Low-Dose Decitabine for Patients With

Letters

RESEARCH LETTER the decitabine group vs 27.3% in the control group (P = .001). In the treatment group, platelet counts increased signifi- Low-Dose Decitabine for Patients With cantly 4 weeks after decitabine injections (Figure), with a Thrombocytopenia Following Allogeneic median time of 22 days to achieve platelet transfusion- Hematopoietic Stem Cell Transplantation: independence, and maintained until the sixth month, except A Pilot Therapeutic Study for the patient with minor response. Isolated thrombocytopenia after hematopoietic stem cell trans- In bone marrow morphological analysis, patients in both plantation (HSCT) is defined as consistently low platelet counts groups revealed low levels of megakaryocytes at week 0. How- after transplantation, with recovery of all other peripheral blood ever, the significantly increasing megakaryocyte level, espe- cell lines.1 It represents a challenging clinical problem be- cially the “platelet shedding” megakaryocyte, was observed cause it often leads to an increased risk of life-threatening hem- only in decitabine group at week 4 (Figure). Transplantation- orrhage, frequent requirement of platelet transfusions, and ex- related complications (eg, chronic GVHD), antiplatelet anti- tended hospital stays.2 Previous studies have demonstrated bodies, and T-cell subsets did not noticeably change after that decitabine, a hypomethylating agent, can increase plate- decitabine treatment. No clinically significant myelosuppres- let counts by enhancing platelet release and megakaryocyte sion, febrile neutropenia, or nonhematologic toxic effects were maturation in mice.3 Herein, we report a pilot study showing observed during the study period. efficacy of decitabine in patients with isolated thrombocytopenia post-HSCT. Discussion | Our study shows a very encouraging result of decitabine in increasing peripheral platelets in HSCT recipi- Methods | An open-label study was designed to evaluate ents, with remarkably increased megakaryocyte counts. There decitabine treatment for isolated thrombocytopenia in allo- was no evident change in antiplatelet antibodies and T-cell sub- geneic HSCT patients with hematological malignant neo- types after decitabine administration, implying that decitabine plasms. The inclusion criteria were (1) primary or secondary functions independent of immune regulation. In mice, platelet count of 30 × 103/μL or less persistently at day 60 decitabine was found to induce megakaryocyte differentia- post-HSCT or later; (2) recovered neutrophil and hemoglo- tion and promote platelets release.3 This mechanism may have bin; (3) full donor chimerism; and (4) no response to conven- contributed to our results. tional therapies (eg, thrombopoietin, immunoglobulin, Myelosuppression is the main concern of decitabine. rituximab, plasma exchange alone or in combination) for a Low-dose decitabine could optimize clinical responses duration of at least 4 weeks. Patients with relapse of their with less toxic effects.5 Based on previous studies, we malignant disease, active infections, uncontrolled graft-vs- used 15 mg/m2 for 3 days, which was well tolerated by the host disease (GVHD), severe organ damage, or transplant- participants. related thrombosis were excluded. Enrolled patients were Although the sample size of this study is small, with a distributed into either the control group to receive the con- relatively short follow-up, the clinically significant platelet ventional therapies or the treatment group to receive addi- recovery following decitabine treatment suggest potentially tional decitabine (15 mg/m2 daily intravenously for 3 con- important clinical benefits and warrant the necessity for a secutive days) in random. All participants provided written large-scale clinical trial of this promising therapy. informed consent in accordance with the Declaration of Hel- sinki, and the study protocol was approved by the ethics Yue Han, MD, PhD committee of The First Affiliated Hospital of Soochow Uni- Yaqiong Tang, MD versity, Suzhou, China. Jia Chen, MD Peripheral blood cell counts, virology, antiplatelet anti- Jianying Liang, MD bodies, and T-cell subsets were analyzed routinely. Bone mar- Chunmei Ye, MD row puncture was performed before treatment (week 0) and Changgeng Ruan, MD, PhD then repeated at week 4. Platelet responses were evaluated ac- Depei Wu, MD, PhD cording to an international working group guideline within a 4 8-week study period. Author Affiliations: Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital Results | From July 2013 through February 2014 at our hospi- of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China. tal, 251 patients received allogeneic HSCT, and 72 of them de- veloped isolated thrombocytopenia afterward. During this pe- Corresponding Author: Depei Wu, MD, PhD, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First riod, 22 patients (Table) were enrolled in this study based on Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu the criteria described herein. The response rate was 100% in Province, China 215006 ([email protected]).

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Table. Clinical and Laboratory Characteristics of Patients in 2 Groups

Platelet Count, MK Count, MK Morphology Patient No./ ×103/μL per Smear (GMK/PMK/NMK) Sex/ Transplant Age, y Disease Typea Post-HSCT, d Previous Therapy Wk 0 Wk 4 Wk 8 Wk 0 Wk 4 Wk 0 Wk 4 Response Control Group 1/F/34 NHL MMRD 97 Thrombopoietin, 300 U/kg/d; 13 18 7 1 0 1/0/0 0/0/0 No prednisone, 1 mg/kg/d 2/M/28 AML MRD 63 Thrombopoietin, 300 U/kg/d; 13 7 9 6 7 3/1/2 3/1/2 No prednisone, 1 mg/kg/d 3/F/36 ALL MMRD 95 Thrombopoietin, 300 U/kg/d; 5 21 28 4 19 2/0/1 9/2/5 Minor prednisone, 1 mg/kg/d 4/F/16 ALL MMRD 160 Thrombopoietin, 300 U/kg/d; 12 8 Death 8 5 4/1/2 2/0/2 No prednisone, 1 mg/kg/d; immunoglobulin, 400 mg/kg/d ×5 d 5/M/31 ALL MMRD 62 Thrombopoietin, 300 U/kg/d; 10 19 55 6 22 3/0/1 12/1/9 Major prednisone, 1 mg/kg/d 6/M/18 ALL MUD 186 Thrombopoietin, 300 U/kg/d; P 13 10 7 0 1 0/0/0 1/0/0 No 7/M/23 CMML MMRD 112 Thrombopoietin, 300 U/kg/d; 15 43 22 2 54 2/0/0 30/13/10 Major prednisone, 1 mg/kg/d 8/M/28 AML MMRD 120 Thrombopoietin, 300 U/kg/d; 22 10 18 16 17 8/1/4 10/0/5 No prednisone, 1 mg/kg/d; immunoglobulin, 400 mg/kg/d ×5 d 9/F/51 AML MRD 131 Thrombopoietin, 300 U/kg/d; P; 4 11 14 33 7 27/1/4 4/0/1 No prednisone, 1 mg/kg/d 10/M/25 ALL MMRD 129 Thrombopoietin, 300 U/kg/d; 13 8 21 29 13 15/2/10 8/0/4 No prednisone, 1 mg/kg/d 11/F/51 NHL MRD 65 Thrombopoietin, 300 U/kg/d; 14 9 17 18 4 10/2/4 2/0/0 No prednisone, 1 mg/kg/d Decitabine Group 1/F/36 AML MRD 76 Thrombopoietin, 300 U/kg/d; 12 60 72 20 52 9/1/10 34/3/15 Major immunoglobulin, 400 mg/kg/d ×5 d; prednisone, 1 mg/kg/d 2/F/46 ALL MMRD 65 Thrombopoietin, 300 U/kg/d ; 16 35 55 15 51 11/1/1 44/1/6 Major prednisone, 1 mg/kg/d 3/F/22 MDS MMRD 62 Thrombopoietin, 300 U/kg/d; 17 70 78 8 133 6/0/1 92/28/13 Major prednisone, 1 mg/kg/d 4/F/37 AML MRD 211 Thrombopoietin, 300 U/kg/d; 13 65 72 10 127 7/0/2 88/23/14 Major prednisone, 1 mg/kg/d 5/M/8 ALL MMRD 97 Thrombopoietin, 300 U/kg/d; 18 37 35 5 30 4/0/1 22/3/4 Major prednisone, 1 mg/kg/d 6/F/57 AML MUD 138 Thrombopoietin, 300 U/kg/d; 30 90 82 15 24 12/1/2 18/1/5 Major prednisone, 1 mg/kg/d 7/M/32 MDS MMRD 84 Thrombopoietin, 300 U/kg/d; 18 45 67 12 129 7/0/4 106/5/5 Major prednisone, 1 mg/kg/d 8/M/43 MDS MMRD 99 Thrombopoietin, 300 U/kg/d; 12 97 140 17 105 10/0/7 80/10/8 Major rituximab, 375 mg/m2;P; immunoglobulin, 400 mg/kg/d ×5 d 9/M/34 AML MMRD 63 Thrombopoietin, 300 U/kg/d; 10 124 163 0 128 0/0/0 105/5/10 Major prednisone, 1 mg/kg/d 10/F/52 NHL MRD 196 Thrombopoietin, 300 U/kg/d; 8 28 26 2 0 1/0/0 0/0/0 Minor prednisone, 1 mg/kg/d 11/M/37 AML MRD 472 Thrombopoietin, 300 U/kg/d; P; 11 115 203 5 17 3/0/1 9/1/5 Major prednisone, 1 mg/kg/d

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; a Transplant type of MMRD and MUD, conditioning regimen (with T-cell CMML, chronic myelomonocytic leukemia; ); GMK, granular megakaryocyte; depletion): antithymocyte globulin (ATG) + busulfan-cyclophosphamide GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; (BUCY); GVHD prophylaxis: cyclosporinA, methotrexate, and mycophenolate MDS, myelodyplastic syndrome; MK, megakaryocyte; MMRD, mismatched mofetil. Transplant type of MRD, conditioning regimen (without T-cell related donor; MRD, matched related donor; MUD, matched unrelated donor; depletion): BUCY. GVHD prophylaxis: cyclosporinA and methotrexate. NHL, non-Hodgkin lymphoma; NMK, naked nuclear megakaryocyte; P, plasma exchange; PMK, platelet-shedding megakaryocyte.

Published Online: February 26, 2015. doi:10.1001/jamaoncol.2014.316. Drafting of the manuscript: Han, Tang, Chen. Author Contributions: Dr Wu had full access to all of the data in the study and Critical revision of the manuscript for important intellectual content: All authors. takes responsibility for the integrity of the data and the accuracy of the data Statistical analysis: Han, Tang, Chen. analysis. Administrative, technical, or material support: Liang, Ye. Study concept and design: Han, Wu. Study supervision: Ruan, Wu. Acquisition, analysis, or interpretation of data: Han, Tang. Conflict of Interest Disclosures: None reported.

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Figure. Increase of Platelets and Megakaryocytes With Decitabine Treatment

A 150 P =.004 180 P =.009 P =.005 Control 160 Control 120 Decitabine Decitabine 140 P =.003 /μL 3 120 90

100 P =.93

80 60 P =.27 Decitabine 60 Decitabine administration administration 30 Megakaryocytes, per Smear Platelet Counts, ×10 40 P =.10 20 0 0 −2 0 +2 +4 +6 +8 0 +4 0 +4 Weeks Weeks

A, Number of peripheral platelets (left) and megakaryocytes (right) on a bone marrow smears of a patient at week 0 (left) and week 4 (right) after receiving marrow smear. Week 0 denotes when patients received decitabine treatment; decitabine. Arrows indicate megakaryocytes. Inset represents a − or + represent weeks before and after decitabine treatment. The bars platelet-shedding megakaryocyte (Wright-Giesma stain, original magnification indicate the median count of platelets or megakaryocytes. B, Representative ×1000). microscopic images (Wright-Giesma stain, original magnification ×100) of bone

Funding/Support: This work was supported by grants from the Jiangsu 3. Wang J, Yi Z, Wang S, Li Z. The effect of decitabine on megakaryocyte Province of China (BK20131167, RC2011105, and ZX201102), National Nature maturation and platelet release. Thromb Haemost. 2011;106(2):337-343. Science Foundation of China (81270591), National Key Basic Research Program 4. Cheson BD, Bennett JM, Kantarjian H, et al; World Health Organization of China (2012CB526600), Jiangsu Provincial Special Program of Medical (WHO) International Working Group. Report of an international working group Science (BL2012005) and the Priority Academic Program Development of to standardize response criteria for myelodysplastic syndromes. Blood. 2000; Jiangsu Higher Education Institutions (PAPD). 96(12):3671-3674. Role of the Funder/Sponsor: Jiangsu Province of China, National Nature 5. Garcia-Manero G, Jabbour E, Borthakur G, et al. Randomized open-label Science Foundation of China, National Key Basic Research Program of China, phase II study of decitabine in patients with low- or intermediate-risk Jiangsu Provincial Special Program of Medical Science and the Priority Academic myelodysplastic syndromes. J Clin Oncol. 2013;31(20):2548-2553. Program Development of Jiangsu Higher Education Institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Information: Drs Han and Tang contributed equally to this study Suggestibility of Oncologists’ Clinical Estimates and are co–first authors. Quantitative estimates, including prognosis and likelihood of Additional Contributions: We thank Dr Lijun Xia at Oklahoma Medical clinical outcomes, are an integral part of oncologic counsel- Research Foundation, for his critical reading and comments. He was not ing and treatment. In general, estimates should be grounded compensated for his assistance. in the best available data, adjusted as necessary for indi- 1. First LR, Smith BR, Lipton J, Nathan DG, Parkman R, Rappeport JM. Isolated vidual patients’ circumstances. However, it is well estab- thrombocytopenia after allogeneic bone marrow transplantation: existence of lished that judgments are often biased by unrelated or unin- transient and chronic thrombocytopenic syndromes. Blood. 1985;65(2):368-374. formed numerical anchors (eg, guesses).1,2 There is good reason 2. Bernstein SH, Nademanee AP, Vose JM, et al. A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and to suspect that physicians’ clinical assessments may be influ- hematopoietic stem cell transplantation. Blood. 1998;91(9):3509-3517. enced by cognitive shortcuts, or heuristics. We therefore sought

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Figure. Responses for the 2 Scenarios

A Scenario 1, estimated life expectancy B Scenario 2, estimated likelihood of pulmonary embolism

40 100

80 30

60 20 40 Boxplots depict interquartile range 10 (IQR) with whiskers indicating values Life Expectancy, mo Life Expectancy, 20 Estimated Likelihood of Likelihood Estimated Pulmonary % Embolism, within 1.5 times the IQR. Individual P = .02 P = .02 points represent outliers. Lines within 0 0 2-Month anchor 30-Month anchor 1% Anchor 95% Anchor boxes denote median values; (N = 22) (N = 36) (N = 34) (N = 21) medians were equal to the 75th percentile in panel A.

to determine whether oncologists’ clinical estimates might be 48%; P = .21). Information on nonresponders was not avail- biased by extraneous information. able. However, respondents were evenly distributed over time since completing training; this variable did not consistently Methods | Members of the New England and Mid-Atlantic As- affect estimates. sociations of Gynecologic Oncologists received emails con- taininganelectroniclinkto1of2surveyforms.Eachsurvey Discussion | Oncologists’ clinical judgments, including esti- included 2 clinical scenarios. Respondents were not compen- mates of life expectancy, seem to be susceptible to influence sated for their participation. by extraneous information consistent with anchoring bias,a Scenario 1 described a 77-year-old woman with platinum- heuristic very well characterized in cognitive psychology.3 resistant serous ovarian carcinoma who expressed a desire to Quantitative estimates are likely to be disproportionately in- live either an additional 2 months or 30 months (randomized). fluenced by initially presented values, irrespective of rel- Respondents indicated whether they believed that the patient evance or reliability. This study was limited by low response would live as long as desired and provided their estimate of the rate and small sample size. Nevertheless, the results suggest patient’s life expectancy. Scenario 2 described a patient who had that extensive training and availability of data may not pro- recently had cytoreductive surgery for serous ovarian carci- tect clinicians from nonrational clinical decision-making. noma with symptoms clinically ambiguous for pulmonary em- Rather, whenever there is clinical uncertainty, there is poten- bolism. Respondents were told that a medical student be- tial for cognitive bias.4 lieved that the patient had either a 1% or 95% likelihood of Furthermore, awareness alone is not sufficient to avoid pulmonary embolism (randomized). Respondents indicated bias. Existing data suggest that the anchoring effect is robust whether they believed that the medical student’s estimate was and refractory to many possible corrective strategies. How- too high or too low, provided their own estimate of the likeli- ever, one approach that has shown some promise is to “con- hood of pulmonary embolism, and indicated whether they sider the opposite.”5 Oncologists should attempt to identify would order diagnostic imaging or initiate therapeutic antico- possible anchors during counseling and clinical care, and cor- agulation (vs expectant management alone) for the patient de- rect underestimates or overestimates by invoking available evi- scribed. Means were calculated for each group and tested for dence. It may not be possible to completely debias clinical en- significant difference using t tests for prognostic estimates and counters, but physicians should consider critical monitoring 2-proportion z tests for ordering decisions. The partners insti- of their decision-making processes to be an essential part of tutional review board exempted this study from final review. high-quality cancer care.6

Results | Responses were obtained from 58 staff gynecologic on- David I. Shalowitz, MD cologists, for a response rate of 34%. In scenario 1 (Figure,A), John O. Schorge, MD the mean (SD) estimated life expectancy of the patient who desired to live at least 2 additional months was 11.5 (4.9) months Author Affiliations: Division of Gynecologic Oncology, Department of (median, 12.0 months) vs 15.4 (7.8) months (median, 18.0 Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia (Shalowitz); Division of Gynecologic Oncology, Vincent Obstetrics months) for the patients who desired to live at least 30 addi- and Gynecology, Massachusetts General Hospital, Harvard Medical School, tional months (P =.02). Boston (Schorge). In scenario 2 (Figure, B), when the medical student be- Corresponding Author: David I. Shalowitz, MD, Perelman Center for Advanced lieved there was a 1% chance of pulmonary embolism (PE), the Medicine, 3400 Civic Center Blvd, Third Floor W, Philadelphia, PA 19104 (david [email protected]). oncologists’ mean estimate was 18% (21%) (median, 10%). This increased to 33% (25%) (median, 25%) when the medical stu- Published Online: March 12, 2015. doi:10.1001/jamaoncol.2015.62. dent believed there was a 95% chance of PE (P = .02). There Author Contributions: Dr Shalowitz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data was no significant difference in ordering diagnostic imaging analysis. or therapeutic anticoagulation between the 2 groups (65% vs Study concept and design: Shalowitz.

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