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. Author manuscript; available in PMC: 2009 Sep 15.
Published in final edited form as: Cancer. 2008 Sep 15;113(6):1370–1378. doi: 10.1002/cncr.23691

Myeloid Sarcoma Is Associated with Superior Event-Free Survival and Overall Survival Compared with Acute Myeloid Leukemia

Apostolia-Maria Tsimberidou 1, Hagop M Kantarjian 1, Sijin Wen 1, Michael J Keating 1, O’Brien Susan 1, Mark Brandt 1, Sherry Pierce 1, Emil J Freireich 1, L Jeffrey Medeiros 1, Elihu Estey 1
PMCID: PMC2574728  NIHMSID: NIHMS59028  PMID: 18623376

Abstract

Background

It is unknown whether patients with nonleukemic myeloid sarcoma (MS) and those with acute myeloid leukemia (AML) have similar responses to anti-AML treatment. We addressed this question by matching MS patients with analogous AML patients and comparing their clinical outcomes.

Methods

We identified 23 consecutive MS and 1720 consecutive AML patients who presented at The University of Texas M. D. Anderson Cancer Center from 1990 to 2004. All AML patients and 16 MS patients received cytarabine plus idarubicin or fludarabine as induction remission therapy. We matched treated MS and AML patients according to cytogenetics, age, Zubrod performance status, and time of treatment. Event-free survival (EFS) and overall survival (OS) were compared using Kaplan-Meier analyses.

Results

Complete response rates were 69% in MS and 57% in AML (p=0.45). The respective 2-year EFS and OS rates were 32% and 18% (p=0.08) and 43% and 29% (p=0.11). Matches could be found for 14 MS patients, who were paired repeatedly with 91 AML patients to produce 94 matches (3 AML patients were matched twice). EFS was longer in 56 MS pair-mates, shorter in 26, and similar in 12 (p=0.01, Fisher exact test). OS analyses gave similar results.

Conclusions

Anti-AML therapy is highly effective in patients with non-leukemic MS. This study emphasizes the need to treat patients with non-leukemic MS with AML-type therapy.

Keywords: sarcoma, myeloid, chloroma, AML, therapy

INTRODUCTION

The term myeloid sarcoma (MS) is used to define an extramedullary mass composed of cells of myeloid lineage. Other terms used as synonyms for this process are chloroma, granulocytic sarcoma, myeloblastoma, and extramedullary myeloid cell tumor.1-4 The 2001 World Health Organization classification currently recommends the term MS for this disease.5 Patients with MS most often have evidence of concurrent acute myeloid leukemia (AML) involving blood and bone marrow or only bone marrow. Patients also may have a history of AML and relapse after therapy. Less commonly, myelodysplastic syndrome or chronic myeloproliferative disease can transform to MS. Very rarely, patients present with MS as an isolated mass, with no evidence of AML after extensive workup.6 MS can be characterized by granulocytic, monoblastic, or myelomonocytic differentiation and is often associated with distinctive cytogenetic and molecular abnormalities.7

One option for patients who present in such a fashion is anti-AML therapy, as if the patient had typical AML.8 However, there is little information comparing the effects of anti-AML treatment for MS patients without AML in the bone marrow with those for patients with typical AML. Here we address this question by matching MS patients with comparable AML patients according to age, performance status, year of treatment, and to the extent possible, cytogenetics.

PATIENTS AND METHODS

We searched The University of Texas M. D. Anderson Cancer Center leukemia database from 1990 to 2004 for patients who met the following three criteria: pathologically confirmed extramedullary MS, fewer than 5% bone marrow blasts, and no history of AML. Twenty-three patients with MS were identified. In 22 of 23 cases, markers were assessed to prove myeloid lineage.6 In one case, cytochemical studies were performed on touch imprints. In a second case, histochemical study for chloroacetate esterase was performed using histologic sections. In the remaining 20 cases, immunohistochemical analysis was performed using fixed, paraffin-embedded tissue sections and, in some of the earlier cases, frozen tissue sections. In the group assessed immunohistochemically, histochemical analysis for chloroacetate esterase was also performed in 7 cases, and flow cytometry immunophenotyping was performed in 3 cases. Sixteen of the 23 patients with MS received cytarabine plus idarubicin or fludarabine at M. D. Anderson Cancer Center, as previously described.9 Two patients had surgical resection only, while 5 were treated outside of M. D. Anderson. The 1720 patients with AML in the bone marrow (> 20% blasts and excluding patients with acute promyelocytic leukemia) presented during the same time period and received similar induction therapy; however, MS patients were less likely to receive post-complete response (CR) therapy (Table 1). All patients gave informed consent for treatment, which was carried out in accordance with the Declaration of Helsinki; the M. D. Anderson IRB approved the analyses described below.

Table 1.

Patient Characteristics

Myeloid sarcoma
N=23 (%)
Acute myeloid leukemia
N=1720 (%)
Age
 Median 57 60
 Range 7-81 14-89
Zubrod PS
 0 8 (35) 158 (9)
 1 13 (57) 1006 (58)
 2 1 (4) 383 (22)
 3 1 (4) 112 (7)
 4 0 (0) 61 (4)
Cytogenetics
 Inv 16 or t(8;21) 2 (9) 138 (8)
 Normal 11 (48) 640 (37)
 +8 5 (22)* 127 (7)
 -5, -7 1 (4) 372 (22)
 Abnormal 11 q or other ** 3 (11) 358 (21)
 Insufficient 0 76 (4)
 Not done 0 9 (0.005)
AHD 3 (13) 688 (40)
WBC count
 Median 6.7 10.1
 Range 1.3 - 70.6 0.2 - 394
Hemoglobin
 Median 13.5 8.0
 Range 4.8 - 16.1 2.1 - 15.0
Platelets
 Median 246 48
 Range 110 - 534 2 - 2292
Post-remission therapy
 Idarubicin+AraC, % 40 44
 Low-dose AraC, % 8 0
 None, % 24 0
 Other, % 8 10
 Fludarabine+AraC, % 8 0
 Topotecan+AraC +/- Cyclophosphamide, % 8 14
 Stem cell transplantation, % 0 1
Therapy at 1st relapse
 High-dose AraC, % 25 7
 Fludarabine+AraC+Topotecan, % 25 0
 Fludarabine+AraC+Idarubicin, % 0 20
 Idarubicin+AraC, % 25 17
 Topotecan+AraC+/- Cyclophosphamide, % 0 12
 Decitabine + 5-azacytidine, % 0 3
 Stem cell transplantation, % 0 9
 Other, % 25 27
 Unknown, % 0 5

AHD = Antecedent hematologic disorder; PS = performance status; WBC = white blood cells

*

One additional patient had 8q deletion.

**

These chromosomal abnormalities were del12 (1 patient) and dup1 (1 patient).

Statistical methods

The Fisher exact test was used in univariate analyses. Survival curves were estimated using the Kaplan-Meier method, and survival between groups was compared using the two-sided log-rank test. The multivariate Cox proportional hazards regression model was used to examine risk factors related to survival or EFS after adjusting for other factors, including diagnosis (MS vs. AML).

We were principally interested in event-free survival (EFS) (with an “event” defined as relapse, death, or failure to achieve CR) and overall survival (OS). For patients with AML, the criteria for a CR were as defined previously, whereas the criterion for a CR for patients with MS was complete radiologic disappearance of disease. Differences in EFS and OS between patients with MS and AML were quantified with the log-rank test. To reduce the possibility that any differences merely reflected a better inherent prognosis in the MS (or the AML) group, we attempted to find as many prognostically comparable matches (“pair-mates”) as possible for each MS patient from among the 1720 patients with AML. Criteria for matching were as follows: cytogenetics, as described below; age (within ± 3 years); Zubrod performance status (0-2 vs. >2); and time of treatment (1990-1997 vs. 1998-2004). Matches fell into three categories: (a) an event had occurred in the MS patient and the patient’s AML pair-mate, (b) an event had occurred in either the patient or the pair-mate, or (c) an event had occurred in neither the patient nor the pair-mate. If, in cases (a) and (b), EFS was longer in the patient with MS than in the AML pair-mate, the patient with MS was considered to be the “winner,” whereas if EFS was longer in the AML pair-mate, the MS patient was considered to be the “loser”. Cases in category (c) were considered “ties.” The numbers of wins and losses for patients with MS were summed. If EFS in patients with MS and AML was equivalent, the number of wins would be expected to equal the number of losses.

OS and EFS in matched MS and AML patients were compared using Kaplan-Meier methodology. Statistical analyses were carried out using S Plus 2000 (Insightful Corp., Seattle, WA). P values were derived from two-sided tests and were significant if <.05.

RESULTS

The median age of the 23 patients with MS was 57 years (range, 7-81 years); 1 patient (4%) had a Zubrod performance status greater than 2 (Table 1). The biopsy specimens were obtained from the skin (n=10), lymph node (n=5), dura (n=2), breast + skin (n=1), bladder (n=1), widespread involvement of the gynecologic tract (n=1), pleura + chest wall (n=1), retroperitoneum (n=1), and small intestine (n=1). In each case, histological findings were consistent with the diagnosis of MS. The antibodies used for immunohistochemical analysis were highly variable, but in all cases the neoplastic cells were positive for one or more myeloid antigens and were negative for T- and B-cell antigens. Myeloperoxidase was positive in 13/14 cases, lysozyme in 7/8, CD13 in 5/5, CD33 in 4/4, CD34 in 6/8, CD68 in 5/7, and CD43 in 4/4. Six of 9 cases assessed for chloroacetate esterase were positive, including two cases that were not assessed by immunohistochemical analysis. The one neoplasm in this study not assessed by either immunohistochemistry of cytochemistry was histologically well-differentiated, with obvious eosinophilic differentiation.

Among the 9 MS patients older than 60, 1 had cytogenetics assessed in the tumor sample (this patient had a 12p deletion), and 4 had a +8 abnormality in the bone marrow despite no excess blasts. The remaining 4 older MS patients had normal bone marrow cytogenetics but, of course, no excess blasts. Three of the 14 MS patients younger than 60 had cytogenetics assessed in the tumor sample: 1 had an 11q deletion in a complex karyotype, 1 had a deletion of 3 in a complex karyotype, and 1 had an 8q deletion. An additional 4 MS patients younger than 60 had cytogenetic abnormalities in the bone marrow, despite the absence of excess blasts: inv(16) in 2 patients, +8 in 1, and -7 in 1. The remaining 8 MS patients younger than 60 had normal cytogenetics in the bone marrow.

The median age of the 1720 patients with AML was 60 years (range, 14-89 years), and 173 patients (11%) had a Zubrod performance status of 3 or 4 (Table 1). The proportion of patients with a +8 abnormality was much lower in the AML group than in the MS group (127 of 1720 vs. 5 of 23; Fisher exact, p = 0.02).

Response, Event-Free Survival, and Overall Survival

We focused on the 16 MS patients treated at M. D. Anderson with cytarabine combined with idarubicin or fludarabine. Eleven of these 16 patients (69%) entered CR, as did 57% of the similarly treated AML patients (p=0.45). Median follow-up times for patients remaining alive in CR were 3.5 years for MS and 5.3 years for AML. EFS was longer in MS (p=0.08;Figure 1); OS differences were less marked (p = 0.11, Figure 2).

Figure 1.

Figure 1

Comparison of event-free survival in patients with myeloid sarcoma and acute myeloid leukemia by Kaplan-Meier methodology

Figure 2.

Figure 2

Overall survival in patients with myeloid sarcoma and acute myeloid leukemia by Kaplan-Meier methodology

Multivariate Cox analysis in Ara-C—treated patients

We then performed a multivariate analysis of EFS in ara-C—treated patients (MS, 16; AML, 1720). Independent factors predicting shorter EFS were poorer risk cytogenetics (p<0.0001), worse performance status (p<0.0001), history of antecedent hematologic disorder (AHD; history of a hemoglobin level less than 12 g/dL, a platelet count less than 150,000/μL, a neutrophil count less than 1,500/μL, or a WBC count greater than 20,000/μL for at least 1 month before M. D. Anderson presentation) (p<0.0001), and higher leukocyte counts (p=0.001). Diagnosis of MS. vs. AML was not a significant factor (p=0.85).

Similarly, independent factors predicting shorter OS were poorer risk cytogenetics (p<0.0001), worse performance status (p<0.0001), history of AHD (p<0.0001), and higher leukocyte counts (p=0.01), but diagnosis was not significant (p=0.75).

Matching of MS with AML patients

Although cytogenetics is a major prognostic factor in AML, the 12 MS patients for whom tumor cytogenetics were not assessed and who had normal bone marrow cytogenetics were cytogenetically not informative. We addressed this problem as follows. Given that 4 of the 5 MS patients at least 60 years old with known cytogenetic abnormalities had +8 abnormalities (see above), we matched similarly aged MS patients in whom cytogenetics were not assessed in MS and with normal marrow with AML patients who had +8 abnormalities. Analogously, the distribution of cytogenetic abnormalities in MS patients younger than 60 for whom cytogenetics were evaluated in MS or known to be abnormal in bone marrow (2 prognostically favorable [inv 16], 2 prognostically intermediate [+8, 8q-], and 3 prognostically unfavorable [11q, complex del 3q , -7]) led us to attempt to pair each MS patient younger than 60 with normal bone marrow cytogenetics and unknown MS cytogenetics with an equal number of AML patients with favorable, intermediate, and unfavorable cytogenetics, as generally considered.10

Details regarding matching of MS and AML patients are shown in Table 2. Matches were found for 14 of the 16 patients with MS. One MS patient had no AML match because he was 7 years old (all the AML patients in our database were older than 14). The second MS patient had a performance status of 4, for which there was no match among the AML patients.

Table 2.

Matching of Patients with Myeloid Sarcoma with Patients with Acute Myeloid Leukemia Treated with Cytarabine-Containing Therapies

Patient Cytogenetics Age Zubrod
PS
Year
of
Treatment
Event-free
Survival
(weeks)
Overall
Survival
(weeks)
MS1 +8 64 2 1990 8 18
M1 for MS1 +8 67 1 1991 2 2
M2 for MS1 +8 67 1 1991 5 5
M3 for MS1 +8 67 1 1992 19 34
M4 for MS1 +8 65 2 1994 9 9
M5 for MS1 +8 65 0 1994 45 68
M6 for MS1 +8 66 1 1995 44 60
M7 for MS1 +8 62 0 1995 10 10
M8 for MS1 +8 61 1 1997 39 43
M9 for MS1 +8 64 1 1997 12 12
M10 for MS1 * +8 67 2 1996 3 3
M11 for MS1 ** +8 67 1 1996 6 178
MS2 Normal 53 1 1991 16 22
M1 for MS2 11Q 52 1 1991 5 5
M2 for MS2 INV 16 50 0 1994 572 572+
MS3 +8 57 0 1991 26 42+
M1 for MS3 +8 58 1 1995 545 545+
M2 for MS3 +8 58 2 1995 63 127
M3 for MS3 +8 59 2 1996 159 263
M4 for MS3 +8 57 1 1998 47 65
MS4 +8 70 1 1992 9 9+
M1 for MS4 +8 70 1 1993 655 655+
M2 for MS4 +8 71 1 1995 0 0
M3 for MS4 +8 69 1 1993 183 258
M4 for MS4 +8 68 1 1993 31 40
M5 for MS4 +8 73 1 1995 29 51
M6 for MS4 +8 72 0 1996 68 85
M7 for MS4 +8 73 2 1997 2 2
M8 for MS4 +8 68 1 1998 10 25
M9 for MS4 +8 73 2 1998 6 223
M10 for MS4 +8 68 1 1999 128 168+
M11 for MS4 +8 72 2 1999 4 4
M12 for MS4 * +8 67 2 1996 3 3
M13 for MS4 ** +8 67 1 1996 6 178
MS5 Normal 45 0 1994 36 36+
M1 for MS5 11Q 46 1 1998 3 58
M2 for MS5 T(8,21) 45 1 1996 6 6
M3 for MS5 +8 46 1 1999 3 3
MS6 Normal 31 1 1994 350 350+
M1 for MS6 T(8,21) 30 1 1996 105 170
M2 for MS6 11Q 30 1 1997 15 15
M3 for MS6 +8 34 1 1998 5 50
MS7 DEL 12 69 0 1995 71 71
M1 for MS7 MISC 67 1 1999 148 323
M2 for MS7 MISC 72 1 1996 103 272
M3 for MS7 MISC 71 1 1996 3 3
M4 for MS7 MISC 69 1 1997 5 5
M5 for MS7 MISC 68 2 1997 3 3
M6 for MS7 MISC 72 0 1997 37 64
M7 for MS7 MISC 72 1 1998 6 51
M8 for MS7 MISC 68 2 1999 5 43
M9 for MS7 MISC 70 1 1999 23 23
M10 for MS7 MISC 70 2 1999 1 1
M11 for MS7 MISC 72 2 2000 168 168
M12 for MS7 MISC 67 2 2000 22 24
M13 for MS7 MISC 69 1 2000 3 35
M14 for MS7 MISC 66 1 2000 3 29
M15 for MS7 MISC 69 1 2000 4 4
M16 for MS7 MISC 71 1 2002 7 24
M17 for MS7 MISC 68 1 2001 12 24
M18 for MS7 MISC 67 0 2002 166 166+
M19 for MS7 MISC 66 1 2002 8 21
M20 for MS7 MISC 70 1 2002 9 25
M21 for MS7 MISC 68 1 2002 31 161+
MS8 INV 16 57 0 1995 357+ 357+
M1 for MS8 INV 16 55 1 2001 245+ 245+
M2 for MS8 T(8,21) 56 1 2001 182+ 182+
M3 for MS8 INV 16 59 1 2002 79 147+
MS9 Normal 48 1 1995 255+ 255+
M1 for MS9 11Q 49 1 1998 23 23
M2 for MS9 +8 50 1 1998 61 63
M3 for MS9 T(8,21) 51 1 2001 46 46
MS10 Normal 59 1 1997 4 4
M1 for MS10 INV 16 59 1 2003 125 125+
M2 for MS10 *** +8 59 0 2003 42 90
MS11 Normal 60 0 1998 154+ 155+
M1 for MS11 +8 62 1 2003 4 4
M2 for MS11 +8 57 2 2001 8 8
M3 for MS11 +8 57 1 2002 92 134+
M4 for MS11 *** +8 59 0 2003 42 90
MS12 Normal 25 1 1998 44+ 45+
M1 for MS12 11Q 25 1 1995 529+ 529+
M2 for MS12 INV 16 23 1 2002 59 117
MS13 INV 16 47 0 1998 128+ 128+
M1 for MS13 INV 16 44 2 2001 27 81
M2 for MS13 INV 16 44 1 2001 216+ 216+
M3 for MS13 INV 16 49 0 2001 201+ 201+
M4 for MS13 INV 16 44 1 2002 156+ 156+
M5 for MS13 T(8,21) 47 1 2002 37 85
M6 for MS13 T(8,21) 47 0 2004 38+ 38+
M7 for MS13 T(8,21) 48 2 2004 66 118+
M8 for MS13 T(8,21) 49 1 2001 334+ 334+
M9 for MS13 T(8,21) 50 1 2001 81 222+
M10 for MS13 T(8,21) 50 1 2002 18 71
M11 for MS13 T(8,21) 50 1 2003 121+ 121+
MS14 Normal 71 1 2000 12 17
M1 for MS14 +8 69 1 2003 12 77
M2 for MS14 +8 69 2 2000 3 5
M3 for MS14 +8 71 1 2001 4 44
M4 for MS14 +8 74 1 2001 3 4
M5 for MS14 +8 69 0 2003 6 12
M6 for MS14 +8 70 1 2001 33 64
M7 for MS14 +8 74 0 2002 4 18
M8 for MS14 +8 72 1 2002 20 20
M9 for MS14 +8 69 1 2003 12 37
M10 for MS14 +8 73 2 2003 2 2
M11 for MS14 +8 68 0 2003 6 86
M12 for MS14 +8 74 1 2004 4 11

Abbreviations: MS=myeloid sarcoma, M = match (with acute myeloid leukemia)

*

This AML patient matches two different MS patients.

**

This AML patient matches two different MS patients.

***

This AML patient matches two different MS patients.

Ninety-four matches, representing 91 patients with AML, were found, with 3 AML patients each found to be matches for 2 separate MS patients. For 3 MS patients younger than 60, only AML patients with favorable and intermediate cytogenetics could be found as matches; the absence of an unfavorable AML match would presumably tend to make the MS group appear less favorable. Among the 11 AML matches for the first MS patient (MS1), 7 had longer EFS and 4 had shorter EFS compared with MS1 (Table 2). Proceeding in this fashion, we found 56 matches favoring MS, 26 favoring AML, and 12 inconclusive matches (Table 3). If EFS duration in MS and AML was identical, one would expect MS cases to have an equal number of “wins” and “losses,” i.e., 47 wins and 47 losses. Using the Fisher exact test comparing 56 of 82 and 47 of 94, the p-value was 0.01.

Table 3.

Event-free Survival in Patients with Myeloid Sarcoma and Matched Patients with Acute Myeloid Leukemia

MS
Patient
Number
of
matches
Matches in
which EFS
was longer
in MS
patient
Matches in
which EFS
was longer
in AML
patient
Inconclusive
match (see
text)
Matches
in which
OS was
longer in
MS
patient
Matches
in which
OS was
longer in
AML
patient
Inconclusive
match (see
text)
1 11 4 7 0 6 5 0
2 2 1 1 0 1 1 0
3 4 0 4 0 0 0 4
4 13 7 6 0 4 0 9
5 3 3 0 0 2 0 1
6 3 3 0 0 3 0 0
7 21 17 4 0 16 5 0
8 3 1 0 2 0 0 3
9 3 3 0 0 3 0 0
10 2 0 2 0 0 2 0
11 4 4 0 0 3 0 1
12 2 0 0 2 0 0 2
13 11 5 0 6 3 0 8
14 12 8 2 2 5 7 0

Totals 94 56 26 12 46 20 28

When analysis was limited to MS patients with informative cytogenetics (patients MS1, MS3, MS4, MS7, MS8, and MS13), the observed 32 wins for MS vs. 26 wins for AML, with 5 ties, translated into a 71% probability of longer EFS in patients with MS.

When OS was similarly compared in matched patients, 46 matches favored MS, 20 favored AML, and 28 were inconclusive (Tables 2 and 3). Using the Fisher exact test comparing 46 of 66 and 47 of 94, the p-value was 0.01.

EFS and OS of 14 MS patients and 91 AML control patients by Kaplan-Meier methodology are compared in Figures 3 and 4.

Figure 3.

Figure 3

Event-free survival in 14 Ara-C-treated patients with myeloid sarcoma and 91 matched patients with acute myeloid leukemia (Kaplan-Meier).

Figure 4.

Figure 4

Overall survival in 14 Ara-C-treated patients with myeloid sarcoma and 91 matched patients with acute myeloid leukemia (Kaplan-Meier).

Outcomes in the 2 unmatched MS patients

At the time of this writing, the 7-year-old MS patient is alive in a first CR 11 months after beginning treatment, and the MS patient with Zubrod performance status 4 died 4 months into treatment without achieving a CR.

DISCUSSION

The current study demonstrates that anti-AML therapy is highly effective in patients with non-leukemic MS and is associated with higher rates of EFS and OS in MS than in AML after matching MS patients with comparable typical AML patients according to age, performance status, year of treatment, and to the extent possible, conventional cytogenetics.

This is the first study to suggest that EFS is longer in patients with MS than in patients with AML (Figure 1). However the data in Figure 1 do not address the issue of comparability between the MS and AML patients, i.e., how do we know that the results can be attributed primarily to a different diagnosis (MS vs. AML), rather than to differences in treatment, follow-up time, or prognostic covariates? Regarding treatment, patients with MS and patients with AML each received cytarabine-containing induction therapy, although the MS patients were less likely to receive post-remission therapy (Table 1). Follow-up was similar in the two groups, and median follow-up was > 3 years, which is relevant given previous suggestions that the risk of relapse declines 3 years after the CR date and such patients can be considered potentially cured.

The cytogenetically noninformative status (cytogenetics not done on MS samples and normal in bone marrow) of 8 of the 14 MS patients used in our matching analysis made it difficult to assess comparability with AML patients. It is, of course, possible that patients for whom cytogenetics were not evaluated in MS tissue and were normal in bone marrow were, in fact, cytogenetically normal in the MS tissue, i.e., these cases were cytogenetically informative. Arguing against this possibility is the incidence of cytogenetic abnormalities (4 of 4) in patients for whom cytogenetics were investigated in MS tissue. The possibility that MS patients with normal bone marrow cytogenetics would have been cytogenetically abnormal if MS tissue had been examined led us to match these patients with AML patients who had abnormal cytogenetics, with the AML patients chosen on the basis of the distribution of cytogenetic abnormalities observed in the informative MS patients.

The matching analysis suggested a 99% probability that EFS and OS are longer in MS patients, after accounting for age, performance status, year of treatment, and cytogenetics. Limiting our analysis to matches involving cytogenetically informative MS patients, we reached a qualitatively similar conclusion, i.e., a diagnosis of MS is associated per se with longer EFS. It remains possible that any conclusion is influenced by selection bias; specifically, only 16 of 23 MS patients received cytarabine-containing therapy, in contrast to >90% of the AML patients. More generally, our MS patients may not be representative of MS patients in the general population; for example, in the current study, the median age of our MS patients (57 years) was higher than the median age (37 years) in a previous review of 74 MS patients.11

The better outcomes of the MS patients in our study may be explained by earlier-stage disease, with less of a tumor load associated with infiltration of extramedullary sites by leukemic blasts compared with AML. It is also conceivable that the better outcomes simply reflect the fact that, even if untreated, MS patients may not die until they develop AML. This would indicate the presence of a lead-time advantage for the MS patients. Even if this is the case, we are not prepared to recommend that the treatment of MS patients be postponed until AML develops.

This study emphasizes the need to treat patients with non-leukemic MS with AML-type therapy. Patients with non-leukemic MS should be enrolled in clinical trials for AML and may benefit from risk-adapted therapies that account for age, performance status, and cytogenetics.

Acknowledgments

Grant support: E Estey: National Cancer Institute grants P01CA108631, P01CA55164-, U01HL069334, R01CA085843, R01CA092115, R01CA083932, P50CA100632, P50CA100632; AM Tsimberidou: American Society of Clinical Oncology: Career Development Award

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