The n e w e ng l a n d j o u r na l of m e dic i n e case records of the massachusetts general hospital Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor Case 28-2009: A 68-Year-Old Man with Fatigue, Cough, and Peripheral-Blood Monocytosis Bimalangshu R. Dey, M.D., Ph.D., Thomas R. Spitzer, M.D., and Robert P. Hasserjian, M.D. Pr e sen tat ion of C a se Dr. Alfred Ian Lee (Oncology): A 68-year-old man was seen in the cancer center of this hospital because of fatigue, cough, and peripheral-blood monocytosis. The patient had been well until approximately 7 weeks earlier, when fatigue and cough developed, followed by burning on urination and suprapubic discomfort. Approximately 3 weeks before evaluation at this hospital, he saw his primary care provider. Laboratory-test results are shown in Table 1. Trimethoprim–sulfamethoxa zole was prescribed for a presumptive diagnosis of prostatitis. Culture of a urine specimen reportedly grew Escherichia coli. Six days later (17 days before evaluation at this hospital), the patient returned to his primary care provider for follow-up; his urinary symptoms had resolved, and the fatigue had lessened. The physical examination was normal. A monospot test for Epstein–Barr virus mononucleosis was negative, and results of dipstick screening of the urine were normal; other test results are shown in Table 1. He was referred to a hematologist, whom he saw 10 days before the current evaluation; results of additional tests are shown in Table 1. Ten days later (on the day of the current evaluation), results of flow cytometry performed on a specimen of peripheral blood obtained at the earlier visit to the hematologist were reported and revealed 58% myeloid blasts, which expressed CD33, CD14, CD15, CD34, HLA-DR, and CD64. Neither the V617F mutation of the Janus kinase 2 (JAK2) gene nor the BCR-ABL translocation was detected. The patient was referred urgently to the cancer center of this hospital, where he was seen later the same day. He felt well and reported no chills, chest pain, shortness of breath, night sweats, or weight loss. He was married and semiretired. He had worked in an office in a navy yard and also had worked on antique cars, and he may have had exposure to paints and thinners. He had smoked a pipe in the past, and he drank one to two alcoholic beverages per day. His only medication was acetylsalicylic acid (81 mg daily). He had no allergies. He was of western European ancestry. Two siblings had diabetes mellitus, his children and grandchildren were healthy, and there was no family history of leukemia, lymphoma, or blood disorders. The physical examination was normal. Levels of serum electrolytes, total protein, albumin, globulin, total and direct bilirubin, calcium, and uric acid and tests of renal and liver From the Hematology–Oncology Unit (B.R.D., T.R.S.) and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (B.R.D., T.R.S.) and Pathology (R.P.H.), Harvard Medical School. N Engl J Med 2009;361:1099-106. Copyright © 2009 Massachusetts Medical Society. n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 1099 The n e w e ng l a n d j o u r na l of m e dic i n e Table 1. Laboratory Data.* Reference Range, Adults† 23 Days Earlier Hematocrit (%) 41.0–53.0 (men) 34.8 36.9 33.0 31.2 Hemoglobin (g/dl) 13.5–17.5 (men) 11.9 12.6 11.9 10.7 4,500–11,000 20,900 33,400 37,200 18,300 40–70 23 16 20 35 Variable White-cell count (per mm3) 17 Days Earlier 10 Days Earlier Evaluation at This Hospital Differential count (%) Neutrophils Band forms Lymphocytes Atypical lymphocytes Monocytes Blasts 0–10 5 6 1 0 22–44 13 27 18 21 0 39 35 25 0 4–11 20 16 36 26, some immature 0 Platelet count (per mm3) 150,000–350,000 Mean corpuscular volume (μm3) 80–100 Prostate-specific antigen (ng/ml) Urea nitrogen (mg/dl) 8–25 0.6–1.5 Leukocyte alkaline phosphatase (IU/liter) 40–100 d-Dimer (ng/ml) 0 18 250,000 201,000 179,000 105 102 101 3.98 (ref <4.0) Creatinine (mg/dl) Fibrinogen (mg/dl) 200,000 28 (ref 6–26) 24 (ref 6–26) 20 1.6 (ref 0.5–1.3) 1.5 (ref 0.5–1.3) 1.2 100 <500 526 150–400 292 Activated partial-thromboplastin time (sec) 22.1–34.0 27.8 Prothrombin time (sec) 10.3–13.2 13.8 International normalized ratio Lactate dehydrogenase (U/liter) 1.2 110–210 360 *Ref denotes reference range; these ranges are those used by the patient’s primary care provider. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. †Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. function were normal; other results are shown in Table 1. A diagnostic test was performed, and a management decision was made. Pathol o gic a l Discussion Dr. Robert P. Hasserjian: The diagnostic test consisted of a bone marrow biopsy and aspiration. Examination of the biopsy specimen showed that the bone marrow was replaced by sheets of large cells with folded and often lobulated nuclei, prominent nucleoli, and abundant pink cytoplasm (Fig. 1A). On the smear of the aspirate (Fig. 1B), 1100 73% of the cells were promonocytes and 11% were monoblasts. On cytochemical staining, the blasts and promonocytes were positive for alphanaphthyl butyrate (nonspecific) esterase (Fig. 1C) and negative for myeloperoxidase, confirming their monocytic lineage. Bone marrow flow cytometry revealed a predominant population of CD33+, CD13+, CD117+/−, CD14−, and CD4dim+ cells, a subgroup of which expressed CD34. The constellation of findings confirms a diagnosis of acute myeloid leukemia (AML) with monocytic differentiation. This case illustrates one of the pitfalls in the diagnosis of AML on the basis of the morphologic features of the peripheral blood: manual n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital A B C D 1 6 2 7 3 8 4 9 13 14 15 19 20 21 5 10 11 12 16 17 18 22 X Y ? del(16) Relative Fluorescence E 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 270 290 310 330 350 370 390 Base Pairs Figure 1. Findings in the Bone Marrow at Diagnosis. The bone marrow–biopsy specimen (Panel A) shows is markedly hypercellular and has been RETAKE 1st AUTHOR: Deythat the bone marrow ICM 2nd replaced by sheets of large cells with oval-to-irregular nuclei. The bone marrow–aspirate specimen (Panel B) conREG F FIGURE: 1 of 2 3rd gray or pale basophilic cytosists of a predominant population of promonocytes, which appear as large cells with CASE Revised plasm and folded nuclei (arrowhead), and fewer monoblasts,Line which appear cells with a higher nuclear:cytoplasm 4-C as large EMail SIZE ARTIST: ts ratio and more prominent nucleoli than the promonocytes (arrow).H/T Cytochemical staining of the bone marrow–aspiH/T 33p9 Enon Combo butyrate esterase (Panel C). Cytogenetic analysis rate specimen revealed blasts that are positive for alpha-naphthyl (Panel D) reveals an abnormal 47,XY,+8,del(16)(q2?1q2?2) karyotype in 2 of 20 cells in metaphase (additional chromoAUTHOR, PLEASE NOTE: Figure hasdal been redrawn type has been reset. some 8, arrow). (Karyotype provided by Paola Cin, Ph.D.,and Laboratory of Cytogenetics, Brigham and Women’s Please check carefully. Hospital and Massachusetts General Hospital.) Polymerase-chain-reaction analysis of the bone marrow, with primers flanking the site of recurrent internal tandem duplication (ITD) of the FLT3 gene (Panel E), reveals an FLT3-ITD 36111 ISSUE: 09-10-09 mutation (arrow) in addition toJOB: wild-type FLT3 (arrowhead). (Image provided by A. John Iafrate, M.D., Ph.D., Molecular Diagnostics Laboratory, Massachusetts General Hospital.) n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 1101 The n e w e ng l a n d j o u r na l differential counts performed at other hospitals included “atypical lymphocytes” (Table 1), which in retrospect probably represented the promonocytes and monoblasts of this patient’s AML. To define distinct clinicopathological entities and to predict the prognosis for patients with AML, such as this one, the current World Health Organization (WHO) classification uses immunophenotype, cytogenetics, and molecular genetic findings, as well as clinical features (e.g., a history of myelodysplastic syndrome or previous therapy that is known to cause myeloid neoplasia, neither of which was present in this case).1 Thus, additional studies were performed in this case. An abnormal karyotype — 47,XY,+8,del(16) (q2?1q2?2) — was identified (Fig. 1D); fluorescence in situ hybridization (FISH) did not reveal an inversion of chromosome 16 that was affecting the CBFB and MYH11 genes. These findings do not represent any distinct cytogenetic category of AML, and thus, the case is classified as AML not otherwise specified. In such cases, mutation analysis of the nucleophosmin (NPM1), CCAAT/enhancer binding protein α (CEBPA), and fms-related tyrosine kinase 3 (FLT3) genes is helpful in stratifying patients prognostically.2,3 In particular, point mutations in the NPM1 gene (in the setting of a normal karyotype and wild-type FLT3 gene) predict a favorable prognosis.2 Polymerase-chain-reaction analysis of a bone marrow sample revealed no mutation of NPM1. However, an internal tandem duplication of the FLT3 gene (FLT3-ITD) was identified (Fig. 1E). Although FLT3-ITD is not considered to represent a discrete genetic category of AML (since FLT3 mutations can occur in any type of AML), it confers an adverse prognosis.4 The final WHO diagnosis in this case is acute myeloid leukemia not otherwise specified (acute monocytic leukemia) with FLT3-ITD. Discussion of M a nagemen t of m e dic i n e roughly half of all patients with AML. The response to treatment in this group is variable, and patients are thus further stratified according to the status of the FLT3 and NPM1 genes.3 This patient had FLT3-ITD, an adverse prognostic factor. Treatment of AML in the elderly Even though the patient was healthy, with a good performance status, we knew that in a retrospective analysis of patients with AML who were older than 65 years, the mortality at 1 year was 86%, and only 6% were alive at 2 years.5 Thus, an important initial discussion with this patient must focus on deciding whether standard AML induction treatment, investigational therapy in the context of a clinical trial, or palliative and supportive care is the most appropriate strategy. Whereas standard induction regimens containing an anthracycline and cytarabine result in complete remission in about half of elderly patients with AML, this patient’s probability of remaining in remission at 3 years is less than 15%,6,7 and the treatment-related mortality rate can be 12 to 50%.8 Furthermore, there is no defined, well-established, standard postremission or consolidation therapy for older patients. We discussed enrolling our patient, who had a good performance status and no concurrent illnesses, in a clinical trial of a new agent. Clofarabine, which is a nucleoside analogue (a hybrid molecule derived from fludarabine and cladribine) that is approved by the Food and Drug Administration (FDA) for the treatment of acute lymphoblastic leukemia, has recently been found to be an effective agent with an acceptable adverseevent rate for investigational use in older patients with AML.9 Because of his high risk of treatmentrelated death with conventional therapy, this elderly patient was enrolled in a phase 2 clinical trial (ClinicalTrials.gov number, NCT00373529) that used induction therapy with 5 days of offlabel intravenous clofarabine. He had no clinically significant side effects and achieved a complete remission. Dr. Bimalangshu R. Dey: This patient with a new diagnosis of AML is at the median age at which Stem-Cell Transplantation for AML patients receive a diagnosis of this disease — 68 in the Elderly years. Since AML is rarely cured by a single course of chemotherapy, treatment typically involves addiPrognostic factors in AML tional chemotherapy, known as consolidation. The prognosis is determined principally by age The next challenge in this patient with AML, who and cytogenetic aberrations. The patient was older was at high risk because of his age and FLT3-ITD– than 60 years and had trisomy 8, putting him positive leukemia, was to offer a consolidation into an intermediate-risk group, which constitutes strategy that might improve his chance of cure 1102 n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital and avoid unacceptable treatment-related side effects or death. The options typically available include additional chemotherapy followed by allogeneic stem-cell transplantation, or consolidative chemotherapy, with or without autologous stemcell rescue. In patients such as this one, who have a genetically based adverse risk, a high-intensity, myeloablative chemotherapy regimen that eradicates all bone marrow elements, followed by allogeneic stem-cell transplantation, offers a 44% probability of 5-year survival, better than the 15% or less with additional chemotherapy, with or without autologous stem-cell rescue.10 However, in this patient, who is older than 60 years, the risk of transplantation-related death with myeloablative conditioning is high (27% by 3 months and 43% by 3 years after transplantation).11 The observation that the development of graftversus-host disease (GVHD) is associated with better relapse-free survival12,13 led to the idea that a graft-versus-leukemia effect might be occurring, which could be exploited in patients such as this one, who could not tolerate high-dose conditioning regimens. Several trials have shown the feasibility of nonmyeloablative allogeneic stem-cell transplantation for patients up to the age of 75 years; with a 2-year overall survival rate of 40 to 60%.14,15 As consolidation therapy during the patient’s first remission, he received an HLA-matched allo geneic stem-cell transplant from a related donor, after nonmyeloablative conditioning with off-label low-dose busulfan and fludarabine and prophylaxis against GVHD with off-label cyclosporine and mycophenolate mofetil. He recovered well after the transplantation, was discharged, and did not require rehospitalization for more than 100 days after the transplantation; there was no GVHD during this time. Mycophenolate mofetil was discontinued before discharge, and low-dose cyclo sporine was continued. Dr. Hasserjian: A bone marrow sample obtained after induction and before transplantation revealed normal hematopoiesis; neither morphologic assessment nor flow cytometric analysis revealed evidence of residual acute leukemia, and FISH revealed no evidence of trisomy 8, factors consistent with a remission. However, a bone marrow aspirate obtained on a routine visit 100 days after the bone marrow transplantation showed 60% blasts, representing relapsed AML. A chimerism FISH study on the patient’s bone marrow (Fig. 2A), with specific probes to the X and Y chromosomes (this was possible because the patient had a female donor), revealed 48% donor cells with two X signals and 52% recipient cells with one X signal and one Y signal. Treatment of relapsed AML Dr. Thomas R. Spitzer: Unfortunately, even after stemcell transplantation, relapse of AML remains a major obstacle, especially after reduced-intensity stem-cell transplantation. This is the chief cause of treatment failure, particularly among patients with AML who are at high risk for relapse, as in this case. Treatment options for such patients have been largely unsatisfactory. Palliative chemotherapy, supportive care, and enrollment in a clinical trial evaluating new agents are appropriate for selected patients unable or unwilling to under go more aggressive therapy. Transplantation of stem cells from the same or an alternative donor has occasionally been attempted16,17 and has been successful mostly in younger, otherwise healthy patients who were in remission for at least 6 months after the initial transplantation. Recently, infusions of lymphocytes from the transplant donor have been used for the treatment of hematologic malignant conditions in patients with relapse after allogeneic stem-cell transplantation, usually preceded by some type of chemotherapy to reduce the number of leukemic cells (cytoreduction).18-20 When the disease relapsed in this patient, the leukemic cells were of host origin, whereas normal hematopoietic cells were of donor origin, as shown by FISH analysis of the X and Y chromosomes. The goal is to induce remission and a return to normal donor hematopoiesis by means of cytoreductive chemotherapy and to maintain that remission by means of adoptive cellular immunotherapy (i.e., infusions of donor lymphocytes intended to induce a stronger graft-versus-leukemia effect). The best evidence of a graft-versus-leukemia effect has been observed in patients with chronic myeloid leukemia, who had a 70 to 80% probability of achieving a complete and durable molecular genetic remission.18,19 However, GVHD and bone marrow aplasia have each occurred in up to half of those patients. Unfortunately, infusions of donor lymphocytes have been less successful for the treatment of AML that relapsed after stem-cell transplantation, with approximately 20% of patients achieving remissions lasting 2 years.20 On the basis of retrospective rather than prospective observations of cases of AML, the best results n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 1103 The n e w e ng l a n d j o u r na l A B C D of m e dic i n e Figure 2. Pathologic Changes after Initial Therapy for AML. A fluorescence in situ hybridization (FISH) study on bone marrow at the time of first relapse, with specific probes to the X and Y chromosomes (Panel A), reveals 48% donor cells with two red X signals (arrow) and 52% recipient cells RETAKE 1st AUTHOR Dey with one red X signal and one greenICM Y signal (arrowhead). A skin-biopsy specimen obtained 1 month later shows in2a-d At the dermal–epidermal2nd FIGURE terface dermatitis with dyskeratotic REG cellsF (Panel B, arrow). junction (Panel C), lymphocytes 3rd CASE TITLEkeratinocytes (arrowheads), effecting (arrows), presumably of donor origin, surround Revised the epithelial damage characterEMail Line 4-C istic of cutaneous GVHD. FISH analysis of bone marrow chimerism during theSIZE second remission (Panel D) reveals Enon ARTIST: mst H/T H/T red X and one green Y signal, arrow). (Pan96.5% donor cells (two red X signals) and only 3.5% recipient cells (one FILL 33p9 Combo els A and D courtesy of Paola dal Cin, Ph.D., Laboratory of Cytogenetics, Brigham and Women’s Hospital and MasAUTHOR, PLEASE NOTE: sachusetts General Hospital.) Figure has been redrawn and type has been reset. Please check carefully. JOB: 36111 have occurred in young patients, those in posttransplantation remission for more than 5 months, those with a favorable karyotype, and those in whom cytoreductive chemotherapy resulted in remission before the infusion of donor lymphocytes.20 This patient’s risk factors thus do not predict a durable response to an infusion of donor lymphocytes. Another strategy that is being explored in patients with AML that is in relapse after stem-cell transplantation is the off-label or investigational use of hypomethylating agents such as azacitidine and decitabine, which are approved by the FDA for use in myelodysplastic syndromes.21,22 These agents are thought to act by decreasing or 1104 ISSUE: 9-10-09 reversing hypermethylation of genes, including tumor-suppressor genes; therefore, they inhibit the growth of tumor cells (cytoreduction) and potentially cause other epigenetic modifications that may expose new antigens on tumor cells that could be targets for a graft-versus-leukemia effect. Our patient received decitabine to reduce the number of tumor cells, with planned infusions of donor lymphocytes. He achieved a second complete remission of the AML, but cutaneous and gastrointestinal GVHD developed, requiring immunosuppressive therapy with increased doses of cyclosporine, oral prednisone, and oral beclo methasone and precluding the use of a donorlymphocyte infusion. n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital Dr. Hasserjian: A skin biopsy performed 130 days after the stem-cell transplantation (Fig. 2B and 2C) showed prominent interface dermatitis with numerous dyskaryotic cells, vacuolation of the dermal–epidermal junction, and focal lymphocytic infiltration surrounding basal keratinocytes, all of which are features of GVHD. Five months later, 9 months after transplantation, a bone marrow sample revealed bone marrow in remission, with maturing trilineage hematopoiesis. A FISH study of bone marrow chimerism (Fig. 2D) revealed 96.5% donor cells (two X signals) and only 3.5% recipient cells (one X signal and one Y signal). However, 5 months later (14 months after transplantation), leukocytosis again developed, with 66% circulating blasts, indicating a second relapse of the AML. Dr. Spitzer: The patient is undergoing additional chemotherapy with decitabine. His immunosuppression is being tapered to potentiate a graftversus-leukemia effect. The ultimate goal of this strategy is to take advantage of his persistent donor immunity and to induce a strong and more durable graft-versus-leukemia response. The challenge in this case and most others is to separate the beneficial graft-versus-leukemia effect of the transplantation from the deleterious manifestations of GVHD. Dr. Nancy Lee Harris (Pathology): Dr. Attar, can you tell us how the patient is doing now? Dr. Eyal Attar (Hematology–Oncology): Because of his previous excellent response to decitabine, I elected to treat him with additional decitabine. He has received two cycles of decitabine chemotherapy and has had complete resolution of his peripheral-blood blasts. The GVHD in the skin has resolved, and symptoms related to his upper gastrointestinal tract are under control with oral beclomethasone. We hope that this combined strategy of cytoreduction and a graft-versusleukemia effect will result in complete remission. He continues to have an excellent performance status. Dr. Philip C. Amrein (Hematology–Oncology): Since relapse is a concern after nonmyeloablative transplantation, would you consider a con- solidation cycle of chemotherapy before transplantation? Dr. Dey: Although rates of early death associated with transplantation are reduced in patients undergoing nonmyeloablative allogeneic stem-cell transplantation as compared with myeloablative transplantation, the leukemic relapse rate is high er. Therefore, various strategies, including consolidation therapy before nonmyeloablative transplantation, additional cytoreductive therapy, and infusions of donor lymphocytes after the transplantation, are currently being explored in order to reduce the post-transplantation leukemic relapse. Dr. Spitzer: Also, clinical trials are under way to look at post-transplantation chemotherapy with hypomethylating agents. Dr. Harris: It sounds as though you have turned an acute leukemia into a chronic disease, in which you are balancing GVHD against graftversus-leukemia and giving the patient chemotherapy that is not terribly toxic, which is resulting in a reasonable quality of life despite persistent leukemia a year and a half after the diagnosis. Dr. Spitzer: Unfortunately, most patients with AML who have a relapse after transplantation have another relapse, even if we are able to get them back into remission, and very few are cured — that is, in remission for 2 years or more. The precise role of the strategy of nonmyeloablative stem-cell transplantation in elderly patients with AML, particularly in regard to survival, cost-effectiveness, and quality of life, remains to be defined in future clinical trials. A nat omic a l Di agnosis Acute myeloid leukemia, not otherwise specified (acute monocytic leukemia), with FLT3-ITD. This Clinicopathological Conference was presented at the Massachusetts General Hospital Cancer Center Grand Rounds, March 26, 2009. Dr. Dey reports receiving lecture fees from Celgene (which makes azacitidine); Dr. Spitzer, consulting fees from Genzyme (which makes clofarabine and fludarabine), Hospira, and Viropharma; and Dr. Hasserjian, consulting fees from Genzyme. No other potential conflict of interest relevant to this article was reported. We thank Drs. Alfred Lee and Eyal Attar for assistance in preparing the case history and for review of the manuscript. References 1. Vardiman JW, Brunning RD, Arber DA, et al. Introduction and overview of the classification of the myeloid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press, 2008:18-30. 2. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005;352:254-66. 3. Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007;109:431-48. 4. Scholl S, Theuer C, Scheble V, et al. Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplica- n engl j med 361;11 nejm.org september 10, 2009 The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on February 16, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 1105 case records of the massachusetts gener al hospital tions in patients older than 60 yr with acute myeloid leukaemia. Eur J Haematol 2008;80:208-15. 5. Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 2002;162:1597-603. 6. Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1302-11. 7. Löwenberg B, Suciu S, Archimbaud E, et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy — the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute mye loid leukemia in the elderly: final report. J Clin Oncol 1998;16:872-81. 8. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood 2006;107:3481-5. 9. Erba HP, Kantarjian H, Claxton DF, et al. Phase II study of single agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy. Blood 2008;112: 209. abstract. 10. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000;96:4075-83. 11. Wallen H, Gooley TA, Deeg HJ, et al. Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 2005;23:3439-46. 12. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75:555-62. 13. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versushost disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300:1068-73. 14. Hegenbart U, Niederwieser D, Sandmaier BM, et al. Treatment for acute mye logenous leukemia by low-dose, total-body, irradiation-based conditioning and hema topoietic cell transplantation from related and unrelated donors. J Clin Oncol 2006; 24:444-53. 15. Kröger N, Shimoni A, Zabelina T, et al. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS). Bone Marrow Transplant 2006;37:339-44. 16. Blau IW, Basara N, Bischoff M, et al. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant. Bone Marrow Transplant 2000;25:41-5. 17. Eapen M, Giralt SA, Horowitz MM, et al. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 2004;34:721-7. 18. Loren AW, Porter DL. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant 2008;41:483-93. 19. Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH. Induction of graftversus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 1994;330:100-6. 20. Schmid C, Labopin M, Nagler A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007;25:4938-45. 21. Plimack ER, Kantarjian HM, Issa JP. Decitabine and its role in the treatment of hematopoietic malignancies. Leuk Lymphoma 2007;48:1472-81. 22. Kröger N. Epigenetic modulation and other options to improve outcome of stem cell transplantation in MDS. Hematology Am Soc Hematol Educ Program 2008: 60-7. Copyright © 2009 Massachusetts Medical Society. 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