat (IAV) (SWOG 1203). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission, positive for CBFB rearrangement in 0.3% of cells. Subsequent chemotherapy regimens included 4 cycles of IAV consolidation. Eleven months after initial diagnosis, her disease relapsed and was treated with mitoxantrone, cytarabine, and etoposide, A subsequent marrow showed second complete remission, and she underwent a course of high dose cytarabine consolidation, complicated by fungal sepsis, respiratory failure, and subsequent profound deconditioning. She was felt not to be a candidate for further therapy and was discharged to hospice, where she died 19 months after initial diagnosis.

Case presentation of UPN 196371. 42 year old female diagnosed with AML M4. Blood counts at presentation were WBC 8,300/mm3, hemoglobin 8.0 g/dl, platelets 84,000/mm3, with 38% circulating blasts. The bone marrow cellularity was 90%, with 38% blasts. Cytogenetics showed a 46,XX karyotype. Molecular diagnostic studies: NPM1 positive, FLT3 ITD positive, and FLT3 D835 positive. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at day 28 confirmed complete remission. Subsequent chemotherapy regimens included three cycles of high dose cytarabine consolidation, prior to disease relapse five months after diagnosis. Salvage chemotherapy consisted of mitoxantrone, cytarabine, and etoposide, following which a repeat marrow biopsy showed persistent disease. She subsequently underwent a myeloablative 10/10 matched unrelated donor stem cell transplant with refractory disease, following clofarabine/busulfan conditioning. Repeat marrow biopsies at approximately one, three, and six months post-transplant have demonstrated complete remission, with 90% donor engraftment at day 30, and subsequent conversion to full donor chimerism. Her post-transplant course has been complicated by acute (skin) and chronic (skin) GVHD, but improving on immunosuppression (sirolimus/low dose corticosteroids). She remains alive in remission 12 months after diagnosis.

Case presentation of UPN 220882. 71 year old female diagnosed with AML M2. Blood counts at presentation were WBC 60,200/mm3 hemoglobin 8.7 g/dl, platelets 66,000/mm3 with 86% circulating blasts. The bone marrow cellularity was >90% with 82% blasts. Routine cytogenetics were non-diagnostic (no metaphases). FISH probes for chromosomes 5q, 7q, and 8, as well as PML/RARA, CBFB-MYH11, MLL, or AML/ETO rearrangements were all negative (normal). Molecular diagnostic studies: NPM1 positive, FLT3-ITD negative, FLT3 D835 negative, and JAK2 negative. Initial therapy consisted of 7+3 induction, which was poorly tolerated due to sepsis and deconditioning. A bone marrow biopsy at day 14 was deferred. A day 35 marrow demonstrated complete remission; however, routine cytogenetics demonstrated trisomy 8 in 11/20 metaphases; this abnormality was not present in the patient's original leukemia. She subsequently underwent two cycles of azacytidine consolidation over a 6-month period, which were again poorly tolerated due to infectious complications. A bone marrow biopsy performed after her first cycle showed ongoing remission with 2/20 metaphases showing trisomy 8. A repeat bone marrow biopsy after her second cycle demonstrated relapse, with monosomy 7q as a sole karyotypic abnormality in 19/20 metaphases, and trisomy 8 in 1/20 metaphases. She received one cycle of cladrabine, high dose cytarabine, and mitoxantrone (CLAM) salvage chemotherapy. A followup marrow biopsy at count recovery showed persistent disease. She received no further chemotherapy and expired shortly thereafter, approximately 10 months after diagnosis.

Case presentation of UPN 275291. 54 year old male diagnosed with AML M4 with eosinophilia. Blood counts at presentation were WBC 220,500/mm3, hemoglobin 6.9 g/dl, platelets 35,000/mm3, with 48% circulating blasts. The bone marrow cellularity was 90%, with 87% myeloblasts/promonocytes, and scattered eosinophils. Cytogenetics showed no metaphases; FISH was notable for a CBFB rearrangement (inversion 16). Molecular diagnostic studies included KIT, which was negative. Initial therapy consisted of idarubicin, cytarabine, and vorinostat (IAV) (SWOG 1203). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission, negative for CBFB rearrangement. Subsequent chemotherapy regimens included 4 cycles of IAV consolidation. Nine months after initial diagnosis, his disease relapsed and was treated with cladribine, cytarabine, and idarubicin (CLAG-Ida). A subsequent marrow showed second complete remission, and he underwent a 6/6 matched sibling donor stem cell transplant following myeloablative busulfan/cyclophosphamide (Bu/Cy) conditioning. He subsequently relapsed in his central nervous system (with low level marrow relapse) and was treated with craniospinal radiation followed by systemic cytarabine chemotherapy. He died of sepsis prior to planned second allogeneic stem cell transplant 18 months after his initial diagnosis.

Case presentation of UPN 286032. 50 year old male diagnosed with AML M2. Blood counts at presentation were WBC 18,900/mm3, hemoglobin 6.1 g/dl, platelets 190,000/mm3, with 20% circulating blasts. The bone marrow cellularity was 90%, with 32% blasts. Cytogenetics showed a 46,XY karyotype. Molecular diagnostic studies included NPM1 positive, FLT3 ITD positive, and FLT3 D835 negative. Initial therapy consisted of idarubicin and cytarabine (IA) (SWOG 1203). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at day 28 confirmed first complete remission. Subsequent chemotherapy regimens included 4 cycles of IA consolidation. Eleven months after initial diagnosis, his disease relapsed and was treated with mitoxantrone, cytarabine, and etoposide, A subsequent marrow showed second complete remission, and he underwent 1 cycle of decitabine consolidation, prior to 9/10 mismatched unrelated donor stem cell transplantation with myeloablative busulfan/cyclophosphamide (Bu/Cy) conditioning. His post-transplant course has been complicated by gvhd of gut, improving on prednisone taper. He remains alive in remission 5 months post transplant, 20 months after initial diagnosis.

Case presentation of UPN 334228. 63 year old male diagnosed with AML M2. Blood counts at presentation were WBC 1,600/mm3, hemoglobin 9.7 g/dl, platelets 83,000/mm3, with 16% circulating blasts. The bone marrow cellularity was 80-90%, with 71% blasts. Cytogenetics showed a 46,XY karyotype. Molecular diagnostic studies: NPM1 positive, KIT (exons 8 and 17) negative, FLT3-ITD negative, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission. Subsequent chemotherapy regimens included 4 cycles of high dose cytarabine consolidation. He remains in remission approximately 32 months after diagnosis.

Case presentation of UPN 352569. 62 year old female diagnosed with AML M5B. Blood counts at presentation were WBC 33,900/mm3, hemoglobin 11.1 g/dl, platelets 104,000/mm3, with 12% circulating blasts, and 63% monocytes . The bone marrow cellularity was 80%, with 55% blasts/promonocytes. Cytogenetics showed a 47,XX karyotype, with inv(16) and trisomy 9. Molecular diagnostic studies included KIT mutation negative. Initial therapy consisted of 7+3 induction with concurrent dasatinib (CALGB 10801). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy included 4 cycles of high dose cytarabine consolidation with concurrent dasatinib, followed by maintenance dasatinib for 12 months. She remains alive and in remission 23 months after initial diagnosis.

Case presentation of UPN 354259. 61 year old male diagnosed with AML M2. Blood counts at presentation were WBC 3,300/mm3, hemoglobin 9.3 g/dl, platelets 83,000/mm3, with 4% circulating blasts. The bone marrow cellularity was 90%, with 63% blasts. Cytogenetics showed a 46,XY karyotype in 17 metaphases, and a subclone with a deletion of chromosome 9 (q13q23) in 3 metaphases. Molecular diagnostic studies: NPM1 negative, FLT3-ITD negative, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission. Subsequent chemotherapy regimens included 4 cycles of high dose cytarabine consolidation. He remains in remission approximately 36 months after diagnosis.

Case presentation of UPN 467522. 69 year old male diagnosed with AML M4. Blood counts at presentation were WBC 8,600/mm3, hemoglobin 8.8 g/dl, platelets 22,000/mm3, with 2-3% circulating blasts. The bone marrow cellularity was >90% with 26% blasts/promonocytes. Cytogenetics showed a complex hyperdiploid karyotype. Molecular diagnostic studies: NPM1 negative, FLT3 ITD negative, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow with a "small focus of immature cells". A repeat marrow at count recovery demonstrated complete remission, with 1% tetrasomy for chromosomes 8,15, 17, and 21 by FISH probes for AML/ETO and PML/RARA rearrangement. Subsequent chemotherapy consisted of one cycle of high dose cytarabine, following which his disease relapsed. He was started on a salvage regimen of decitabine, which was subsequently aborted due to declining performance status. He expired shortly thereafter, approximately 3 months after diagnosis.

Case presentation of UPN 554023. 71 year old male diagnosed with AML M1. Blood counts at presentation were WBC 9,100/mm3, hemoglobin 10.2 g/dl, platelets 103,000/mm3 with 18% circulating blasts. The bone marrow cellularity was >90% with 75% blasts. Cytogenetics showed a complex hyperdiploid karyotype, including +13, +8, -5 and -7. Molecular diagnostic studies were not performed. Initial therapy consisted of cladrabine, high dose cytarabine, and mitoxantrone (CLAM). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission, although cytogenetics did identify +8 in 2 of 20 cells. Subsequent chemotherapy regimens included one cycle of decitabine, following which his disease relapsed, and one subsequent cycle of azacytidine. He then underwent a matched unrelated donor stem cell transplant, following a reduced intensity-conditioning regimen of fludarabine, busulfan, and thymoglobulin. A repeat marrow biopsy one month post transplant showed complete remission with 95% donor engraftment, however one month later his disease relapsed, and he expired approximately 7 months after his diagnosis.

Case presentation of UPN 688691. 53 year old female diagnosed with AML M2. Blood counts at presentation were WBC 49,700/mm3, hemoglobin 6.4 g/dl, platelets 48,000/mm3, with 48% circulating blasts. The bone marrow cellularity was >90%, with 73% blasts. Cytogenetics showed a 46,XX karyotype. Molecular diagnostic studies: NPM1 positive, FLT3 ITD positive, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission. Subsequent chemotherapy regimens included 2 cycles of high cytarabine consolidation. She subsequently underwent a reduced intensity 10/10 HLA-matched unrelated donor stem cell transplant in first remission, following fludarabine/busulfan/thymoglobulin conditioning. Bone marrow biopsies at approximately 1, 3, 6, and 12 months post-transplant demonstrated remission with full donor engraftment. She was subsequently diagnosed with lung adenocarcinoma (T3N3M1b) with adrenal and brain metastases approximately 20 months after her AML diagnosis, and treated with gammaknife radiosurgery, 2 cycles of carboplatin/pemetrexed, and palliative right upper lobe and right adrenal radiation. Patient subsequently had 2 large brain metastases and received whole-brain radiotherapy, but succumbed to metastatic disease 25.6 months after initiation of AML therapy. Her leukemia remained in remission at the time of death.

Case presentation of UPN 695558. 46 year old male diagnosed with AML M2. Blood counts at presentation were WBC 5,700/mm3, hemoglobin 8.6 g/dl, platelets 17,000/mm3, with 18% circulating blasts. The bone marrow cellularity was 20%, with 28% blasts. Cytogenetics showed a 46,XY t(8;21) karyotype. Molecular diagnostic studies included NPM1 negative, FLT3-ITD negative, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated persistent disease with 20% cellularity and 7% blasts. Re-induction chemotherapy consisted of 5+2. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy regimens included 4 cycles of high dose cytarabine consolidation. Eleven months after initial diagnosis, his disease relapsed and was treated with fludarabine, cytarabine, and idarubicin (FLAG-Ida). A subsequent marrow showed second complete remission. He received one cycle of decitabine consolidation, prior to 10/10 matched unrelated donor stem cell transplantation with myeloablative busulfan/cyclophosphamide (Bu/Cy) conditioning. His post transplant course was complicated by GVHD (skin/GI), CMV colitis, and sepsis. He died in remission approximately 21 months after initial diagnosis.

Case presentation of UPN 746628. 53 year old male diagnosed with AML M2. Blood counts at presentation were WBC 6,800/mm3, hemoglobin 10.3 g/dl, platelets 12/mm3, with 3% circulating blasts. The bone marrow cellularity was 70%, with 33% blasts. Cytogenetics showed a 46,XY karyotype. Molecular diagnostic studies included NPM1 negative, FLT3 ITD negative, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction with a concurrent oral Hedgehog inhibitor. A bone marrow biopsy at day 21 demonstrated persistent disease. Re-induction consisted of 7 + 3 with a concurrent oral Hedgehog inhibitor. A repeat marrow at count recovery confirmed first complete remission. A repeat marrow at day 46 confirmed first complete remission. Subsequent chemotherapy included 4 cycles of high dose cytarabine consolidation with a concurrent oral Hedgehog inhibitor, followed by Hedgehog inhibitor maintenance for 12 months. Eighteen months after initial diagnosis, his disease relapsed and was treated with fludarabine, cytarabine, and idarubicin. A bone marrow biopsy at count recovery demonstrated second complete remission. He remains alive and in remission 20 months after initial diagnosis, with plans to proceed to allogeneic stem cell transplant.

Case presentation of UPN 763312. 58 year old female diagnosed with AML M2. Blood counts at presentation were WBC 93,900/mm3, hemoglobin 10.1 g/dl, platelets 26,000/mm3, with 95% circulating blasts. The bone marrow cellularity was >90%, with 75% blasts. Cytogenetics showed a 46,XX t(8;21) karyotype. Molecular diagnostic studies included KIT negative, NPM1 negative, FLT3 ITD negative, and FLT3 D835 negative. A breast mass was biopsied and showed a myeloid sarcoma. Initial therapy consisted of 7+3 induction with concurrent dasatinib (CALGB 10801). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy included 4 cycles of high dose cytarabine consolidation with concurrent dasatinib, followed by maintenance dasatinib. Eleven months after initial diagnosis, her disease relapsed and was briefly treated with ruxolitinib without response, and subsequently with cladrabine, cytarabine, and idarubicin (CLAG-Ida). A subsequent marrow showed second complete remission, and she underwent 6/6 matched sibling donor stem cell transplantation following myeloablative busulfan/cyclophosphamide (Bu/Cy) conditioning. Her disease relapsed 4 months post-transplant, and was briefly treated with vorinostat without response, and subsequently with cladrabine, cytarabine, and idarubicin (CLAG-Ida), followed by second (haploidentical) allogeneic stem cell transplantation with myeloablative fludarabine/total body irradiation (Flu/TBI) conditioning and post-transplant cyclophosphamide. She remains alive and in remission, on ongoing corticosteroid/cyclosporine immunosuppression, 11 months post-second transplant and 28 months after initial diagnosis.

Case presentation of UPN 784096. 55 year old female diagnosed with AML M1. Blood counts at presentation were WBC 22,500/mm3, hemoglobin 12.3g/dl, platelets 30,000/mm3, with 91% circulating blasts. The bone marrow cellularity was 70-80%, with 89% blasts. Cytogenetics showed a 46,XX karyotype. Molecular diagnostic studies included NPM1 negative, FLT-ITD positive, and FLT3 D835 negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at day 25 confirmed first complete remission. One month later she underwent a myeloablative 6/6 sibling donor allogeneic stem cell transplant in first remission with busulfan/cyclophosphamide (Bu/Cy) conditioning, complicated by acute (skin), and chronic (vaginal) GVHD which responded to corticosteroids, and as of 25 months post-transplant she is off all immunosuppression in ongoing remission.

Case presentation of UPN 823477. 51 year old male diagnosed with AML M0. Blood counts at presentation were WBC 10,900/mm3, hemoglobin 9.8, platelets g/dl 129,000/mm3, with 44% circulating blasts. The bone marrow cellularity was >90%, with 72% blasts. Cytogenetics showed a 46,XY karyotype. Molecular diagnostic studies included CEBPA negative, NPM1 negative, FLT3 ITD negative, and FLT3 D835 negative. Initial therapy consisted of idarubicin and cytarabine (IA) (SWOG 1203). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy regimens included 4 cycles of IA consolidation. Nine months after initial diagnosis, his disease relapsed (marrow and CSF) and was treated with mitoxantrone, cytarabine, and etoposide, in addition to intrathecal methotrexate. A subsequent marrow showed second complete remission, and he underwent 6/6 matched sibling donor stem cell transplant following myeloablative cyclophosphamide/total body irradiation (Cy/TBI) conditioning. He remains alive and in remission 5 months post transplant, 14 months after initial diagnosis.

Case presentation of UPN 875663. 68 year old female diagnosed with AML M4. Blood counts at presentation were WBC 57,700/mm3, hemoglobin 10.0 g/dl, platelets 59,000/mm3, with 25% circulating monocytes. The bone marrow cellularity was 80%, with 59% blasts. Cytogenetics showed a 46,XX karyotype (5 metaphases). Molecular diagnostic studies: NPM1 positive, FLT3-ITD negative, and FLT3 D835 positive. Initial therapy consisted of 7+3 induction with concurrent sorafenib. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission. Subsequent chemotherapy regimens included 2 cycles of high dose cytarabine consolidation with concurrent sorafenib maintenance, until relapse approximately 12 months following diagnosis. She was subsequently treated with an investigational anti-CD33 antibody without response, followed by decitabine without response, and azacytidine without response. She then underwent a 7/8 HLA-mismatched unrelated donor stem cell transplant following a reduced intensity conditioning regimen of fludarabine, busulfan, and thymoglobulin. A bone marrow biopsy one-month post transplant demonstrated complete remission with 92-97% donor engraftment. A repeat marrow two months later demonstrated relapse, for which she was treated with mitoxantrone, high dose cytarabine, and etoposide (MEC) and a subsequent donor lymphocyte infusion (DLI). A day 14 bone marrow biopsy demonstrated an ablated marrow, however three weeks later circulating blasts were observed in peripheral blood, for which no further therapy was given, and she expired shortly thereafter, approximately 22 months after diagnosis.

Case presentation of UPN 959485. 62 year old female diagnosed with AML M0. Blood counts at presentation were WBC 47,900, hemoglobin 8.7, platelets 35,000, with 83% circulating blasts. The bone marrow cellularity was 80%, with 75% blasts. Cytogenetics showed a complex karyotype, including deletions of chromosomes 5q, 7, and 20q. Molecular diagnostic studies included NPM1 negative, FLT3 ITD negative, FLT3 D835 negative, and CEBPA negative. Initial therapy consisted of clofarabine induction (ECOG 2906). A bone marrow biopsy at day 14 demonstrated persistent disease. Re-induction consisted of clofarabine. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy included 1 cycle of clofarabine consolidation, with relapse at approximately 4 months. Patient underwent sibling donor allogeneic stem cell transplantation while still with persistent disease. After transplantation the patient continued to have persistent disease that was refractory to cytarabine and idarubicin and then decitabine. Patient was referred to hospice and expired.

Case presentation of UPN 969651. 39 year old female diagnosed with AML M2. Blood counts at presentation were WBC 23,700/mm3, hemoglobin 7.4 g/dl, platelets 15,000/mm3, with 18% circulating blasts. The bone marrow cellularity was >90%, with 27% blasts. Cytogenetics showed a 46,XX, t(8;21) karyotype. Molecular diagnostic studies included KIT mutation negative. Initial therapy consisted of 7+3 induction. A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy included 4 cycles of high dose cytarabine consolidation. She remains alive and in remission 22 months after initial diagnosis.

Case presentation of UPN 970171. 73 year old female diagnosed with AML M2. Blood counts at presentation were WBC 19,500/mm3, hemoglobin 7.1 g/dl, platelets 13,000/mm3, with 11% circulating blasts. The bone marrow cellularity was >90%, with 21% blasts. Cytogenetics showed a complex monosomal karyotype. Molecular diagnostic studies were not performed. Initial therapy consisted of an investigational liposomal formulation of cytarabine and daunorubicin (CPX351). A bone marrow biopsy at day 14 demonstrated an ablated marrow. A repeat marrow at count recovery demonstrated remission, although FISH detected an abnormal signal in 1% of nuclei (2 of 200 nuclei). Subsequent chemotherapy regimens included one cycle of CPX351 consolidation, following which she underwent minimal conditioning with fludarabine and cyclophosphamide prior to infusion of haploidentical activated natural killer (NK) cells. A bone marrow biopsy one month later demonstrated disease relapse. She was subsequently treated with two cycles of decitabine, with modest response (decreased marrow blast percentage), prior to discontinuation of therapy due to declining performance status. She expired shortly thereafter, approximately 8 months after diagnosis.

Case presentation of UPN 976838. 37 year old female diagnosed with AML M2. Blood counts at presentation were WBC 2,400/mm3, hemoglobin 10.6 g/dl, platelets 43,000/mm3, without circulating blasts. The bone marrow cellularity was 80%, with 46% blasts. Cytogenetics showed a 46, XX karyotype. Molecular diagnostic studies included NPM1 positive, FLT3 ITD negative, and FLT3 D835 negative. Initial therapy consisted of idarubicin and cytarabine induction (SWOG 1203). A repeat marrow at count recovery confirmed first complete remission. Subsequent chemotherapy included 4 cycles of idarubicin and cytarabine consolidation. She remains alive and in remission 17 months after initial diagnosis.

• Primary Phenotype: Leukemia, Myeloid, Acute

• Principal Investigator
  • Timothy J. Ley, MD. Department of Medicine, Department of Genetics, The Genome Center, Siteman Cancer Institute, Washington University School of Medicine, St. Louis, MO, USA.
• Institute
  • Siteman Cancer Center, The Genome Center. Washington University School of Medicine, St. Louis, MO, USA.
• Funding Sources
  • P01 CA101937. National Institutes of Health, Bethesda, MD, USA.