Volume 16, Issue 3 , Pages 358-367, March 2010
Outcome of Transplantation for Myelofibrosis
Article Outline
Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients.
Key Words: Myelofibrosis, Allogeneic transplantation
Introduction
Myelofibrosis (agnogenic myeloid metaplasia; primary myelofibrosis) is a clonal myeloproliferative disorder, characterized by inefficient hematopoiesis and bone marrow (BM) fibrosis [1]. The disease can present de novo (primary myelofibrosis) or following a previously known polycythemia vera or essential thrombocythemia. Clinical manifestations include anemia, splenomegaly, and cachexia [2]. Various prognostic factors, including hemoglobin and white blood cell (WBC) counts, have been used to classify patients into a “long-lived” group with a median survival of 10 years and a “short-lived” group with a median survival of 2 years [3]. Factors associated with a poorer prognosis include age >60 years, weight loss, hemoglobin <10 g/dL, WBC <4 or >30 × 109/L, and peripheral blasts 4, 5. Recently, Cervantes and colleagues [6] have published a new prognostic scoring system, based on age, constitutional symptoms, WBC, hemoglobin, and blast percentage. Investigators have studied the role of JAK-2 kinase, interleukin-8, transforming growth factor B, and impaired GATA-1 expression in the development of the disease and in an effort to improve classification and prognostic assessment 7, 8, 9.
There are several treatment approaches for patients with myelofibrosis. The median age at diagnosis is 67 years, and many elderly patients are managed with supportive care. Erythropoietin has been helpful for the treatment of anemia in some patients, and hydroxyurea has been used to control the WBC count [10]. Thalidomide combined with prednisone has been tested in a Phase II trial; 62% of patients had improvement in anemia [11]. Interferon therapy has been effective in decreasing splenomegaly, but side effects limit its use [12]. Other therapies include thalidomide derivatives, androgens, cladarabine, and splenectomy [13]. Currently, the role of JAK2 inhibitors is being investigated [14]. However, none of these treatment strategies are curative.
The only known treatment for myelofibrosis that has been shown to have curative potential is allogeneic hematopoietic cell transplantation (HCT). Several reports have shown survival rates of 40% to 60% after allogeneic transplantation. Guardiola and colleagues [15] reported a 47% 5-year probability of survival in a study of 55 patients. The Canadian group reported on 25 patients, with a projected 2-year overall survival (OS) of 41% [16]. Deeg and colleagues 17, 18 have reported a 3-year survival of 58%. Several small series of older patients transplanted with reduced-intensity conditioning (RIC) regimens have shown encouraging results, with decreased treatment-related mortality (TRM) 19, 20.
In this study, we examine the outcome of 289 primary myelofibrosis patients receiving allogeneic HCT from 1989 to 2002. This data set represents the largest series of patients transplanted for myelofibrosis and allows identification of prognostic indicators.
Patients and Methods
Data Sources
The Center for International Blood and Marrow Transplant Research (CIBMTR) is a research affiliation of the International Bone Marrow Transplant Registry (IBMTR), Autologous Blood and Marrow Transplant Registry (ABMTR), and the National Marrow Donor Program (NMDP) that comprises a voluntary working group of more than 500 transplant centers worldwide. Participating centers contribute detailed data on consecutive allogeneic and autologous HCT to a Statistical Center at the Medical College of Wisconsin. Demographic and clinical data are collected on a representative sample of patients in the registry using a weighted randomization scheme. Participating centers are required to report all consecutive transplant data; compliance is monitored by on-site audits. Patients are followed longitudinally, with yearly follow-up.
The CIBMTR collects data at 2 levels: registration and research. All CIBMTR teams contribute registration data. Research data are collected on subsets of registered patients and include comprehensive pre- and posttransplant clinical information. Computerized checks for errors, physician reviews of submitted data, and on-site audits of participating centers improve the quality of data. Observational studies conducted by the CIBMTR are done by a waiver of informed consent and in compliance with HIPAA regulations as determined by the institutional review board (IRB) and the Privacy Officer of the Medical College of Wisconsin.
Eligible Patients
Patients with primary myelofibrosis who underwent a first allogeneic BM or peripheral blood stem cell transplant (PBSCT) using an HLA matched sibling donor, unrelated donor (URD), or alternative related donor between the years 1989 and 2002 were eligible if reported to the CIBMTR. Data were reported by 118 teams from 29 countries. Patients with myelofibrosis progressing to acute leukemia (>30% BM myeloblasts) were excluded from this analysis. There were 6 patients with BM myeloblast percentage between 20% and 30%. Patients who had progressed to myelofibrosis from polycythemia vera or essential thrombocythemia were also excluded. All surviving recipients receiving a transplant from a URD included in this analysis were retrospectively contacted and provided informed consent for participation in the NMDP. Informed consent for retrospective data analysis was waived by the NMDP IRB for all deceased patients. The NMDP IRB had only 1 member affiliated with the NMDP. Surviving participants who did not provide informed consent to allow analysis of clinical data were excluded. Three patients were excluded by this corrective action plan. To adjust for the potential bias introduced by exclusion of nonconsenting surviving patients, a corrective action plan (CAP)-modeling process randomly excluded approximately the same percentage of deceased patients using a biased coin randomization with exclusion probabilities based on characteristics association with not providing consent for use of the data in survivors [21].
Endpoints
Primary endpoints were hematopoietic recovery, acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), OS, and response. Hematopoietic recovery was defined as time to neutrophils (absolute neutrophil count [ANC]) >0.5 × 109/L for 3 consecutive days and time to platelets ≥20 × 109/L. aGVHD was defined as the occurrence of grade II, III, or IV skin, gastrointestinal (GI), or liver abnormalities fulfilling the Glucksberg criteria of aGVHD [22]. cGVHD was the occurrence of symptoms in any organ system fulfilling the criteria of cGVHD. OS was defined as the time to death. Patients were censored at time of last follow-up. Graft failure was defined by no neutrophil engraftment by day 35. Response and treatment failure, when possible, were defined according to the criteria of Guardiola et al: (1) hematologic remission (normal PB counts, disappearance of symptoms, splenomegaly, and cytogenetic abnormalities), (2) complete histohematologic remission (hematologic remission plus disappearance of the marrow fibrosis), (3) partial histohematologic remission (hematologic remission plus partial reduction of marrow fibrosis), and (4) treatment failure (disease recurrence or persistence) [15]. Disease free survival (DFS) was considered a continuous complete hematologic remission after transplant.
Statistical Analysis
Descriptive tables of patient-, disease-, and treatment-related factors list median and range for continuous variables and percent of total for categoric variables. The product-limit estimator proposed by Kaplan-Meier was used to estimate the median and range of the follow-up time. Probabilities of DFS and OS were calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood's formula. Variables for other endpoints were generated using cumulative incidence estimates [23]. Comparison of survival curves was done using the log-rank test. Multivariate analyses were performed using proportional hazards models. These analyses fit models to determine which risk factors may be related to a given outcome. All variables were first examined to assure that they comply with the proportional hazards assumption. Factors found to have nonproportional hazards were adjusted in subsequent analyses. A stepwise model building approach was used to develop models for relapse, TRM, DFS, and OS. A CAP modeled data set was used in this article. No further statistical adjustments were made. This CAP modeling procedure was reviewed and approved by the NMDP IRB. The corrective action plan was submitted to the Office for Human Research Protection (OHRP) and approved by the division of compliance oversight. This methodology has been extensively used and published by all studies from the CIBMTR using the NMDP datasets. The CAP model was developed on a sample of 3693 survivors, of which 2966 (80.3%) had given consent to have their data used. The predictive model for consent included indicators of age group, disease, stem cell source, patient cytomegalovirus (CMV) status, and sex, and had an area under the curve (AUC)/C statistic of 0.75.
Results
Patient and Disease-Related Characteristics
Table 1 outlines the characteristics of patients receiving allogeneic transplants for myelofibrosis. All patients were reported by the transplant center as having primary myelofibrosis, without prior polycythemia vera or essential thrombocythemia. One hundred sixty-two recipients underwent an HCT from HLA identical sibling donors, 101 from URD, and 26 patients from other related donors. The median ages at transplantation for these 3 groups were 45 years, 49 years, and 46 years, respectively. The majority of patients had moderate or severe fibrosis in the BM at the time of transplant, as graded by the transplant center. There was no uniform assessment of marrow fibrosis. Nine patients had an elevated WBC count of >30,000/μL and a hemoglobin of <10 g/dL at the time of transplant. Splenectomy had been performed in 18% of the identical sibling recipients, 38% of the URD patients, and 13% of the patients receiving alternative related donor transplants. Among the patients without a splenectomy, 58% of the identical sibling recipients, 68% of the URD recipients, and 40% of the other related donor recipients had splenomegaly at the time of transplantation. The presence of splenomegaly was reported by the transplant center, and may have been based on physical examination or radiographic findings, or both. The median follow-up was 41, 48, and 46 months, respectively. The indication for transplantation was not ascertained on the CIBMTR forms. Thirty-two percent of patients had a Lille score of 0, 36% a Lille score of 1, and 31% a Lille score of 2.
Table 1. Characteristics of Adult Patients Receiving Allogeneic Transplantation between 1989 and 2002 for Myelofibrosis Reported to the CIBMTR
| Variables | N eval | Identical Sibling | N eval | Other related | N eval | Unrelated |
|---|---|---|---|---|---|---|
| Number of patients | 162 | 26 | 101 | |||
| Age at transplant, N (%) | 162 | 45 (18-73) | 26 | 46 (20-65) | 101 | 49 (18-70) |
 <45 years | 80 (49) | 12 (46) | 33 (33) | |||
| ≥45 years | 82 (51) | 14 (54) | 68 (67) | |||
| Male sex, N (%) | 162 | 101 (62) | 26 | 18 (69) | 101 | 60 (59) |
| Karnofsky score prior to transplant | 158 | 25 | 97 | |||
| <90 | 63 (40) | 9 (36) | 49 (51) | |||
| ≥90 | 95 (60) | 16 (64) | 48 (49) | |||
| Blast in peripheral blood prior to transplant, N (%) | 140 | 50 (36) | 17 | 8 (47) | 90 | 43 (48) |
| Splenectomy prior to transplant, N (%) | 153 | 27 (18) | 23 | 3 (13) | 92 | 35 (38) |
| Splenomegaly prior to transplant, N (%) (Among patients without splenectomy) | 126 | 73 (58) | 20 | 8 (40) | 57 | 39 (68) |
| Time from diagnosis to transplant, median(range) in months | 162 | 11 (1-196) | 26 | 11 (2-157) | 101 | 13 (1-284) |
| <24 months | 113 (70) | 19 (73) | 66 (65) | |||
| ≥24 months | 49 (30) | 7 (27) | 35 (35) | |||
| Cytogenetics prior to transplant, N(%) | 61 | 8 | 27 | |||
| Normal | 32 (52) | 5 (63) | 13 (48) | |||
| Abnormal | 29 (48) | 3 (37) | 14 (52) | |||
| Hemoglobin prior to transplant, N (%) | 133 | 20 | 64 | |||
| <10 g/dL | 75 (56) | 15 (75) | 34 (53) | |||
| ≥10 g/dL | 58 (44) | 5 (25) | 30 (47) | |||
| Graft type, N (%) | 162 | 26 | 101 | |||
| BM | 95 (59) | 14 (54) | 74 (73) | |||
| PBSC/BM + PBSC | 67 (41) | 12 (46) | 27 (27) | |||
| WBC count, N(%) | 153 | 22 | 70 | |||
| ≤30,000/ μL | 143 (93) | 22 (100) | 59 (84) | |||
| >30,000/μL | 10 (7) | --- | 11 (16) | |||
| Conditioning regimens types N (%) | 162 | 26 | 101 | |||
| Cy+tbi±others | 41 (25) | 6 (23) | 43 (42) | |||
| By+cy | 86 (53) | 16 (62) | 23 (23) | |||
| Flu + TBI | 2 (1) | --- | 12 (12) | |||
| Flu+other | 2 (1) | --- | 1 (1) | |||
| Bu | 16 (10) | 3 (11) | 8 (8) | |||
| Mel | 6 (4) | 1 (4) | 6 (6) | |||
| TBI | 4 (3) | --- | 8 (8) | |||
| Others | 5 (3) | --- | --- | |||
| Conditioning regimen, N (%) | 162 | 26 | 101 | |||
| TBI | 48 (30) | 6 (23) | 63 (62) | |||
| Non-TBI | 114 (70) | 20 (77) | 38 (38) | |||
| Regimen types, N (%) | 162 | 26 | 101 | |||
| Ablative | 134 (83) | 23 (88) | 72 (71) | |||
| Nonmyeloblative/reduced intensity | 28 (17) | 3 (12) | 29 (29) | |||
| ATG given as conditioning or GVHD prophylaxis | 162 | 26 | 101 | |||
| No | 144 (89) | 20 (77) | 79 (78) | |||
| Yes | 18 (11) | 6 (23) | 22 (22) | |||
| GVHD prophylaxis | 162 | 26 | 101 | |||
| MTX + CsA ± other | 102 (62) | 12 (46) | 54 (53) | |||
| MTX ± other | 1 (1) | --- | --- | |||
| FK506± other | 18 (11) | 2 (8) | 25 (25) | |||
| CsA ± other | 36 (22) | 6 (23) | 19 (19) | |||
| T-depletion ± other | 3 (2) | 1 (4) | 2 (2) | |||
| Cortico ± other | 1 (1) | --- | --- | |||
| Other or none | 1 (1) | 5 (19) | 1 (1) | |||
| Year of transplant, N (%) | 162 | 26 | 101 | |||
| 1989-1995 | 55 (34) | 5 (19) | 13 (13) | |||
| 1996-2002 | 107 (66) | 21 (81) | 88 (87) | |||
| HLA matching | NA | 26 | 101 | |||
| Well matched | --- | 38 (37) | ||||
| Partially matched | 5 (19) | 34 (34) | ||||
| Mismatched | 14 (54) | 19 (19) | ||||
| HLA data missing | 7 (27) | 10 (10) | ||||
| Median (range) follow-up, months | 162 | 41 (3-144) | 26 | 46 (12-118) | 101 | 48 (4-124) |
Transplant characteristics are outlined in Table 1. The majority of patients received BM as a source of stem cells. Thirty percent of the identical sibling transplantations, 62% of the URD transplantations, and 23% of the other related donor transplantations were performed with total body radiation (TBI) as part of the conditioning regimen. The majority of patients received a myeloablative (MA) conditioning regimen. T cell depletion was used in <5% of patients in all groups. For the purpose of classification of HLA matching, the new classification system proposed by Wesidorf et al. [24] for retrospective studies was used.
TRM
At 100 days, the TRM was 18% for the identical sibling transplants, 35% for the URD patients, and 19% for the other related donor patients. For the HLA identical sibling transplants, TRM was 27% at 1 year, and 35% at 5 years. TRM was 24% at 1 year and 38% at 5 years for patients using a related donor graft not from an HLA identical sibling. The URD patients, as expected, experienced higher TRM (P = .02 at 5 years for HLA identical siblings versus URDs). TRM was 43% at 1 year, and 50% at 5 years in this group. TRM, relapse rate, DFS, and OS are presented in Table 2. TRM by donor type is summarized in Figure 1.
Table 2. Survival Analysis of Transplant Outcomes among Patients Receiving Allogeneic Transplantation between 1989 and 2002 for Myelofibrosis Reported to the CIBMTR
| Identical Sibling | Other Related | Unrelated | ||||
|---|---|---|---|---|---|---|
| Outcomes | N eval | Probability (95%CI) | N eval | Probability (95% CI) | N eval | Probability (95% CI) |
| ANC500 @ 100 days | 162 | 95 (91-98)% | 26 | 73 (56-87) % | 101 | 83 (76-90) % |
| PLT20 @ 12 months | 159 | 79 (72-85) % | 26 | 54 (35-72) % | 98 | 59 (49-69) % |
| aGVHD@ 100 days | 162 | 43 (35-50) % | 25 | 24 (10-42) % | 99 | 40 (31-50) % |
| cGVHD @ 24 months | 161 | 40 (32-48) % | 26 | 23 (10-41) % | 101 | 32 (23-41) % |
| Relapse | 160 | 25 | 100 | |||
| @ 1 year | 25 (18-32)% | 12 (2-28)% | 21 (13-29)% | |||
| @ 3 years | 28 (21-35)% | 18 (5-38)% | 23 (15-32)% | |||
| @ 5 years | 32 (24-41)% | 40 (11-74)% | 23 (15-32)% | |||
| TRM | 160 | 25 | 100 | |||
| @ 100 days | 18 (12-24)% | 19 ( 5-38)% | 35 (26-44)% | |||
| @ 1 year | 27 (20-34)% | 24 ( 9-44)% | 43 (33-53)% | |||
| @ 3 years | 32 (25-40)% | 38 (17-62)% | 48 (38-58)% | |||
| @ 5 years | 35 (27-43)% | 38 (17-62)% | 50 (39-61)% | |||
| DFS | 160 | 25 | 100 | |||
| @ 1 year | 48 (40-56)% | 64 (43-82)% | 37 (27-47)% | |||
| @ 3 years | 40 (32-48)% | 43 (21-67)% | 29 (20-39)% | |||
| @ 5 years | 33 (25-42)% | 22 (1-59)% | 27 (18-37)% | |||
| Survival probability | 162 | 26 | 101 | |||
| @ 1 year | 54 (46-62)% | 60 (39-79)% | 41 (31-51)% | |||
| @ 3 years | 44 (36-52)% | 40 (19-63)% | 33 (23-43)% | |||
| @ 5 years | 37 (26-46)% | 40 (19-63)% | 30 (20-40)% | |||
Figure 1
Cumulative incidence of nonrelapse mortality after receiving allogeneic HCT by donor type for myelofibrosis reported to the CIBMTR between 1989 and 2002.
Engraftment
Neutrophil engraftment occurred in 95% of the matched sibling patients at a median of 18 days. The engraftment rate was lower for alternative donor patients, 73% for patients receiving grafts from other related donors, and 83% for patients receiving grafts from URD. Thirty-two patients did not achieve an ANC of 500; 17 of these patients were URD transplant, 8 HLA identical sibling, and 7 other related donors transplant recipients. Platelet engraftment occurred at a median of 27 days. Graft failure occurred in 9% of the patients receiving grafts from HLA identical group, 27% from other related group, and 20% from the URD group. Thus, graft failure is an important limitation of transplantation from alternative donors in this disease. Graft failure rate was not increased in patients with splenomegaly. Graft failure was seen in 13.3% of patients with splenomegaly versus 13.2% in those patients without splenomegaly. However, the determination of splenomegaly may have been suboptimal as splenomegaly was reported by transplant centers as being present or absent. The size of the spleen and the method for determining splenomegaly was not reported. The graft failure rate was 15.3% for patients who had a prior splenectomy. The median time to engraftment was not significantly different in patients with or without splenomegaly (19 days versus 17 days, respectively). Seven patients received a second transplant for graft failure.
GVHD
Grade II-IV aGVHD occurred in 43% of matched sibling patients, 40% of URD patients, and 24% of other related donors (Figure 2). cGVHD was reported in 40% of matched sibling patients, 32% of URD patients, and 23% of other related donors. There was no effect of GVHD on relapse or survival. Only 7 patients were reported as receiving donor lymphocyte infusions (DLIs; 5 from matched sibling donors and 2 from URD); 4 of these patients (all matched siblings) died of disease progression.
Figure 2
Cumulative incidence of relapse after receiving allogeneic HCT by donor type for myelofibrosis reported to the CIBMTR between 1989 and 2002.
Relapse Rate
Relapse rates are summarized in Table 2. At 1 year after HCT, the cumulative incidence of relapse was 25%, 21%, and 12% in recipients of HLA identical sibling donor, URD, or alternative donor transplants, and increased to 32%, 23%, and 40%, respectively, at 5 years posttransplant (P value of .65 for HLA identical siblings versus other donors). Disease relapses continue to occur beyond 3 years in some patients. Relapse by donor type is summarized in Figure 2.
DFS and OS
Probability of OS at 1 year was 54%, 41%, and 60% in the HLA-identical sibling, URD, and other related transplants, respectively. OS is outlined in Figure 3. Probability of OS at 5 years posttransplantation was 37%, 30%, and 40%, respectively (P = .94 for HLA identical sibling versus other donor transplants). Probability of DFS at 5 years was comparable among the different donor groups at 33%, 27%, and 22% for HLA-identical sibling, URD, and other related transplants, respectively, P = .64 for HLA identical siblings versus other donors.
Figure 3
Survival probability of adult patients receiving allogenic transplantation (HLA identical sibling donor and unrelated donor) for myelofibrosis reported to the CIBMTR between 1989 and 2002.
Causes of Death
The causes of death posttransplantation are listed in Table 3. Causes of death were provided by the transplant centers. The primary cause of death in the HLA identical sibling patients was progressive disease, followed by infection and organ failure. In the URD patients, the most common cause of death was infection, followed by GVHD. Patients who died of infection may also have had GVHD; 17 of 35 patients who died of infection also were reported as having GVHD. For the other related donor group, the most common causes of death were progressive disease and organ failure. Deaths from graft failure may be difficult to ascertain, as many of these patients may be coded as dying of infection.
Table 3. Causes of Death in Adult Patients Receiving Allogenic Transplantation between 1989 and 2002 for Myelofibrosis Reported to the CIBMTR
| HLA sibs | Other | Unrelated | |
|---|---|---|---|
| Causes of Death | N (%) | N (%) | N (%) |
| Number of patients | 162 | 26 | 101 |
| Number of deaths | 89 (55) | 18 (69) | 71 (70) |
| Primary disease | 24 (30) | 3 (17) | 9 (16) |
| Infection | 20 (25) | 1 (5) | 14 (25) |
| Interstitial pneumonitis | 2 (3) | --- | 2 (3) |
| GVHD | 7 (9) | 1 (5) | 10 (18) |
| Organ failure | 10 (12) | 3 (17) | 7 (12) |
| Graft failure | --- | 1 (5) | 2 (3) |
| ARDS | 1 (1) | --- | 1 (1) |
| Bleeding | 4 (5) | 2 (12) | 2 (4) |
| Other | --- | 2 (12) | 1 (2) |
| Secondary malignancy | 1 (1) | 1 (5) | --- |
| Unknown | 12 (15) | 3 (17) | 9 (16) |
| Missing | 8 (9) | 1 (5) | 14 (20) |
Predictors for Superior DFS
Multivariate analysis was performed for patients receiving transplant from HLA-identical sibling and URDs. Table 4 lists the variables examined in the multivariate model. The final multivariate model is illustrated in Table 5. In multivariate analysis, performance status <90% (relative risk [RR] 1.41 [95% CI, 1.04-1.92], P = .0284) and the presence of PB blasts (RR 1.75 [95% CI 1.24-2.47], P = .0013) predicted for worse DFS. Patients who received a transplant from a URD had a trend toward lower DFS. DFS for recipients of URD transplant with poor Karnofsky score and PB blasts was 29% and 15% at 1 year and 3 years, respectively (Figure 4). Among 56 patients with favorable risk factors (HLA identical sibling donor, performance status ≥90%, and no PB blasts) 1- and 3-year probabilities of survival were 69% and 60%, respectively (Figure 5). WBC count, splenomegaly, hemoglobin at transplant, and a prior splenectomy were not predictive of DFS. The Lille score was available on 198 patients. There was no difference in DFS based on Lille score.
Table 4. Variables Examined in the Multivariate Analysis
| Patient related: |
| - Age (<45 years versus ≥45 years) |
| - Sex (male versus female) |
| - Karnofsky performance status (<90% versus ≥90%) |
| Disease related: |
| - Subdisease (myeloid metaplasia versus acute or myelosclerosis) |
| - Fibrosis in marrow prior to conditioning (Grade III [osteomyelosclerosis] versus other) |
| - Peripheral blood blasts (present versus absent) |
| - Splenomegaly prior to conditioning (yes versus no versus splenectomy) |
| - Time from diagnosis to HSCT (<24 months versus ≥24 months) |
| - Cytogenetics prior to conditioning (normal versus other) |
| - Hemoglobin at time of transplant (<10 versus ≥10) |
| Transplant related: |
| - Source of stem cells (BM versus PBSC/both) |
| - Conditioning Regimen (TBI versus non-TBI) |
| - Myeloblative versus reduced-intensity conditioning or nonmyeloblative |
| - Year of BMT (<1996 versus ≥1996) |
Table 5. Multivariate Analysis of Disease-Free Survival for Adult Myelofibrosis Patients Receiving HLA Siblings or Unrelated Transplants between 1989 and 2002, Reported to the CIBMTR (Patients with Missing Relapsed Data Were Excluded)
| Variables | N | Relative Risk | P-Value |
|---|---|---|---|
| Donor | |||
| HLA-identical sibling | 156 | 1.00 | |
| Unrelated | 96 | 1.32 (0.96-1.83) | .0924 |
| Karnofsky performance status | |||
| ≥90 | 142 | 1.00 | |
| <90 | 110 | 1.41 (1.04-1.92) | .0284 |
| Blast in peripheral blood prior to transplant | |||
| Absent | 133 | 1.00 | .0045 (2 df) |
| Present | 86 | 1.75 (1.24-2.47) | .0013 |
| Missing | 33 | 1.53 (0.95-2.48) | .0819 |
| Splenomegaly prior to conditioning | |||
| No | 70 | 1.00 | .5332 (3 df) |
| Yes | 106 | 0.81 (0.56-1.17) | .2508 |
| Splenectomy | 58 | 0.77 (0.49-1.21) | .2573 |
| Missing | 18 | 1.03 (0.56-1.90) | .9228 |
| Fibrosis in marrow prior to conditioning (osteomyelosclerosis) | |||
| No | 74 | 1.00 | .1352 (2 df) |
| Yes | 79 | 1.52 (1.01-2.29) | .0455 |
| Missing | 99 | 1.28 (0.86-1.91) | .2292 |
Figure 4
DFS probability of adult patients receiving HLA-identical sibling HCT by different risk groups for myelofibrosis reported to the CIBMTR between 1989 and 2002.
Figure 5
Survival probability of adult patients receiving unrelated donor allogeneic HCT by different risk groups for myelofibrosis reported to the CIBMTR between 1989 and 2002.
RIC/Nonmyeloablative Transplants
Seventeen percent of the HLA identical sibling donor recipients and 29% of the URD recipients received RIC or nonmyeloablative (NMA) conditioning transplants. Conditioning regimens were categorized as RIC or NMA using consensus criteria proposed by the Regimen-Related Toxicity Working Committee of the CIBMTR. Regimens employing TBI ≤500 cGy as a single fraction or ≤800 cGy if fractionated, busulfan (Bu) doses ≤9 mg/kg, or melphalan (Mel) doses ≤150 mg/m2 were categorized as RIC. Regimens using fludarabine (Flu) without Bu and/or Mel and regimens using TBI doses of 200 cGy (with or without Flu) were categorized as NMA. Regimens that did not fit these criteria were assigned by the authors based on recommendations of the Regimen-Related Toxicity Working Committee [25]. Of these, 21 recipients received an NMA regimen and 39 received an RIC regimen. A total of 21 patients received BMT (17 RIC, 4 NMA) and 39 received a PBSCT (22 RIC, 17 NMA). Graft failure was seen in 7 patients (6 RIC, 1 NMA), 4 of these received a PBSCT. All of these 7 patients died. One died of graft failure, 1 died of organ failure, 1 died of infection, 1 died of primary disease, and cause of death was unknown for 3 remaining patients. One hundred-day TRM for the RIC sibling donor transplants was 11%. One-year TRM for these patients was 15%. DFS at 3 years was 39%, which is comparable to that seen in the MA transplant group. However, for the 28 URD RIC transplant recipients, the TRM at 1 year was 49%, and DFS at 3 years was only 17%.
Discussion
Allogeneic HCT is a therapeutic option for some patients with myelofibrosis. Myelofibrosis is incurable with standard chemotherapy. Autologous transplantation has been investigated in a small series of patients, but is not thought to be curative for this clonal stem cell disorder [26]. Mittal et al. [27], Ditschkowski et al. [28], Deeg et al. [17], Guardiola et al. [15], Kerbauy et al. [18], and Daly et al. [16] have reported on the results of allogeneic HCT for myelofibrosis. These series have reported 3-year probabilities of OS of 37% to 58%. An updated report from Seattle describes 104 patients with myeloproliferative disorders, including 62 with chronic idiopathic myelofibrosis [29]. Use of a targeted Bu/cyclophosphamide (Cy) regimen, younger age, and low comorbidity score predicted for improved survival. Patriarca and colleagues [30] have recently reported on 100 myelofibrosis patients from 26 Italian centers. Three-year OS was 42%, with a trend to improved survival in patients receiving PBSCs as the graft source.
In this current study, we extend the observations of these investigators, using the resources of the CIBMTR. Two hundred eighty-nine adult patients contributed data to the analysis, the largest reported series of transplantation for myelofibrosis. The analysis was hampered by its retrospective nature and included patients treated in many transplant centers with a variety of conditioning regimens. The majority of patients received MA conditioning regimens, and, as expected, had a median age lower than the median age reported for myelofibrosis patients at diagnosis. In addition, diagnosis was not confirmed by central pathology review. Given the low rate of splenomegaly (58% for patients receiving sibling donor transplants) it is possible that some patients may have been misclassified at the transplant center. The definition of response proposed by Guardiola and the International Working Group [31] was published after many of the transplants reported here had been performed. Therefore, relapse and DFS data were not based on those criteria and may be difficult to interpret. Cytogenetic analysis was missing for many patients. Because of missing data, Cervantes and Dupriez scores could not be used in a multivariate analysis. Multivariate analysis was not performed for the alternative donors, because of the small sample numbers. In addition, Jak2 kinase information was not available on our patients, as the patients were all transplanted before 2002.
The 3-year probability of OS was 44% for patients receiving transplants from HLA matched sibling donors, similar to outcomes reported in other series. As expected, TRM was higher for URD recipients. Disease relapses continue to be seen beyond 3 years in some patients. Multivariate analysis indicated that an HLA identical sibling donor, performance status 90% or greater, and absence of PB blasts predicted for superior DFS. Patients transplanted with a URD, poor Karnofsky score, and presence of blasts in PB did worse with a 15% 3-year DFS. Small patient numbers precluded further analysis as to unrelated donor match and survival. Guardiola and others [15] also identified high pretransplant hemoglobin and the absence of grade III fibrosis as positive predictors of survival.
The issue of splenectomy prior to transplant is controversial [29]. Li and colleagues [32] showed faster neutrophil engraftment (18 versus 23 days) for 26 patients receiving high-dose conditioning and allogeneic HCT. However, an operative mortality rate of up to 8% has also been reported 33, 34. In our series, approximately 25% of patients had received a splenectomy prior to transplant. Splenectomy did not predict for better survival;, however, the study was not designed to test this particular issue. The graft failure was high in patients receiving URD and alternative donor transplants, but was not influenced by splenomegaly.
Point mutation in the JAK-2 gene is now reported in approximately 50% to 60% of patients with myelofibrosis. The significance of the mutation for long-term outcomes posttransplant is unknown. Kroger and colleagues [35] reported on 41 patients receiving allogeneic transplantation for myelofibrosis; 51% were positive for the V617F point mutation in JAK2. Seventy-eight percent of patients became JAK2 mutation-negative after a median of 89 days after HCT. Clinical trials with oral JAK2 kinase inhibitors are in progress.
Recently, several investigators have analyzed results of transplantation using RIC regimens 36, 37, 38, 39. RIC regimens may be appropriate for a disease such as myelofibrosis, because of the older age of the population. Kroger and colleagues [35] treated 24 patients with myelofibrosis with a conditioning regimen of Flu, Bu, and antithymocyte globulin (ATG), followed by related donor (n = 6) or URD (n = 18) transplantation [20]. There were no graft failures and no 100-day TRM. At 3 years, the estimated DFS was 84%. Seventy-eight percent of JAK2 kinase mutated patients became PCR negative for the JAK2 mutation. Rondelli et al. [19] reported on another cohort of 21 patients treated with a variety of fludarabine-based reduced intensity regimens. DFS was 74% at 3 years. The Swedish group reported on 27 patients: 17 with an MA regimen, and 10 with an RIC regimen [40]. As expected, TRM was less in the patients receiving an RIC regimen (10% versus 30%). With a median follow-up of 55 months, 9 of 10 RIC patients and 9 of 16 MA patients are alive. In our series, 60 patients were treated with NMA or RIC regimens. The TRM at 1 year was lower for HLA-identical sibling recipients of HCT using RIC regimens, but remained high in URD recipients. RIC HLA-identical sibling HCT may be an attractive option for older patients with myelofibrosis, and should be the subject of further study in large cohorts of patients; a prospective international trial will be addressing this issue.
This analysis suggests that allogeneic HCT for myelofibrosis is being performed in many centers worldwide, with long-term survival rates of 30% to 40%, depending on donor source. Several investigators have examined prognostic factors to guide the timing of transplantation 41, 42. Future research will focus on the selection of the appropriate patients, conditioning regimen, and timing of transplantation.
CIBMTR Support List
Financial disclosure: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); 2 Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; PDL BioPharma, Inc; Pfizer Inc; Pharmion Corporation; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; Teva Pharmaceutical Industries;; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.
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Financial disclosure: See Acknowledgments on page 366.
PII: S1083-8791(09)00496-0
doi:10.1016/j.bbmt.2009.10.025
© 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 16, Issue 3 , Pages 358-367, March 2010
