Hematopoietic Stem-Cell Transplantation for Advanced Systemic Mastocytosis (original) (raw)

Abstract

Purpose

Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.

Patients and Methods

In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).

Results

Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.

Conclusion

AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

INTRODUCTION

Systemic mastocytosis (SM) is a hematopoietic stem-cell disease defined by clonal expansion of mast cells in various organs. SM comprises a pathologically and clinically heterogeneous group of disease variants with variable prognoses.1–5 The clinically indolent forms do not shorten life expectancy and require cytoreductive therapy, whereas advanced SM variants, including mast cell leukemia (MCL), SM with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD), and aggressive systemic mastocytosis (ASM), are associated with survival rates ranging from months to a few years despite cytoreductive therapy.1,4,6,7

No standard treatment exists for advanced SM. Cytoreductive therapy with cladribine or interferon alfa has been used, but no long-lasting responses have been reported.8–10 A majority of patients with SM (> 80%) have a gain of function mutation in the gene encoding the tyrosine kinase KIT, usually KITD816V.11–17 Although various tyrosine kinase inhibitors have been tested in advanced SM,18–26 their clinical benefit seems to be limited.1,18,19,23 Allogeneic hematopoietic stem-cell transplantation (alloHCT) has curative potential for hematologic malignancies such as acute myelogenous leukemia (AML).27 Although alloHCT has been used to treat life-threatening SM and hematologic malignancies associated with SM,28–40 the outcome of alloHCT in patients with advanced SM has never been systematically studied. Indeed, the largest published case series consisted of only three patients.37

The purpose of this retrospective study was to evaluate the clinical outcomes of alloHCT in advanced SM and to assess potential benefits and hazards of alloHCT in all identifiable cases in the United States and Europe.

PATIENTS AND METHODS

Patients were included in the study if they underwent alloHCT for the treatment of SM-AHNMD, MCL, or ASM and if their data on mast cells—and AHNMD in case of SM-AHNMD—were available at both time points (before and after alloHCT). In case of SM-AHNMD, only patients whose SM component was known at the time of AHNMD diagnosis or before alloHCT were included, whereas patients whose SM component was discovered later (ie, hidden and/or occult mastocytosis) in a study were excluded. All these patients were indeed suffering from overt advanced mastocytosis requiring therapy. Note that in all of our patients, overt SM was documented and that any type of myelodysplastic syndrome (MDS) or AML that occurred in the context of SM was regarded as secondary and part of the entire clonal disease process (SM-AHNMD). Patients were identified at individual major transplantation or SM centers in the United States and Europe (the European Competence Network on Mastocytosis was the main source), the Center for International Blood and Marrow Transplant Research, and published reports. After approval by the individual center's institutional research board, information on patients was collected anonymously by using a data collection form. The diagnosis of SM was confirmed by a local investigator before reporting data to the data collection center at the University of Minnesota. Fifty-seven patients were identified: the data on 52 patients (43 never published and nine published) were obtained from 33 individual institutions (Appendix Tables A1, A2, and A3, online only).28,29,33,37–40 The remaining five patients were identified from the literature, but no contact with the respective centers for participation was secured.30,32,34–36 Data on surviving patients were updated during the study period of more than 2 years.

Response Evaluation in SM

Given the limitations of obtaining detailed source data for all patients, we could not use the SM response criteria developed by Valent et al41 or the consensus statement developed by the International Working Group-Myeloproliferative Neoplasms Research and Treatment and the European Competence Network on Mastocytosis.42 Therefore, three parameters were used to assess response in SM: the percentage of bone marrow mast cells, serum tryptase levels, and organ involvement. Organ involvement in SM at the time of diagnosis and changes over time (ie, improved, stable, or progressing) were reported and were included in the criteria used to determine responses (ie, laboratory measures, physical examination, imaging, or a combination thereof). Response was defined as ≥ 50% decrease in both serum tryptase levels and bone marrow mast cell percentage from biopsies (not aspirates) when both tests were available or, if the results of only one test were available, ≥ 50% improvement in one test if the results were corroborated by clinical determination of improvement and the absence of worsening of any other organ involvement. The lowest level of response was recorded if there was inconsistency among these three parameters. Complete response (CR) was defined as resolution of SM in all organs along with normalization of serum tryptase levels. Progression was defined as ≥ 50% increase in any of the three parameters, and stable disease was defined as less than 50% change in all three parameters. Although quantitative assessment was desirable for response evaluation, qualitative assessment that clearly indicated outcome (eg, worsened, increased, no evidence of mast cells in biopsies) was used in few patients. Because this is a retrospective analysis, there were no predetermined uniform time points for response evaluations. However, a vast majority of patients were evaluated at day 100, at relapse of hematologic malignancy or SM, or at progression of SM. Duration of response was analyzed in 36 patients (nonresponders are excluded as well as four responders with missing time of response). Response assessments were made independently by C.U., C.A., and P.V., and each investigator who provided patient information confirmed the final assigned response. In some patients, the local hematopathologist re-evaluated the original bone marrow specifically for mast cell burden. Response was accepted as reported to the French Registry by the individual institutions (n = 5; patients 42 to 46, and as previously published (n = 5; patients 1, 6, 12, 14, and 16). Treatment history in these patients was focused on SM-directed cytoreductive therapy that consisted primarily of interferon, steroids, tyrosine kinase inhibitors, and cladribine, but included other agents such as hydroxyurea, thalidomide, gemtuzumab ozogamicin, arsenic trioxide, cyclosporine, fludarabine, and cytarabine.

Statistical Analysis

Patient and disease characteristics were summarized by disease type. Cumulative incidence of treatment-related mortality was calculated with relapse as a competing risk. Kaplan-Meier estimations and the log-rank test were used to estimate and compare overall survival (OS) and progression-free survival (PFS) from time of transplantation. At the beginning of the study, the poor prognosis of patients with MCL was apparent and, therefore, we excluded these patients from univariable analysis of OS and PFS to eliminate possible confounding of MCL with other effects. We defined a P value of ≤ .05 as significant in the univariable analysis of risk factors for survival. Analysis was performed by using SAS version 9.2 (SAS Institute, Cary, NC).

RESULTS

Patient, Donor, and AlloHCT Characteristics

Fifty-seven patients with advanced SM underwent alloHCT between 1990 and May 2013 (Table 1). The majority of patients (n = 38, including one patient with MCL-AML and one patient with myelomastocytic leukemia) were diagnosed with SM-AHNMD, with the most common AHNMD being AML (n = 20, including one patient with myelomastocytic leukemia). Most patients had SM involvement in at least one extramedullary organ or tissue, primarily in the spleen (n = 33), liver (n = 26), skin (n = 12), and lymph nodes (n = 11). The most frequent recurrent cytogenetic abnormality was t(8;21)(q22,q22) (n = 5), and the most frequent molecular abnormality was KITD816V (n = 21). Of 20 patients with AML, 11 had abnormal cytogenetics, and nine had a KIT mutation, 17 received anthracycline plus cytarabine for induction, and six had persisting leukemia at the time of alloHCT. Patient and disease characteristics for each patient are detailed in Appendix Table A1.

Table 1.

Patient and Donor Characteristics in Different SM Subtypes

Characteristic ASM MCL SM-AHNMD Total
No. % No. % No. % No. %
No. of patients 7 12 38 57
Age, years
Median 50 43 45 46
Range 31-62 13-60 11-67 11-67
Male sex 4 57 5 42 21 55 30 53
KIT mutations
Positive 1 14 4 33 19 50 24 42
Negative 0 0 4 33 5 13 9 16
Not reported 6 86 4 33 14 37 24 42
Cytogenetics
Normal 3 43 6 50 16 42 25 44
t(8;21) or its variants 0 0 0 0 5 13 5 9
Abnormal (other than t(8;21)) 0 0 4 33 10 26 14 25
Not reported 4 57 2 17 7 18 13 23
No. of involved organs (in addition to bone marrow)
0 3 43 1 8 8 21 12 21
1-2 3 43 5 42 15 39 23 40
≥ 3 0 0 6 50 12 32 18 32
Not reported 1 14 0 0 3 8 4 7
No. of SM treatment categories
0 0 0 2 17 21 55 23 40
1-2 3 43 7 58 9 23 19 33
≥ 3 2 29 3 25 7 18 12 21
Not reported 2 29 0 0 1 3 3 5
Time from SM diagnosis to alloHCT
Median 19 9 9 9
Range 7-192 3-216 2-96 2-216
Karnofsky performance score
≥ 90 0 0 5 42 16 42 21 37
< 90 3 43 4 33 9 24 16 28
Not reported 4 57 3 25 13 34 20 35
Donor
Sibling 4 57 5 42 25 66 34 60
Unrelated 2 29 5 42 10 26 17 30
UCB or haploidentical 0 0 2 17 1 3 3 5
Not reported 1 13 0 0 2 5 3 5
Donor age, years
Median 32 39 44 42
Range 22-54 21-52 23-65 21-65
Recipient-donor sex mismatched
Matched 2 29 6 50 23 61 31 54
Mismatched 4 57 5 42 13 34 22 39
Not reported 1 14 1 8 2 5 4 7

Most patients received either sibling or unrelated alloHCT, although two patients received alloHCT from umbilical cord blood (UCB) and one received alloHCT from an HLA-haploidentical relative (Table 2). All patients received HLA-matched alloHCT except three patients whose unrelated donors were 9/10 HLA-locus and allele matched, two patients whose UCB was 5/6 HLA matched, and one patient whose HLA-haploidentical donor was 4/8 matched. Although the majority of patients (63%) received myeloablative conditioning (MAC), more than a third of patients received reduced-intensity conditioning (RIC). Detailed information on donor characteristics and alloHCT for individual patients is provided in Appendix Table A2.

Table 2.

AlloHCT Treatment, Complications, and Outcomes in Different SM Subtypes

Variable ASM MCL SM-AHNMD Total
No. % 90% CI No. % 90% CI No. % 90% CI No. % 90% CI
No. of patients 7 12 38 57
Conditioning
Reduced intensity 4 57 3 25 14 37 21 37
Myeloablative 3 43 9 75 24 63 36 63
With TBI 1 14 3 25 12 32 16 28
Transplantation year
1990-2004 1 14 6 50 14 37 21 37
2005-2013 6 86 6 50 24 63 36 63
GVHD prophylaxis
Methotrexate 3 43 6 50 19 50 28 49
No methotrexate 2 29 5 42 16 42 23 40
Not reported 2 29 1 8 3 8 6 11
Tacrolimus 0 0 3 25 9 24 12 21
Cyclosporine 5 71 4 33 24 63 33 58
Not reported 2 29 5 42 5 13 12 21
Response in SM
Primary resistance 1 14 3 25 1 3 5 9
Stable disease 1 14 0 0 11 30 12 21
Response 5 72 9 75 26 68 40 70
Complete remission 3 43 3 25 10 26 16 28
Acute GVHD*
None or grade 1 5 71 6 50 19 50 30 53
Grade 2 to 4 2 29 5 42 16 42 23 40
Not reported 0 0 1 8 3 8 4 7
Chronic GVHD*
None 3 43 8 67 12 32 23 40
Limited or extensive 3 43 0 0 21 55 24 42
Extensive 1 14 0 0 12 32 13 23
Not reported 1 14 4 33 5 13 10 18
Transplantation-related mortality
6 months 14 1 to 30 25 6 to 44 5 1 to 11 11 4 to 17
1 year 14 1 to 30 33 12 to 54 17 7 to 27 20 11 to 28
Overall survival
1 year 43 14 to 70 25 8 to 46 78 64 to 87 62 50 to 72
3 years 43 14 to 70 17 4 to 37 74 60 to 84 57 46 to 68
Progression-free survival
1 year 43 14 to 70 17 4 to 37 70 55 to 80 55 44 to 65
3 year 43 14 to 70 17 4 to 37 63 47 to 75 51 39 to 61

Disease Responses After AlloHCT

Responses were assigned to 12 patients with one criterion, 30 patients with two criteria, and 10 patients with all three criteria. Overall, SM responded to alloHCT in 40 patients (70%; Tables 2 and 3). The median bone marrow biopsy number after transplantation was 2.2. The median bone marrow mast cell percentage in biopsies (21% [range, 2% to 90%] before alloHCT v 1.8% [range, 0% to 90%] after alloHCT) and serum tryptase levels (130 ng/mL [range, 11 to 889 ng/mL] before alloHCT and 16 ng/mL [range, 2 to 404 ng/mL] after alloHCT) decreased significantly after alloHCT in patients with data available for before and after alloHCT (Figs 1A to 1D). In this comparison, the best values after alloHCT were used, and the median time to reach the best responses for both variables was 3 months (range, 1 to 36 months) after alloHCT. Of the 40 responding patients, 16 (28%) achieved CR (KIT mutations were negative in two of two patients with CR when tested after alloHCT). Twelve patients (21%) had stable disease. Patients with MCL had more primary resistance (three of five patients) and progression after initial response (three of 10 patients). The median time of response duration was 20 months. All 38 patients with SM-AHNMD achieved CR regarding the AHNMD component, but 10 subsequently relapsed with AHNMD, and five of these died. Details of treatment and outcome are given in Appendix Table A3.

Table 3.

Factors Associated With OS and SM PFS in Patients With no MCL Only (n = 45)

Factor No. % OS PFS
1-Year 90% CI P* 1-Year 90% CI P*
Diagnosis
ASM 7 16 43 14 to 70 .05 43 14 to 70 .07
SM-AHNMD 38 84 78 64 to 87 70 55 to 80
AML, ALL, MML 21 47 75 55 to 87 .75 65 45 to 80 .53
MDS, MPN, MM 17 38 81 57 to 92 75 52 to 88
Age, years
< 40 16 36 80 56 to 92 .39 68 44 to 83 .85
≥ 40 29 64 67 50 to 80 65 48 to 77
Sex
Female 20 44 79 58 to 90 .34 74 54 to 87 .32
Male 25 56 65 46 to 79 59 40 to 73
KIT mutations
Negative 5 11 60 19 to 85 .27 40 9 to 71 .40
Positive 20 44 82 60 to 93 74 53 to 87
Unknown 20 44 65 40 to 81 65 40 to 82
Cytogenetics
Normal 19 42 68 47 to 82 .61 68 47 to 82 .92
t(8;21) 5 11 100 60 19 to 85
Other 10 22 67 35 to 86 67 35 to 86
Unknown 11 24 69 38 to 87 62 34 to 82
Treatment for SM
None 21 47 79 59 to 90 .11 70 49 to 83 .27
One to two agents 12 27 81 51 to 94 74 46 to 89
Three or more agents 9 20 44 18 to 68 44 18 to 68
Karnofsky performance score
< 90 12 27 48 23 to 69 .15 49 24 to 70 .28
≥ 90 16 36 80 56 to 92 80 56 to 92
Unknown 17 38 82 60 to 93 64 42 to 80
AML CR status
In CR 14 31 79 54 to 91 .63 71 46 to 86 .37
Not in CR 6 13 60 19 to 85 42 9 to 72
Percentage of BM mast cells before transplantation
< 20 14 31 68 42 to 85 .87 53 29 to 73 .33
≥ 20 15 33 73 49 to 87 73 49 to 87
Time from diagnosis to alloHCT, months
≤ 13 29 64 78 62 to 88 .23 71 54 to 83 .27
> 13 16 36 60 36 to 77 56 34 to 74
Conditioning
Reduced intensity 18 40 57 34 to 74 .10 48 27 to 66 .03
Myeloablative 27 60 81 65 to 91 77 61 to 88
Myeloablative with TBI 13 29 85 59 to 95 .98 85 59 to 95 .59
Myeloablative without TBI 13 29 84 57 to 95 76 49 to 90
Graft source
BM 16 36 75 52 to 88 .86 75 52 to 88 .32
PBSCs 27 60 72 54 to 84 62 45 to 75
Donor age, years
< 40 11 24 64 35 to 82 .31 64 35 to 82 .43
≥ 40 23 51 76 55 to 87 76 57 to 88
Donor sex match
Match 25 56 80 62 to 90 .21 72 54 to 84 .18
Female donor, male recipient 10 22 44 18 to 68 34 11 to 59
Male donor, female recipient 7 16 71 34 to 90 71 34 to 90
Donor relation
Sibling 29 64 74 56 to 85 .50 64 47 to 77 .95
Unrelated 12 27 67 40 to 84 67 40 to 84
Other (UCB) 1 2 0 0
aGVHD
None or grade 1 24 53 73 49 to 87 .49 69 46 to 84 .55
Grade 2 to 4 18 40 66 44 to 81 61 35 to 79

Fig 1.

Fig 1.

Allogeneic hematopoietic stem-cell transplantation (alloHCT) improves responses in patients with advanced systemic mastocytosis. Changes in (A) bone marrow cell percentage (n = 39; P < .01) and (B) serum tryptase levels (n = 23; P < .01) in patients with before and after alloHCT data available. The post-transplantation data represent the best (lowest) values of both mast cell percentage and serum tryptase, both of which were observed a median of 3 months (range, 1 to 36 months) after alloHCT. The median and interquartile range are indicated by a solid line and rectangle, respectively. Observations outside the interquartile range are indicated by dashed lines or dots. Percentage change in mast cells in (C) bone marrow and (D) in serum tryptase levels in each patient with available before and after alloHCT data.

OS and PFS for all patients were 62% (90% CI, 50% to 72%) and 57% (90% CI, 44% to 65%) at 1 year, and 55% (90% CI, 46% to 68%) and 51% (90% CI, 39% to 61%) at 3 years, respectively (Figs 2A and 2B; Tables 2 and 3). OS and PFS were significantly higher in patients with SM-AHNMD and were lowest in patients with MCL (Figs 2C and 2D; P < .01). No deaths or relapses were observed after 15 and 24 months, respectively. The median follow-up among survivors was 32 months (range, 3 to 202 months).

Fig 2.

Fig 2.

Allogeneic hematopoietic stem-cell transplantation (alloHCT or HCT) outcomes in patients with advanced systemic mastocytosis (SM). (A) Overall survival (OS) and (B) progression-free survival (PFS) for all patients with advanced SM. Blue lines represent 95% CIs. (C) OS and (D) SM PFS by type of systemic mastocytosis. (E) OS and (F) SM PFS by conditioning regimen intensity. (G) OS by initial response in SM. ASM, aggressive systemic mastocytosis; MAC, myeloablative conditioning; MCL, mast cell leukemia; RIC, reduced-intensity conditioning; SM-AHNMD, SM with an associated clonal hematologic non–mast cell lineage disease.

Factors Affecting PFS and OS

Univariable analysis of relevant variables and outcomes are shown in Table 3. The strongest risk factor for worse OS was a diagnosis of MCL. Other risk factors were evaluated after excluding patients with MCL (n = 12). In the 45 remaining patients, factors that had an effect on survival included a diagnosis of ASM and RIC (Figs 2E and 2F). The median age for patients receiving MAC regimens was 38 years (range, 11 to 62 years) compared with 50 years (range, 17 to 67 years) for patients receiving RIC. The superior outcome with MAC was not fully accounted for by younger patient age; for patients older than age 40 years, 1-year OS was 85% after MAC (n = 13) and 51% after RIC (n = 16). RIC was used as frequently in the entire study cohort as in patients with Karnofsky performance status (KPSs) ≤ 80%, (21 [37%] of 57 and four [25%] of 16, respectively). A lower KPS before alloHCT seemed to lower survival, and six of seven patients with KPSs ≤ 70% died. OS at 1 year was shorter for patients with progression (20%; 90% CI, 2% to 52%) compared with patients with stable disease (89%; 90% CI, 54% to 98%) and with responders (63%; 90% CI, 49% to 74%; Fig 2G).

Factors without any identifiable impact on OS and PFS were patient age, donor age, donor type (sibling or unrelated donor), graft source (bone marrow or peripheral blood stem cells), bone marrow mast cell percentage at alloHCT, KIT mutation status, cytogenetic groupings, total body irradiation used in MAC regimens, and CR status at alloHCT (Table 3). OS and PFS at 1 year were not affected by whether or not the patient received prior SM-directed cytoreductive therapy (Table 3). When they were specifically evaluated in patients with SM-AHNMD only, OS and PFS were again similar (73% and 68% for patients with history of prior SM-directed therapy [41%] compared with 79% and 70% for those who did not receive therapy [55%], respectively).

All patients who received alternative donor transplants (two UCB and one HLA-haploidentical relative) and all patients with MCL who received RIC (n = 3) died. In contrast, all five patients with t(8;21) or its variant survived.

Donor Lymphocyte Infusions and Second AlloHCT

Six of 10 patients who received donor lymphocyte infusions (DLIs) for mixed chimerism and/or stable SM disease responded to this treatment (three achieved CR, of which two were durable). However, three patients who received DLIs for SM progression (n = 2) or graft failure with AML relapse (n = 1) had no response and died (Appendix Table A3).

A second alloHCT (two RIC and one MAC regimen) was performed for relapse of myelomastocytic leukemia (n = 1), relapse of AML (n = 1), and progression of both MDS and SM (n = 1) at 4, 5, and 44 months after the first alloHCT, respectively. All three patients were alive in CR of SM or hematologic malignancy after the second alloHCT (Appendix Table A3).

AlloHCT Complications

Treatment-related mortality at 6 months and 1 year was 11% and 20%, respectively, and was highest in MCL (25% and 33%; Table 2). Primary and secondary engraftment failure each occurred in one patient. In the first 100 days after initiation of alloHCT conditioning, symptoms possibly related to mast cell degranulation occurred in five patients and included hot flashs (n = 3), skin rash (n = 1), and abdominal cramps and nausea (n = 1). Acute graft-versus-host disease (GVHD) grades 2 to 4 and chronic extensive GVHD occurred in 40% and 23% of patients, respectively (Table 2). Two patients died from complications related to severe acute GVHD (Appendix Table A3).

DISCUSSION

This study has found that alloHCT can confer long-term OS in patients with advanced SM. The greatest survival benefit was observed in patients with SM-AHNMD who had a 3-year survival probability of 74%. The reported median OS of patients with SM-AHNMD without alloHCT was 2 years.6 Favorable OS in our group is especially significant, given that approximately one third of the patients with AML had active disease at transplantation—an indisputably poor prognostic factor for outcomes after alloHCT.27,43–49 Although the t(8;21)(q22,q22) translocation is considered a favorable prognostic factor in patients with AML without SM,50–52 patients with AML with the same cytogenetic abnormality have poor prognosis in the presence of SM, even hidden and/or occult SM.31,53,54 The presence of KIT mutations in patients with AML with t(8;21) is associated with poor prognosis regardless of the presence of SM.55–60 Most of our patients with SM-AML had KIT mutations. It is possible that not all patients had aggressive SM at the diagnosis of AHNMD, given that C findings (clinical findings related to organs involved in SM, eg, pancytopenia) can be caused by the AHNMD component as well. However, regarding survival, there was no difference between patients who received SM-specific cytoreductive therapy before alloHCT (indicating aggressive SM) and those who did not. One can argue that AML diagnosed in the context of SM (or in the context of _KIT_D816V in which an occult SM is often present) should always be judged as secondary AML and thus as high-risk (poor prognosis) disease regardless of the aggressiveness of SM. Together, our data suggest that alloHCT may overcome the unfavorable prognosis in patients with SM-AML. AlloHCT also provided long-term survival in approximately 40% of patients with ASM, which seems superior to reported survival rates in patients who did not have transplantations (median survival, 3.5 years without any evidence of a plateau).6 Patients with MCL had the poorest outcome among all of the SM subtypes in the study. However, given that the reported median survival of patients with MCL without alloHCT is short (< 12 months), our results suggest that alloHCT may be beneficial for patients with MCL as well.6,61 Evidence of treatment failure among the majority of patients with MCL was shown by early treatment–related mortality and rapid disease progression after initial responses. However, those responses, albeit transient, suggest that immunotherapy has an impact on MCL. The fact that the only long-term survivors were among patients prepared for alloHCT with high-intensity MAC regimens may indicate that the actual tumor burden that has to be overcome by donor cells is a critical determinant influencing transplantation outcome. However, when compared with results in patients with SM-AHNMD (many of whom had AML that was not in remission at the time of alloHCT) or those with ASM, this pattern suggests that not only disease burden but also the intrinsic resistance of MCL cells was an important factor. In general, patients conditioned with myeloablative regimens fared better than patients prepared with reduced-intensity regimens; the advantage of lower regimen-related mortality was canceled out by a higher progression incidence.62,63 The observation that patients with a lower KPS (≤ 70%) experienced higher mortality is consistent with results in many reports on various diseases showing the impact of performance status and comorbidities in particular on the outcome of alloHCT.64,65

Responses in SM were observed in 70% of the patients examined. However, because this is a retrospective analysis and thus there were no predetermined evaluation time points after alloHCT, the duration of response and PFS should be viewed with caution. Given that there is a decrease in serum tryptase levels after alloHCT that may reflect responses in the AHNMD component (eg, AML or MDS)66–68 itself, response evaluation mainly depended on bone marrow mast cell percentage. Responses (observed after RIC and MAC regimens and DLI) were often durable and sometimes developed gradually over years, suggesting that donor-derived cells induced a potent graft-versus-mastocytosis effect. Mast cells have been shown to express HLA class I and, at least under certain conditions such as in vitro stimulation of mast cells by interferon gamma, class II antigens.69–72 These antigens are critical for eliciting a graft-versus-tumor effect through alloreactive T cells and natural-killer cells.73 The apparent plateau of both OS and PFS suggests that alloHCT can be curative in some patients with SM. AlloHCT conferred long-term survival not only for the responders but also for the patients having stable disease. Most of the patients with stable disease had AHNMD as well; therefore, benefiting from alloHCT necessitates curing AHNMD but not the SM component. Another explanation could be that perhaps a longer time is needed to observe improvements in the SM component compared with AHNMD in some patients with SM-AHNMD.

SM-specific complications, including anaphylactoid or severe mediator-related reactions74 due to rapid lysis of mast cells and graft failure due to marrow fibrosis, were rare. Low incidence of graft failure might result from the role of mast cells in increasing allograft tolerance. Healthy mast cells are crucial for skin allograft tolerance, probably through regulatory T-cell–dependent peripheral tolerance in mice.75 The frequency of acute and chronic GVHD was similar to that seen in the overall alloHCT population.76,77

Although this study has several limitations because of its retrospective nature, it summarizes transplantation results from the largest cohort of patients with this rare and fatal disease: alloHCT is reasonably safe, and overall outcome is promising. These data support a prospective study in which before-and-after-alloHCT means should be used to further improve outcomes in patients with ASM and MCL.

Acknowledgment

The authors thank Deepti Radia, Lawrence B. Afrin, Koen van Besien, Andy Artz, Russel Bryness, Aaron T. Gerds, and Irene Cavattoni for their invaluable assistance with identifying patients, and Michael J. Franklin and K. Frank Austen for critical review of the manuscript.

Appendix

Table A1.

Patient and SM Characteristics

Author* Country Patient No. Sex Patient Age at AlloHCT (years) Diagnosis Year of Diagnosis of Primary SM Cytogenetic Abnormality KIT Mutation
Chen et al36 Taiwan 1 M 18 MCL-AML 2001 t(8;21)(q22;q22) No
Devine United States 2 M 36 SM-AHNMD (MPN-MDS with Eos) 1997 Normal NA
Födinger et al29 Austria 3 F 11 SM-AHNMD (AML) progressed from MDS-RAEB-II) 1991 t(8;1)(q22,q21), de1(5)(q13,q23) NA
Hsu United States 4 M 62 ASM 2005 Normal NA
Doubek Czech Republic 5 M 57 ASM 2010 Normal D816V
Nagai et al35 Japan 6 F 32 SM-AHNMD (AML) 2006 46XX, t(8;21) (q22;q22), del9 (q22;q34) D816Y
Nakamura et al37 United States 7 M 49 SM-AHNMD (MPN with Eos) 1999 NA D816V
Nakamura et al37 United States 8 F 50 SM-AHNMD (MDS-RA) 1998 NA D816V
Nakamura et al37 United States 9 M 47 MCL (progressed from SM) 1996 NA D816G
Valent Austria 10 F 36 MCL 2005 Normal No D816V found
Valent Austria 11 F 44 SM-AHNMD (AML) 1995 NA NA
Przepiorka et al30 United States 12 M 32 ASM Approximately 1990 Normal NA
Pullarkat et al33 United States 13 F 51 SM-AHNMD (AML) 2003 t(8;21) (q22;22) and del(9)(q12;q22) D816V
Rønnov-Jessen et al32 Denmark 14 F 38 SM-AHNMD (AML) 1991 NA NA
Sperr et al28 Austria 15 M 17 MML 2001 Complex: t(8;10;21)(q22;q21;q22), t(11;19)(q13;13), del(9)(q22) No D816V found
Spyridonidis et al34 Germany 16 M 31 MCL Approximately 2000 t(13;14) (q10;q10) No codon 816 and 560 mutation found
Stuart United States 17 M 56 SM-AHNMD (AML progressed from MDS) 2009 Normal D816V
Popat United States 18 M 46 MCL 2001 Diploidy NA
Hogan United States 19 M 61 SM-AHNMD (AML) 2011 Monosomy 7 D816V
Hogan United States 20 F 26 SM-AHNMD (AML) 2010 Normal D816V
Kreil Germany 21 F 50 ASM 1991 NA NA
Reiter Germany 22 F 27 SM-AHNMD (AML) 2005 Normal D816V
Gruhn Germany 23 M 17 SM-AHNMD (MDS-RCMD) 2007 Normal D816V
Reiter Germany 24 M 65 SM-AHNMD (AML) 2008 Trisomy 8 D816V
Hermine France 25 M 61 SM-AHNMD (AML) 2007 Trisomy 8 D816V
Gromke et al38 Germany 26 M 53 SM-AHNMD (AML) 2002 Normal D816V
Tholouli England 27 F 47 MCL, progressed from SM 2011 Complex: 43,XX,-1,add(2)(p?13),-4,add(5)(p15),-9,del(10)(q2?4q2?6),-11,-17,der(17)? t(11;17) (q13;q25), 20, +2mar,+r[4]/88,idemx2[1]/46,XX[6] D816Y
Chantom et al40 United States 28 F 23 MCL, progressed from solidary mastocytoma 2004 Normal NA
Schmid Germany 29 F 51 SM-AHNMD (AML progressed from MDS-MPN) 2009 Normal No D816V found
Valentini et al39 Italy 30 F 45 MCL Normal D816V
Baurmann Germany 31 F 44 SM-AHNMD (MDS-MPN with Eos) 2003 Normal D816V
Baurmann Germany 32 F 49 SM-AHNMD (MDS-RCMD) 2008 Normal D816V
Shore 33 M 59 MCL 2008 Normal D816V
Shore 34 M 57 SM-AHNMD (MDS) 2011 del7q D816V
Scott United States 35 M 35 SM-AHNMD (MDS-MPN) 2004 Normal NA
Scott United States 36 M 31 MCL 2004 Complex:43-44,XY,?del(3)(p?),-8,?add(9)(q34), −10,?der(11)t(8;11)(q?11.2;q?13), add(16)(q24),?del(17)(q11.2) add(19)(q13.3),add(20)(q13.3)[cp13]/46,XY[7] No D816V found
Scott United States 37 M 21 SM-AHNMD (AML) in CR2 2006 t(8;21)(q22;q22) NA
Scott United States 38 M 46 SM-AHNMD (AML) secondary to MDS 2008 NA No D816V found
Scott United States 39 F 43 SM-AHNMD (MDS) 2010 46,XX[30], abnormal IFISH (25.6%) for additional copy of EVI1 (3q26) D816V
Scott United States 40 F 31 SM-AHNMD (MDS) 2008 Normal No D816V found
Legrand France 41 M 62 SM-AHNMD 2008 −Y D816V
Damaj/Yakoub-agha France 42 F 31 ASM 2001 NA NA
Damaj/Yakoub-agha France 43 M 57 SM-AHNMD (MM) 1998 NA NA
Damaj/Yakoub-agha France 44 M 42 SM-AHNMD (ALL) 2003 NA NA
Damaj/Yakoub-agha France 45 M 47 ASM 2007 NA NA
Damaj/Yakoub-agha France 46 F 50 ASM 2002 NA NA
Godley United States 47 F 50 MCL 2005 del (1p), add (6q), −9, add (16p) NA
Van Lint Italy 48 F 36 SM-AHNMD (AML) 2002 inv16 No D816V found
Perales United States 49 F 40 MCL 1992 NA NA
Perales United States 50 M 50 SM-AHNMD (MPN-MDS), SM secondary to UP 2000 Normal NA
Perales United States 51 F 57 SM-AHNMD (MDS RAEB), SM secondary to UP 2011 Normal NA
Gilman United States 52 F 13 MCL 2012 Normal No D816V found
Vercellotti United States 53 M 60 SM-AHNMD (MPN-MDS RAEB-I, 8% blasts) 2010 +8 D816V
Ustun United States 54 F 64 SM-AHNMD (AML) (therapy induced) 2009 −7 NA
Nakamura United States 55 F 36 SM-AHNMD (MPN-CMML) 2011 Normal NA
Nakamura United States 56 M 67 SM-AHNDM (MDS-MPN) 2011 Normal D816V
Nakamura United States 57 M 41 SM-AHNMD (AML, secondary to MDS) 2003 Normal NA

Table A2.

Transplantation Characteristics

Patient No. Diagnosis Date of First AlloHCT Time From Primary SM Diagnosis to alloHCT (months) CR Status of AML or MML at AlloHCT KPS at AlloHCT (%) Graft Type Conditioning Donor
Intensity Regimen Type Age (years) Sex
1 MCL-AML December 2001 4 CR NA PBSC MAC Busulfan-cyclophosphamide-etoposide NA
2 SM-MPN-MDS March 2001 48 NA 70 BM MAC Busulfan-cyclophosphamide URD 34 F
3 SM-AML 1992 10 CR NA BM MAC Busulfan-cyclophosphamide-etoposide NA
4 ASM February 2007 18 NA 70 PBSC MAC TBI-cyclophosphamide-cytarabine URD 34 M
5 ASM April 2012 21 NA 80 PBSC RIC FLAMSA-RIC and splenic XRT RD 54 F
6 SM-AML 2006 4.5 Active AML NA PBSC MAC TBI-cyclophosphamide RD F
7 SM-MPN 2002 36 NA NA PBSC RIC Fludarabine-cyclophosphamide RD 43 M
8 SM-MDS 2001 36 NA NA PBSC RIC Fludarabine-cyclophosphamide RD 54 F
9 MCL 2001 60 NA NA PBSC RIC Fludarabine-cyclophosphamide RD 52 F
10 MCL March 2007 21 NA 90 PBSC MAC Busulfan-cyclophosphamide-antithymocyte globulin URD M
11 SM-AML December 1996 8 CR 100 BM MAC TBI-etoposide RD 42 F
12 ASM 1996 9 NA NA BM MAC Busulfan-cyclophosphamide-thiotepa NA
13 SM-AML 2004 9 CR 90 PBSC MAC FTBI-etoposide RD 48 F
14 SM-AML 1990 2 Active AML NA BM MAC TBI-cyclophosphamide RD F
15 MML July 2001 4 CR regarding myeloblasts NA PBSC RIC Fludarabine-TBI RD F
16 MCL 2000 Approximately 3 NA NA BM MAC Busulfan-cyclophosphamide URD F
17 SM-AML March 2010 11 Active AML 80 PBSC MAC Busulfan-cyclophosphamide RD 49 M
18* MCL May 2002 9 NA 90 BM RIC Fludarabine-melphalan-antithymocyte globulin URD
19 SM-AML November 2011 6 CR 90 PBSC RIC Fludarabine-melphalan RD 63 M
20 SM-AML September 2011 9 CR 90 PBSC. MAC TBI-cyclophosphamide URD 30 M
21 ASM July 2006 60 NA 50 PBSC RIC Fludarabine-melphalan-thiotepa URD 22 M
22* SM-AML August 2012 84 CR 80 PBSC RIC FLAMSA-RIC URD 23 F
23 SM-MDS September 2008 13 NA 80 BM MAC Busulfan-cyclophosphamide-antithymocyte globulin URD 48 M
24 SM-AML April 2011 7 Relapse/active AML 90 PBSC RIC FLAMSA-RIC RD 63 F
25 SM-AML January 2010 26 Active AML 80 BM MAC RD F
26 SM-AML June 2008 72 CR (CRi) 90 PBSC MAC Tresulfan-fludarabine URD 41 M
27* MCL May 2012 11 NA 100 UCB MAC Fludarabine-cyclophosphamide-TBI UCB M
28 MCL October 2004 216 NA 90 PBSC MAC Fludarabine-busulfan RD 21 F
29 SM-AML March 2011 13 CR (CRi) 90 PBSC RIC FLAMSA-RIC RD 46 F
30 MCL January 2005 21 NA 70 PBSC MAC Busulfan-cyclophosphamide RD 41 F
31 SM-MDS-MPN September 2007 17 NA 90 PBSC MAC TBI-fludarabine -cyclophosphamide-antithymocyte globulin RD 46 F
32* SM-MDS September 2010 85 NA 100 BM MAC Thiotepa-busulfan-cyclophosphamide-antithymocyte globulin URD F
33 MCL March 2009 7 NA 80 PBSC MAC Fludarabine-busulfan-antithymocyte globulin URD M
34 SM-MDS May 2012 5 NA 90 BM MAC Fludarabine-melphalan URD 45 M
35 SM-MDS-MPN October 2000 8 NA NA PBSC MAC Busulfan-cyclophosphamide RD 33 F
36 MCL February 2005 8 NA NA PBSC MAC Fludarabine-busulfan URD 21 M
37 SM-AML February 2005 12 CR2 NA PBSC MAC TBI-cyclophosphamide RD 25 M
38 SM-AML February 2007 5 CR NA PBSC RIC TBI-fludarabine URD 40 M
39 SM-MDS February 2009 10 NA 80 PBSC MAC Busulfan-cyclophosphamide URD 41 M
40 SM-MDS February 2011 5 NA 90 BM MAC TBI-cyclophosphamide RD 26 F
41 SM-MPN January 2009 5 NA 70 BM RIC Fludarabine-melphalan RD 63 F
42 ASM November 2009 65 NA NA BM MAC Busulfan-cyclophosphamide RD 29 M
43 SM-MM February 2003 18 NA NA PBSC RIC Busulfan-fludarabine-antithymocyte globulin RD 39 F
44 SM-ALL January 1999 5 NA NA BM MAC TBI-cyclophosphamide RD 38 M
45 ASM June 2005 19 NA NA PBSC RIC RD M
46 ASM November 2007 7 NA NA PBSC RIC Fludarabine-busulfan RD M
47 MCL August 2002 5 NA 90 PBSC RIC Fludarabine-melphalan-alemtuzumab RD F
48 SM-ASM-AML October 2005 8 Active AML 60 BM MAC TBI-cyclophosphamide RD 44 M
49 MCL June 2003 8.5 NA 70 PBSC MAC TBI-thiotepa-fludarabine RD 37 M
50 SM-MPN-MDS November 2000 96 NA 80 TBI-thiotepa-fludarabine RD 45 M
51 SM-MDS February 2003 32 NA NA BM MAC Busulfan-melphalan RD 53 F
52 MCL July 2011 5 NA 80 PBSC MAC TBI-thiotepa-fludarabine-antithymocyte globulin-local radiation to vertebrae Haploidentical (mother) 42 F
53 SM-MPN-MDS May 2013 5 NA 90 PBSC RIC TBI-cyclophosphamide-fludarabine RD 62 F
54* SM-AML February 2011 3 CR 90 UCB RIC TBI-cyclophosphamide-fludarabine UCB
55 SM-CMML January 2010 4 NA 90 PBSC MAC Fludarabine-melphalan-TMI RD 36 M
56 SM-AML (MDS-MPN) December 2011 8 NA 90 PBSC RIC Fludarabine-melphalan RD 65 F
57 SM-AML secondary to MDS?) December 2011 3 CR 90 PBSC RIC Fludarabine-melphalan URD 44 M

Table A3.

Response in SM and Survival After First AlloHCT

Patient No. Disease Reference Serum Tryptase (ng/mL) Percentage of Mast Cells in BM* Other SM-Related Changes After AlloHCT SM Response to First AlloHCT Progression of SM After Initial Response Treatment After AlloHCT and Response Alive (yes/no) Time From First AlloHCT (months) Cause of Death
At Diagnosis At AlloHCT After AlloHCT At Diagnosis At AlloHCT After AlloHCT Yes/No Time
1 MCL-AML Chen et al36 40 27.5 40 at 1 month Hepatomegaly, splenomegaly, and pancytopenia persisted SD No Yes 12
2 SM-MPN ↑ ↑ ↑ 0 at 3 months Eosinophil infiltrate (44%) in BM resolved (5%); dyserythropoiesis resolved R No No 4 Infection and MOF
3 SM-AML Födinger et al29 ↑ 4 5 at 3 months SD No Yes 60
4 ASM > 200 189 at 3 months 75 30 at 3 months R No No 3 CNS bleeding
5 ASM 0 0 at 1 month Improvement in spleen and liver size R Yes At 7 months Cladribine, steroids, DLI: P No 12 Progression of SM
6 SM-AML Nagai et al35 5 7 ↑ ↑ at 6 months P No treatment Yes 12
7 SM-MPN Nakamura et al37 889 404 at 6 months Eosinophilia decreased (15 × 109/L to 0.6 × 109/L R Yes At 6 months DLI Yes 9
8 SM-MDS Nakamura et al37 150 60 at 10 months ↑ ↑ ↑ Episodic hot flashes and syncope resolved R No DLI† Yes 39
9 MCL Nakamura et al37 > 200 ↑ ↑ Hepatosplenomegaly and pancytopenia worsened P No treatment No 5 Progression of SM
10 MCL 333 95 at 2 months 5 1.5 at 2 months R No No 3 Sepsis
11 SM-AML 7 5 5 at 3 months SD No Yes 206
12 ASM Przepiorka et al30 30 0 at 1 month Splenomegaly resolved R (CR) No Yes 24
13 SM-AML Pullarkat et al33 17.4 90 0 at 10 months R (CR) No Yes 108
14 SM-AML Rønnov-Jessen et al32 ↑ ↑ Liver infiltration persisted SD Yes 8
15 MML Sperr et al28 745 126 73 at 2 months 10 5 5 at 2 months SD Yes At 3 months Second alloHCT after MAC: CR Yes 144
16 MCL Spyridonidis et al34 70 by morphology 14 by flow 5 at 1 month; 2.4 by flow at 12 months Urine histamine level was normalized R No DLI† Yes 44
17 SM-AML 97 69 27 at 3 months 5-10 > 10 1 at 3 months Mediator-related symptoms resolved, skin lesions improved R No Yes 30
18 MCL 90 30 0 at 1 month R (CR) No No 2 Sepsis
19 SM-AML 71 10 10 10 at 3 months SD No Yes 16
20 SM-AML 542 291 30 30 5 at 7 months R No Yes 18
21 ASM 136 142 at 1 month 80 50 at 1 month SD Yes At 3 months Dasatinib: P No 10 Progression of SM
22 SM-AML 230 34 19 at 4 months < 10 0 at 4 months Improvement in liver, skin, and lymph nodes R (CR) No Yes 11
23 SM-MDS 530 200 9.6 at 3 months 50 5 5 at 3 months Improvement in liver and skin R Yes At 24 months DLI: SD; second alloHCT with RIC: CR Yes 52
24 SM-AML 875 114 22 at 1 month 35 10 < 5 at 1 month Improvement in liver function tests R No Second alloHCT with RIC for AML†:CR Yes 21
25 SM-AML 349 15 at 3 months 60 10 0 Improvement in bone, spleen, and liver R No No 11 AML relapse
26 SM-AML Pardanani et al20 90 < 11 at 36 months 70 78 0 at 1 month Improvement in nodes, spleen, and liver R (CR) No Yes 42
27 MCL 496 15 99 40 3 at 2 months Improvement in skin, spleen, and liver; cytogenetic remission R Yes At 4 months No treatment No 4 Progression of SM
28 MCL Chantorn et al40 > 200 5; then 79 (MCL) 60 80 at 1 month Mediator-related symptoms persisted P No treatment No 4 Progression of SM
29 SM-AML 37 38 20 at 3 months 15 Improvement in skin, splenomegaly persisted SD Yes At 3 months Cladribine No 6 Graft failure-sepsis
30 MCL Valentini et al39 > 200 35 90 10 1.5 at 1 month R No No 1 Traffic accident
31 SM-MDS-MPN 216 145 9 at 24 months 5 < 5 0 at 24 months Splenomegaly resolved; _KIT_D816V became undetectable in BM cells R (CR) No DLI† Yes 72
32 SM-MDS 61 48 14 at 34 months 80 35 4 at 34 months Severe myelofibrosis improved R No DLI† Yes 34
33 MCL 535 70 70 10 at 3 months R No No 8 Respiratory failure
34 SM-MDS > 400 25 2.1 at 12 months 80 20 0 at 12 months R (CR) No TKI†, DLI† yes 12
35 SM-MDS-MPN 20-25 0 at 1 month Splenomegaly persisted R No No 7 Severe GVHD
36 MCL 1,500 90 50 at 1 month Splenomegaly worsened P No 1 Progression of SM
37 SM-AML 26 25 1 at 2 months R No Yes 68
38 SM-AML 110 4 0.1 at 2 months R No DLI†,TKI† No 9 AML relapse
39 SM-MDS 919 11.3 6.2 at 3 months 40 2-3 2 at 12 months SD No Yes 28
40 SM-MDS 820 394 4.4 at 12 months 20 0 at 1 month R (CR) No Yes 19
41 SM-AHNMD 230 200 9 at 3 months 30 30 0 at 3 months No evidence of mast cells in liver and GI tract biopsies; _KIT_D816V became undetectable in the BM cells; diarrhea resolved R (CR) No No 30 Pulmonary fibrosis
42 ASM 230 R (CR) No Yes 27
43 SM-MM SD No Yes 105
44 SM-ALL R (CR) No Yes 56
45 ASM 250 P No 6 Progression of SM
46 ASM R (CR) No Yes 30
47 MCL 95 90 0 at 3 months R (CR) Yes At 12 months No 15 Progression of SM
48 SM-AML 15 15 < 5 at 4 months R Yes At 12 months DLI No 12 Progression of SM and AML
49 MCL 38 10 0 at 12 months Mast cells persisted in liver biopsy R No DLI† Yes 82
50 SM-MDS-MPN Present Some mast cells < 5 at 36 months Eosinophils significantly decreased in BM R No DLI† Yes 150
51 SM-MDS Rare Rare-scattered SD No Yes 104
52 MCL > 1,200 63 3 at 1 month 80 10 0 at 1 month R (CR) Yes At 1 month DLI No 2 Progression of SM
53 SM-MDS-MPN 49 45 37 at 1 month 5 5 at 1 month SD No Yes 3
54 SM-AML 5 0 at 3 months R (CR) No No 5 AML relapse
55 SM-MPN 69.4 67 5 at 3 months 5 0 at 3 months Hepatosplenomegaly resolved R (CR) No Yes 33
56 SM-MDS-MPN > 400 > 400 16 at 3 months 15-20 30 0 at 3 months Ascites continued R No No 10 GVHD-sepsis
57 SM-AML 145 9 at 1 month 5 50 0 at 1 month Hepatosplenomegaly persisted R No No 14 AML relapse

Footnotes

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Cem Akin, Novartis (C); Peter Valent, Novartis (C) Stock Ownership: None Honoraria: Wolfgang R. Sperr, Novartis Research Funding: Gregory Vercellotti, Sangart, Seattle Genetics Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Celalettin Ustun, Hans Hagglund, Daniel Weisdorf, Cem Akin, Peter Valent

Collection and assembly of data: Celalettin Ustun, Andreas Reiter, Bart L. Scott, Ryotaro Nakamura, Gandhi Damaj, Sebastian Kreil, William J. Hogan, Miguel-Angel Perales, Tsiporah Shore, Herrad Baurmann, Robert Stuart, Bernd Gruhn, Michael Doubek, Jack W. Hsu, Eleni Tholouli, Tanja Gromke, Lucy A. Godley, Livio Pagano, Andrew Gilman, Eva Maria Wagner, Tor Shwayder, Martin Bornhäuser, Esperanza B. Papadopoulos, Alexandra Böhm, Gregory Vercellotti, Maria Teresa Van Lint, Christoph Schmid, Werner Rabitsch, Faezeh Legrand, Ibrahim Yakoub-agha, John Barrett, Olivier Hermine, Wolfgang R. Sperr, Uday Popat, Steven Devine, H. Joachim Deeg, Peter Valent

Data analysis and interpretation: Celalettin Ustun, Andreas Reiter, Bart L. Scott, Ryotaro Nakamura, Gandhi Damaj, Sebastian Kreil, Ryan Shanley, William J. Hogan, Miguel-Angel Perales, Tsiporah Shore, Herrad Baurmann, Jack W. Hsu, Martin Bornhäuser, Vinod Pullarkat, Wael Saber, John Barrett, Edwin P. Alyea, Steven Devine, H. Joachim Deeg, Daniel Weisdorf, Cem Akin, Peter Valent

Manuscript writing: All authors

Final approval of manuscript: All authors

REFERENCES