Stem Cell Transplantation For Myelofibrosis Research Articles

Graft Failure Following Allogeneic Stem Cell Transplantation for Primary Myelofibrosis: A Case Report

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by marrow fibrosis, splenomegaly with cytopenias, constitutional symptoms and poor quality of life. Rates of graft failure following allogeneic stem cell transplantation range from 0 to 5%, being more frequent in non-HLA identical donors. Here we present an infrequent complication, a graft failure in a patient following identical sibling donor stem cell transplantation for myelofibrosis with objective indicators of disease remission. J Med Cases. 2014;5(2):76-79 doi: http://dx.doi.org/10.14740/jmc1639w

Impact Of Conditioning Regimen, Donor Source, and DIPSS Score On Outcome Of Allogeneic Hematopoietic Stem Cell Transplantation For Myelofibrosis

To investigate impact of conditioning regimen, donor source, and Dynamic International Prognostic Scoring System (DIPSS) on outcome of allogeneic hematopoietic stem cell transplantation for myelofibrosis, we analyzed results in 388 patients transplanted between 1990 and 2011 in three major transplant centers (Essen, Germany: n = 63; Hamburg, Germany; n = 156; Seattle, USA: n = 169), including 216 male and 171 female patients, 18 – 79 (median 54) years old, with either primary (n = 283) or post ET/PV (n = 150) myelofibrosis who received myeloablative (n = 190), reduced intensity (n = 182), or non-myeloablative (n = 16) conditioning and were given stem cells from related (n = 156, including 152 HLA-identical siblings, 1 haplo-identical relative, and 3 identical twins ) or unrelated donors (n = 232; 175 were HLA-matched and 57 were HLA-mismatched). Stem cell source was bone marrow (n = 51) or peripheral blood (n = 337). According to DIPSS at time of transplantation patients were classified as low (n = 35), intermediate-1 (n = 106), intermediate-2 (n = 161), or high (n = 84) risk. The conditioning regimen consisted of busulfan 16 mg/kg and cyclophosphamide (n = 136), busulfan 10 mg//kg and fludarabine (n = 154), treosulfan-based (n = 26), TBI 12 Gy-based (n = 52), or low dose TB 2 Gy and fludarabine (n = 16), and melphalan 140 mg/m2 and fludarabine (n = 4).After a follow-up of 3.5 – 7.7 (median 5) years the 1-year non-relapse mortality (NRM) of the entire study cohort was 24% (95% CI: 20 – 28). In multivariate analysis significant factors for NRM were age as continuous variable (HR: 1.029; 95% CI: 1.011 – 1.048, p = 0.002), HLA mismatch (HR: 2.026; 95% CI: 1.318 – 3.113, p = 0.001), and TBI containing conditioning (HR 1.872; 95% CI: 1.198 – 2.926, p = 0.006). The cumulative incidence of relapse was 17% (95% CI: 13 – 21) at 5 years, negatively impacted by age as continuous variable (HR: 1.030; 95% CI: 1.003 – 1.057, p = 0.028), unrelated donors (HR: 0.560; 95% CI: 0.339 – 0.926, p = 0.024), and the use of ATG (HR: 2.425; 95% CI: 1.342 – 4.381, p = 0.003) or campath (HR: 3.257; 95% CI: 2.129 – 6.985, p < 0.0001 The estimated 3 and 5 year overall survival for the study group was 62% (95% CI: 56 – 68%) and 59% (95% CI: 53 – 65%), respectively. Significant factors for 5-year survival in the univariate analysis were HLA-matched vs. mismatched donor (61% vs. 47%, p = 0.05), related vs. unrelated donors (65% vs. 54%, p = 0.03), high dose conditioning vs. RIC vs. NMA (58% vs. 61% vs. 32%, p = 0.04), non TBI vs. TBI containing conditioning regimens (62% vs. 42%; p = 0.001), and DIPSS score at transplantation (low 83% vs. intermediate-1 64% vs. intermediate-2 58% vs. high risk 45%; p < 0.001). In the multivariate analysis for survival significant factors were age as continuous variable (HR: 1.027; 95% CI: 1.009 – 1.045; p = 0.004), DIPSS score: intermediate-1 (HR: 1.662, p = 0.3), intermediate-2 (HR: 2.069, p = 0.09), high (HR: 2.924, p = 0.02), and TBI-containing conditioning regimen (HR: 1.973; p < 0.001). ConclusionThis analysis of results in a large cohort of patients confirms a high success rate of allogeneic hematopoietic stem cell transplantation for myelofibrosis significantly impacted by DIPSS classification at the time of transplantation. In addition the analysis confirms the risk factors of patient age and donor HLA-mismatch. Furthermore, the data show similar results between RIC and MAC, but less favorable outcome with TBI containing conditioning, regardless of the dose of TBI. Novel approaches need to be developed, particularly for patients with more advanced disease. ContributionThe authors NK and MD contributed equally. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Myelofibrosis with Leukemic Transformation: A Study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation

Transformed acute myeloid leukemia in myelofibrosis results in a median survival of less than 5 months. We identified 46 of 1048 myelofibrosis patients in the European Group for Blood and Marrow Transplantation registry who received allogeneic stem cell transplantation for acute leukemia evolving from myelofibrosis. The cumulative incidence of treatment-related mortality at 1 year was 28% (95% confidence interval, 14 to 42) and of relapse at 3 years was 47% (95% confidence interval, 31 to 63). The 3-year progression-free (PFS) and overall survival (OS) rates were 26% and 33%, respectively. The only significant factor for survival was complete remission versus no complete remission before transplantation (69% versus 22%, P = .008); however, complete remission was achieved only in 8 patients. Allogeneic stem cell transplantation can cure myelofibrosis patients transformed to leukemia.

Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Comparison Between Myeloablative and Reduced Intensity Conditioning

Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Comparison Between Myeloablative and Reduced Intensity Conditioning

Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis

Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis. We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55 ± 7.5 months. Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001). The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation.

Allogeneic Stem Cell Transplantation for Myelofibrosis in 2012

Myelofibrosis (MF) is a heterogeneous disease for which long-term, effective medical therapeutic options are currently limited. The role of allogeneic haematopoietic stem cell transplant (AHSCT) in this population, many of whom are elderly, often provides a challenge with regard to the identification of suitable candidates, timing of transplantation in the disease course and choice of conditioning regimen. This review summarizes key findings from published data concerning AHSCT in MF and attempts to provide a state of the art approach to MF-AHSCT in 2012. In addition, we postulate on how the era of JAK inhibition might impact on transplantation for MF.

Splenic Irradiation as a Component of a Reduced-Intensity Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Myelofibrosis with Massive Splenomegaly

Primary myelofibrosis is a hematologic neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. A similar clinical condition can occur at late stage of myeloproliferative neoplasms such as polycythemia vera and essential thrombocythemia. Although allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy for both conditions, massive splenomegaly frequently observed in patients with myelofibrosis is considered to be a risk factor for graft failure or engraftment delay after transplantation. A proportion of patients can benefit from splenectomy before transplantation but such procedures have been associated with substantial surgical morbidity. Here, we report two elderly patients with myelofibrosis who received scheduled splenic irradiation for massive splenomegaly immediately prior to allogeneic HSCT instead of undergoing splenectomy. The first patient was a 60-year-old woman who received peripheral blood stem cell transplantation for post-essential thrombocythemia myelofibrosis from an HLA-identical sibling; the second patient was a 60-year-old man who received unrelated bone marrow transplantation for primary myelofibrosis. After receiving fractionated splenic irradiation and fludarabine-based reduced-intensity conditioning regimens, these patients showed remarkable reduction of their splenomegaly at the time of transplantation. They attained successful donor cell engraftment without severe complications related to splenic irradiation, while improvement in splenomegaly was durable. Our experience suggests that splenic irradiation before allogeneic HSCT might be a safe and effective alternative to splenectomy for myelofibrosis patients with massive splenomegaly in terms of reducing the risk of surgical morbidity.

Long Term Follow-up of the Prospective Multicenter Study of reduced-Intensity Allogeneic Stem Cell Transplantation for Primary or Post ET/PV Myelofibrosis

Abstract 1019Allogeneic stem cell transplantation is the only curative treatment for myelofibrosis. Here we present a long–term follow up of patients with myelofibrosis treated with reduced-intensity allogeneic stem cell transplantation in the prospective multicenter study conducted by the MDS subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) (study registration NCT 00599547).From 2002 to 2007, a total of 103 patients with primary (63 pts) or post-polycythemia vera and –essential thrombocythemia myelofibrosis (40 pts) from seventeen transplantation centers in three nations were included in the study. There were 62 males and 41 females with a median age of 55 years (range, 32–68 years). Risk profile according to Lille score was low risk with constitutional symptoms (17%), intermediate risk (53%) and high risk (30%). All but three of the patients received peripheral stem cells as stem cell source from either related (n=33) or unrelated donor (n=70) and a conditioning with Busulfan (10mg/kg orally or 8mg/kg intravenously),Fludarabin (180 mg/m2) and antithymocyte-globulin (ATG-Fresenius®) according a previously published protocol. According to high-resolution HLA typing, 21 patients had at least one allele or antigen HLA mismatch. From 88 patients with a known JAK2V617F-status 63 harbored the mutation.After a median follow up of 60 months (range 9–109 months), 41 patients had chronic graft vs. host disease which was extensive in the half of cases. The 5-year and 8-year estimated overall survival (OS) was 68% and 65%, respectively with a stable plateau after 5,3 years follow up (Figure-1). Estimated 5-year disease-free survival was 40%. The cumulative incidence of relapse/progression at 3 and 5 years was 22% and 28% and the non-relapse mortality at 1 and at 3 years was 18% ands 21%, respectively. [Display omitted] Within the overall follow up period, relapse/progression occurred in 28 patients. Twenty one of them were treated with donor-lymphocyte infusions (DLI) and/or a second allogeneic transplantation (n=11). Sixteen of those were at the last follow up alive. The estimated OS of all relapsed patients after a median follow up of 46 months (range 4–62 months) beginning from the time of relapse was 55%.In multivariate analysis advanced age >55years (HR: 4.69, p=0.001), absence of JAK2V617F mutation (HR: 2.50, p=0.02), mismatched donor (HR: 3.62, p=0.002) were significant independent predictors for reduced OS.This update of a prospective trial using reduced intensity conditioning followed by allogeneic stem cell transplantation for myelofibrosis confirmed a very good long-term OS. Relapse still occurs in about 30% and remains the main problem after transplantation. However, with adoptive immunotherapy using DLI or even second allogeneic transplantation a second remission with long term survival can be induced in about 50% of the relapsed patients. Developing methods for remission monitoring and early prediction and treatment of relapse should be the focus of future studies. Disclosures:Kobbe:Celgene: Consultancy, Research Funding; Ortho Biotec: Consultancy. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: PK Guided IV Busulfan Dose Intensity Results in Improved Event Free Survival

Abstract 2006 Background:Allogeneic hematopoietic stem cell transplantation (HCT) is an effective treatment for patients with advanced myelofibrosis. Myeloablative regimens have produced a high rate of morbidity and mortality. Reduced intensity conditioning (RIC) with allogeneic transplantation is being investigated with the goal of reducing non-relapse mortality. There is concern that this benefit might occur at expense of a higher relapse rate. In 2006 we initiated a study of RIC regimen of fludarabine 40mg/m2 (days −5, −4, −3 −2) and IV busulfan 130mg/m2 (day −3,−2). In the first 14 patients (the Bu-low group), 9 patients relapsed. We hypothesized that high dose PK guided IV busulfan would decrease relapse rate without substantially increasing non relapse mortality, thereby improving event free survival (EFS). The next 19 patients received an increased intensity of busulfan (Bu-high group), using pharmacokinetic dose adjustment. Methods:Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients received IV busulfan dose to a target daily AUC of 4000 μmol/L × 4days (days −5, −4, −3 −2) Fludarabine 40mg/m2 (days −5, −4, −3 −2). Average busulfan dose in Bu-high group was 473 mg/m2 (range 304–886 mg/m2) or 10.8 mg/kg, and it was 260mg/m2 or 6.5mg/kg in Bu-low group. Both cohorts of patients received tacrolimus and mini methotrexate as graft versus host disease prophylaxis and similar supportive care. Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and 1) was given to all patients receiving an unrelated donor graft. Results:Between 1/2006 and 12/2010, 33 consecutive patients with myelofibrosis were treated including 14 in the Bu-low and 19 in the Bu-high groups. Patients and disease characteristics were similar for the two treatment groups. There were 16 males and 17 females with a median age of 59 (range 27–70). Eighteen patients had primary MF, 8 post PV MF and 7 Post ET MF. Based on Lille criteria, 17 patients had intermediate risk disease and 16 had high risk disease. Eleven patients had splenectomy prior to transplant; remaining 22 patients had enlarged spleen at the time of transplant. Twenty patients had mutated Jak 2. Median peripheral blood CD 34 count was 54/μl (range 1–16426/μl). Karyotype was abnormal in 12 patients and diploid in 21. Donors were matched siblings for 12 patients, matched unrelated for 17, and one antigen or allele mismatched unrelated for 4 patients. Stem cell source was marrow in 4 and peripheral blood in 29. Circulating blasts were present in 17 patients.All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days and a median time to platelet engraftment of 18 (0–105) days. Cumulative incidence of acute GVHD was 28% and chronic GVHD 35% (limited 7%, extensive 28%). Cumulative incidence of non relapse mortality was 10% with overall 3 treatment related deaths: 1 in Bu-high group and 2 in Bu-low group (p=0.44). With a median follow up of 1.6 (0.2–5) years, current EFS (p=0.02) and the cumulative incidence of relapse (p=0.04) were significantly different between Bu-high and Bu-low groups, while overall survival (OS) was not (0.28). Two year estimates for the Bu-high and Bu-low groups are as follows: EFS: 69% and 29%; OS: 87% and 71%; cumulative incidence of relapse: 26% and 57%. Multivariate analysis showed that Bu-high dose (HR 0.25; p=0.01) and peripheral blood CD 34 count >100 μl (HR 3.56; p=0.02) were significant predictors of EFS. Conclusion:Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non relapse mortality, resulting in better EFS in patients with MF. [Display omitted] Disclosures:Popat:Otsuka: Research Funding. Andersson:Otsuka American Pharmaceuticals, Inc.: Consultant for Clinical Protocol Development. Nieto:Otsuka: Research Funding. Qazilbash:Otsuka: Research Funding. Champlin:Otsuka: Research Funding.

Alemtuzumab based reduced intensity conditioning allogeneic haematopoietic stem cell transplantation for myelofibrosis

We report the results of 11 patients myelofibrosis, who have received a uniform alemtuzumab-based RIC HSCT. The median recipient age was 51 years. Stem cells were obtained from 8 full HLA-matched and 3 HLA-mismatched donors. The 2-year OS and TRM at 2-years was 46% and 54% with no disease relapse observed. For patients with a full HLA-matched donor, the 2-year TRM and OS was 37.5% and 62.5%. All 4 JAK2 V617F mutant positive patients achieved molecular remission after a median of 90 days post-transplant, and the median time to regression of bone marrow fibrosis was 180 days.

Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis

AbstractAllogeneic stem cell transplantation (ASCT) after reduced-intensity conditioning has become a reasonable treatment option for patients with advanced myelofibrosis. The role of characteristic molecular genetic abnormalities, such as JAK2V617F on outcome of ASCT, is not yet elucidated. In 139 of 162 myelofibrosis patients with known JAK2V617F mutation status who received ASCT after reduced-intensity conditioning, the impact of JAK2 genotype, JAK2V617F allele burden, and clearance of mutation after ASCT was evaluated. Overall survival was significantly reduced in multivariate analysis in patients harboring JAK2 wild-type (hazard ratio = 2.14, P = .01) compared with JAK2 mutated patients. No significant influence on outcome was noted for the mutated allele burden analyzed either as continuous variable or after dividing into quartiles. Achievement of JAK2V617F negativity after ASCT was significantly associated with a decreased incidence of relapse (hazard ratio = 0.22, P = .04). In a landmark analysis, patients who cleared JAK2 mutation level in peripheral blood 6 months after ASCT had a significant lower risk of relapse (5% vs 35%, P = .03). We conclude that JAK2V617F-mutated status, but not allele frequency, resulted in an improved survival and rapid clearance after allografting reduces the risk of relapse.

Reduced-Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis

Hematopoietic stem cell transplantation offers a curative therapy for patients with myelofibrosis. Because of toxicity, allografting following myeloablative regimens is mainly applicable to young patients. With the introduction of dose-reduced conditioning using busulfan or melphalan with fludarabine, transplantation has become tolerable also for older patients. Implementation of antithymocyte globulin in the conditioning has resulted in effective prevention of graft-versus-host disease and an increased use of alternative donors. Through the discovery of new disease-specific mutations, close monitoring of residual disease became feasible in many patients and the outcome of posttransplant strategies improved. Still challenging is the achievement of new, transplant-derived models to estimate risk status and possible outcome for every individual patient, to help in therapeutic decision making and the determination of the optimal timing of stem cell transplantation. Such a tool may optimally include not only clinicomorphologic characteristics but also other potentially relevant factors such as cytogenetics and novel molecular markers.

Nonmyeloablative And Reduced Intensity Conditioning In Allogeneic Stem Cell Transplantation For Myelofibrosis

The only potentially curable therapy for myelofibrosis is allogeneic transplantation. Traditionally, myeloablative conditioning regimens have been utilized but have been limited by high regimen related mortality (RRM), poor 5 year overall survival, advanced patient age and comorbidities. For these reasons, NST and RIC have become an attractive transplant modality. We analyzed the results of 16 consecutive patients with MF transplanted using NST and RIC conditioning regimens at our institution.

Improved Outcomes Using Tacrolimus/Sirolimus for Graft-versus-Host Disease Prophylaxis with a Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX.

Hematopoietic Stem Cell Transplantation for Myelofibrosis

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder resulting from the proliferation of aberrant hematopoietic progenitors. Hence MMM is curable if the abnormal clone can be eradicated and replaced by normal cells from healthy donors. Myeloablative allogeneic transplantation results in high rates of durable engraftment and cure in approximately 50% of patients. Treatment-related mortality rather than disease recurrence accounts for the majority of treatment failures. Higher rates of treatment failure are associated with more advanced disease and age. More recently, nonmyeloablative (reduced-intensity) conditioning regimens have been shown to induce encouraging rates of engraftment and prolonged survival. When recommending transplantation for a particular patient, the prospect of cure should be weighed against the considerable risks of the procedure. Transplantation is typically recommended for patients under the age of 50 years with intermediate- and high-risk features, or for patients aged 50 to 60 years with an anticipated survival of less than 5 years. Finally, autologous transplantation has also been evaluated as a potential treatment approach. This procedure is unlikely to be curative, but might have a palliative role.

Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis with Myeloid Metaplasia (MMM) - Transplantation Should Be Performed before Transfusion Dependence Occurs.

Introduction: MMM is a clonal myeloproliferative disorder of later life with a wide range of life expectancy from months to many years. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option, however associated with considerable morbidity and mortality. We analyzed the results of HSCT in 15 consecutive patients (pts) with MMM referred to our institution during the last four years in order to determine the best time point for transplantation.Patients and Methods: Ten males and five females with primary (n = 13) and secondary MMM following myeloproliferative syndrome (n = 2) were grafted with unmanipulated bone marrow (n = 10) or peripheral stem cells (n = 5) from a related (n = 6) or unrelated (n = 9) donor. Median (md) age was 49 (36 – 64) years, md time from diagnosis to transplant 27 (6 – 132) months. Five pts had low, eight intermediate and two high risk disease (Dupriez score 0, 1, 2). All intermediate risk pts were categorized Dupriez 1 because of hemoglobin levels (Hb) < 10 g/dl. In low risk pts indication for transplant were severe constitutional symptoms. Mean risk score was 0.4 (0–1) in related and 1.1 (0–2) in unrelated transplants. 8 pts were transfusion dependent and two had portal hypertension. Eleven pts received a conditioning of intermediate intensity containing TBI(8Gy)/Flud/Cy (n = 10) or Bu(12)/Flud (n = 1). Four pts had standard TBI/Cy or Bu/Cy (n = 2 each). GvHD prophylaxis consisted of CsA and short course MTX. In all unrelated and two related transplants rabbit ATG (Genzyme n = 6, Fresenius n = 5) was added before grafting.Results: All pts engrafted at a md of 23 (11 – 28) days. Four pts developed extended cGvHD. Four pts died at a md of 266 (177–407) days: One from liver cirrhosis, one from cerebral aspergillosis and two from infections associated with cGvHD. At a md follow up of 21 (4 – 53) months probability of disease free survival (DFS) is 66% for the whole cohort and 100% vs 45% for pts with a related versus an unrelated donor. Results of MUD transplants are confounded with the higher risk score of pts grafted from an unrelated donor, as DFS according to disease risk was 100% for score 0 and 52% for score 1 and 2. Need for red blood cell transfusions before transplant was an even better predictor of DFS with 100% in untransfused and 36% in transfusion dependent pts. A log rank test was performed for the following variables: Conditioning intensity, donor type (MUD vs MRD), stem cell source, Dupriez score and need for blood transfusions: Only transfusion dependence proved to be significant (p = 0.03).Conclusions: Although the number of pts is small our results support the use of related and unrelated allogeneic SCT as a curative treatment option in MMM. Hb below 10 g/dl has been reported to be a predictor of adverse outcome after HSCT (Guardiola et al, Blood 93, 1999: 2831; Deeg et al, Blood 102, 2003: 3912). In our hands however, red cell transfusion dependence is the relevant cut off point for survival as pts with risk score 1 without need for transfusions had the same DFS as pts with risk score 0. Transfusion dependence may be a marker of disease progression and of increased toxicity at a time. AlloHSCT therefore should be performed earlier during the natural course of the disease, ie before transfusion dependence occurs, when DFS is excellent.

Stem cell transplantation for myelofibrosis: a report from two Canadian centers.

We describe the course of 25 patients with myelofibrosis (MF) due to agnogenic myeloid metaplasia (n=19) or essential thrombocytosis (n=6) who underwent allogeneic stem cell transplantation (SCT) at one of two Canadian centers. The median age at transplantation was 48.7 (IQR 45.9-50.4) years and transplantation was carried out at a median of 10.7 (IQR 5.67-26.5) months after diagnosis. Granulocyte engraftment (absolute neutrophil count >0.5 x 109/l) occurred at a median of 20 days after transplantation for splenectomized patients, compared with 27.5 days for nonsplenectomized individuals (P=0.03). Increased risk of grade II-IV acute graft-versus-host disease (P=0.04) was noted in patients transplanted after splenectomy. Patients with MF received 0.264+/-0.189 U of packed red blood cells per day over the first 180 days after transplantation, and remained dependent on red blood cell transfusions for a median of 123 (IQR 48-205) days. Complete remission of MF was documented in 33% of evaluable patients. The 1 year cumulative nonrelapse mortality was 48.3%. Median survival for this group of patients was 393 (IQR 109-1014+) days, with a projected 2-year overall survival of 41%. We conclude that allogeneic SCT offers a reasonable chance for prolonged survival in patients with advanced MF, but this occurs at the cost of considerable toxicity and nonrelapse mortality.