Myeloablative Group Research Articles

Pediatric Myelodysplastic Syndromes and Allogeneic Hematopoietic Progenitor Cell Transplantation (HPCT): A Single Center Perspective.

Abstract 1780Poster Board I-806 IntroductionMyelodysplastic syndromes (MDS) in pediatrics comprise a heterogenous group of disorders that are poorly understood and difficult to treat. Allogeneic HPCT remains the only curative treatment, but published outcomes in children are limited. MethodsWe performed a retrospective review of pediatric patients with MDS who received an allogeneic HPCT on IRB approved protocols between 1992 and 2009 at Children's Memorial Hospital (Chicago, IL). ResultsThe study population consisted of 23 consecutive patients. Median age at transplant was 9.2 years (range 4.6-17.2 years) and median time to transplant from diagnosis was 4.3 months (range 2.2-9.9 months). Nine patients (39%) had de novo MDS, whereas 14 of 23 (61%) patients had treatment-related MDS, and 4 patients in this group had received a previous autologous transplant for a previous malignancy. All patients had a documented cytogenetic abnormality: monosomy 7/7q- in 12 patients (52%), trisomy 8 in 3 (13%), translocation (6;9) in 3 (13%), and others in 5 (22%). Donors were HLA matched siblings in 8 cases (35%), 8/8 loci HLA matched unrelated donors in 6 (26%), and the remaining 9 (39%) were 6-7/8 loci HLA mismatched unrelated donors. HPC source was peripheral blood in 13 patients (57%), cord blood in 7 (30%), and bone marrow in 3 (13%). Fourteen of 23 (61%) patients received a myeloablative conditioning regimen with TBI/Cy in 9 (31%), Bu/Cy in 4 (17%), and Flu/Bu/low-dose TBI in 1. Reduced intensity conditioning (RIC) regimens were used for the remaining 9 (39%) and consisted of Flu/Bu/ATG. Indications for RIC transplant included patient choice in 4 patients, prior autologous transplants in 3 patients, and comorbid conditions in 2 patients. Twenty patients (90%) had evidence of engraftment, with only 1 death prior to day 100. Seven patients (30%) died secondary to transplant-related complications, including infection in 4, GVHD in 2, and toxic epidermolysis in 1. Of the 4 patients that had received a prior transplant, 3 died from transplant-related mortality. Grade 2-4 acute and chronic graft-versus-host disease (GVHD) was seen in 9 (39%) and 11 (48%) patients, respectively. For the entire group, estimated five year relapse-free survival (RFS) and overall survivals (OS) were 47% [95% CI: 28%, 67%] and 50% [95% CI: 25.1%, 71.1%], respectively. Two patients had graft failure, which included 1 patient who received cord blood and 1 patient who received peripheral blood with RIC. Five patients suffered a relapse of original disease, including 3 patients who received RIC. These 3 patients each received a second myeloablative transplant; 2 of these patients remain alive and disease-free. Treatment-related MDS was associated with decreased RFS in comparison to non-treatment-related MDS (33% [95% CI: 11%, 58%]) vs. 70% [95% CI: 22%, 92%], p=0.05). In contrast, five year OS rates reached 80% for those with de novo MDS. There was no significant difference in overall survival between patients who received RIC versus myeloablative conditioning (p=0.17), but RIC regimens were associated with decreased relapse-free survival in comparison to myeloablative conditioning regimens (22% [95% CI: 3%, 51%] vs. 68% [95% CI: 34%, 87%], p=0.02). On univariate analysis, there was no correlation of relapse-free or overall survival with blast count at diagnosis, IPSS score, type of cytogenetic abnormality, receiving AML-like chemotherapy for MDS, CMV serostatus, donor type and HLA match, cell dose, and time to transplant. ConclusionsAllogeneic HPCT is a curative option for pediatric MDS. In this series of high risk patients we achieved OS approaching 80% in patients with de novo MDS. Those who received RIC had an increased relapse rate but were salvaged by myeloablative conditioning regimens and had comparable outcomes to the myeloablative group. The role of RIC regimen transplants in pediatric MDS needs to be studied further. Larger series of pediatric patients are needed to establish a prognostic scoring system to predict outcome and select appropriate conditioning regimens to further improve survival in allogeneic HPCT for MDS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Donor Lymphocyte Infusions (DLI) for the Treatment of Disease Relapse in Hematological Malignancies Following Allogeneic Transplantation: Similar Efficacy Following RIC or Myeloablative Regimen

DLI have been shown to have a potent GVL effect in relapsing chronic phase CML while for reasons that remain unclear, they appear less effective in treating relapsing diseases other than CML. A lack of tumor-specific antigens, the absence of co-stimulatory molecules on tumor cells, or inhibition of effector cells may account for the lower therapeutic effect. Given the sub-optimal results of DLI in non-CML diseases, predictive factors of DLI efficacy such as type and stage of the disease and levels of chimerism would serve to better guide the use of leukocytes infusions.We analyzed a series of 73 patients (pts) who received DLI for various indications (disease relapse or progression, n=66; persistent mixed chimerism (less than 90% donor cells) without evidence of relapse, n=4; EBV lymphoproliferation, n=3). Diagnosis included: CML (n=9), MDS or AML (n=21), LAL (n=5), myeloma (n=18), NHL (n=10), Hodgkin's disease (n=5), CLL (n=2), and other (n=3). Median age at transplantation was 46 (1–62) years. Eigthy-six percent of donors were HLA-matched siblings, while 12% were MUD, one donor was a haplo-identical sibling, and two had one class I mismatch. Reduced intensity conditioning was used in 39 patients (52%; fludarabine, busulfan and ATG), and 35 pts (48%) received a standard myeloablative TBI/cyclophosphamide-based regimen. The graft was T-cell depleted in 14 cases. GHVD prophylaxis consisted of CsA alone in RIC patients, and CsA+Mtx in the myeloablative group. DLI was given at a median of 247 (19–3163) days after transplantation. Escalating dose were given if no response or GVHD were observed: one DLI n=36, 2 infusions (n=36), 3 infusions (n=5), 4 infusions (n=1). The median pre-DLI lymphocyte count was 0.95×109/L (0.05–4.38). In addition to DLI, 22 pts (47%) received prior (n=9, 19%) or subsequent chemotherapy to enhance disease control. In those who received DLI for mixed chimerism alone, all four returned to full donor chimerism. In those who received DLI for relapsing/progressive disease, CR was achieved in 21 pts (28%), including 15 with non-CML diseases (23%): 6/21 AML, 5/18 MM, 2/10 NHL, 1/5 HD, 1/5 ALL. In 16 pts, CR was obtained with DLI only. Two of the three patients who received DLI for EBV lymphoproliferation responded. Response to DLI was comparable between pts receiving RIC regimen and myeloablative regimen (p=ns). The rate of acute GVHD II-IV and chronic GVHD was 27% and 23%. The incidence of acute GVHD II-IV did not differ whether the conditioning was myeloablative or RIC while the rate of GVHD was higher in recipient of DLI from unrelated donor (60%, although the number is small). Chimerism was performed on unselected WBC and available prior DLI for 7/9 of CML pts, and 54/65 non-CML pts. For non-CML disease donor chimerism was <90% for 17 pts (including 6 pts with <50%) and ≥90% for 37 pts with an incidence of acute grade II-III GVHD of 52% and 32% respectively (p=ns). Correlation was observed between GVHD and graft versus malignancy in non-CML diseases (.015). The median overall survival was 28.3 months. The overall probability of survival following DLI at 2 and 4 years was 50.7% and 40.5% (95% CI, 27.7–53.3) for the whole group; the survival at 4 years according to the disease was 38.8% for AML/MDS, 40% for NHL, 35.7% for myeloma. With a median follow-up of 1662 days from the time of the initial DLI, 33/73 pts of the whole group (45%) are alive, while in the non CML group 26/64 (37.5%) pts are alive and 18/64 (28%) alive in CR. These results indicate that DLI combined with chemotherapy for disease relapse or mixed chimerism is similarly effective in non-CML diseases following RIC or standard allografting and works in one case out of four in AML and myeloma. Its efficacy can be further improved with the use of more tumor-specific DLI and reduction of the suppressing activity of regulatory T cells.

Tandem Autologous-Nonmyeloablative (NMA) Allogeneic(Allo) Transplant (Tx) in Newly Diagnosed Multiple Myeloma (MM) Leads to Improved Survival When Compared to Conventional Allogeneic Transplant

Despite various strategies involving autologous Tx and use of newest drugs with anti-MM activity such as bortezomib and lenalidomide, very few patients with MM currently achieve long-term remission. Allo Tx theoretically remains an attractive option due to evidence of graft-versus-MM activity supported by small series of patients with long-term (>10 years) complete remissions (CR) following myeloablative Tx, the association between chronic graft-versus-host disease (Gvhd) and CR, and response in 20–30% of relapsed patients following donor leucocyte infusion. However, to date, the ideal strategy using Allo Tx remains uncertain. Early studies using myeloablative regimens have been associated with high (30–50%) mortality rates and late relapses have been observed despite Gvhd. Low (10–22%) reported mortality in NMA regimens is hampered by reduced CR and higher progression rates compared to ablative regimens. Additionally, long-term outcome following NMA transplant remains unclear. In this present study, we sought to compare outcomes of 2 sequential cohorts of patients with MM who underwent Allo Tx in our institution. Between 01/01 and 10/07, patients with newly diagnosed stage II–III MM were invited to participate in a phase II prospective study consisting of vincristine, adriamycine and decadron x 4 cycles followed by autologous blood stem cell Tx with melphalan 200 mg/m2. Within 3 months post autologous Tx, enrolled patients received outpatient NMA Allo Tx from a 6/6 HLA matched sibling donor with a conditioning of fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 5 days, followed by infusion of >4 x 106 CD34+ cells/kg. Gvhd prophylaxis was chosen to take advantage of low incidence of acute Gvhd and putative protective effect of chronic Gvhd: tacrolimus 3 mg bid was started on day (D)-8 then tapered off by D+100, with mycophenolate mofetil 1000 mg bid D+1 to D+50. Our NMA cohort was compared to MM patients who underwent full myeloablative Allo Tx between 06/90 and 01/01, mostly (N=29) with TBI; marrow was used in 54% and all received short course CSA/MTX. A total of 73 patients received NMA Tx (M/F: 43/30, median age 54 years, 73% stage III) and were compared to 39 patients with myeloablative Tx (M/F: 24/15, median age 47 years, 64% stage III). The incidence of grade II–IV acute Gvhd was significantly higher in the myeloablative group (30.7% vs 6.8%; p=0.0004); in contrast, as expected, chronic Gvhd was more frequent at 3 years following NMA Tx (90% vs 59.4%; p=0.0001). At 4 years, transplant related mortality (TRM) following myeloablative Tx was 50% compared to 17% in the NMA group (p=0.0001). Median (range) follow-up in NMA and myeloablative cohorts were 28 (3.5–82.9) and 37 (0.5–139) months, respectively. Kaplan-Meier estimates of overall survival (OS) at 2 (87% vs 59%; p=0.001) and 5 years (67% vs 44%; p=0.001) are significantly better in the NMA cohort. Similarly, disease free survival (DFS) at 2 (87% vs 48.5%; p=0.0001) and 5 years (67% vs 41%; p=0.0001) are also significantly better with the NMA Tx. In conclusion, our sequential auto-NMA Tx protocol is more effective to control MM than myeloablative Tx with significantly less TRM, better OS and DFS. These results might be explained by less advanced disease and higher incidence of chronic Gvhd in the NMA cohort. Future strategies should focus on reducing the relapse rate and incidence of extensive chronic Gvhd while preserving the graft versus MM effect.

Similar Outcomes Using Myeloablative Versus Reduced Intensity and Non-Myeloablative Allogeneic Transplant Preparative Regimens for AML or MDS: From the Center for International Blood and Marrow Transplant Research

Use of reduced intensity conditioning (RIC) and nonmyeloablative (NMA) regimens in allogeneic transplantation (allo HCT) for AML and MDS has rapidly increased over the past decade. Efficacy of these approaches compared to myeloablative (MA) conditioning has not been clearly established. We compared disease status, donor, graft and recipient characteristics and outcomes of 3731 MA HCT with 1500 RIC/NMA procedures performed at 217 centers between 1997 and 2004 (median f/u 58 vs. 40m, MA vs. RIC/NMA). Patients in the MA group were younger (median age 42 (18–68) vs. 55 (18–69) years), more frequently in CR1, and more often were transplanted from matched sibling grafts, compared to recipients of RIC/NMA. NMA recipients were less often transplanted with >10% blasts and had a lower performance scores. RIC recipients received fully matched unrelated donor (URD) grafts and PBSC as hematopoietic source more often than MApatients. Proportion with adverse cytogenetics, IPSS categories for MDS patients, median time to first relapse in AML CR2 patients, and marrow blasts at HCT were similar in the conditioning groups. 5-years univariate probabilities and multivariate relative risk (RR) outcomes of relapse, transplant-related mortality (TRM), leukemia-free (LFS) and overall survival (OS) are shown below:Outcome:MARIC PBSCRIC BMNMAUnivariate:Relapse, %32 (31–34)39 (35–43)42 (36–48)43 (38–48)TRM,%34 (32–36)34 (30–38)37 (31–43)36 (31–41)Adjusted LFS, %33 (31–34)30 (26–35)28 (23–34)24 (20–29)Adjusted OS, %34 (33–36)33 (29–37)32 (27–38)26 (21–30)Multivariate:Relapse*1.001.05 (0.92–1.21)1.51 (1.23–1.85)1.64 (1.38–1.94)TRM*1.001.26 (1.03–1.54)1.36 (1.01–1.83)1.55 (1.20–1.99)Treatment1.001.03 (0.90–1.17)1.17 (1.01–1.36)1.28 (1.12–1.45)failure*Mortality*1.001.03 (0.91–1.16)1.12 (0.96–1.30)1.20 (1.05–1.36)* overall p<0.001MA regimens were associated with significantly less relapse (RR with RIC/NST 1.32 (0.19–1.46), p <0.001). While early TRM was substantially less with RIC/NMA approaches, 5 year TRM is equivalent (p=0.48). This leads to marginally better 5 year LFS (RR 1.08, p=0.05) but similar OS (RR 1.05, p=0.25) with MA vs. RIC/NST. These data indicate that late TRM negates any early advantage offered by RIC and NMA regimens, resulting in similar but slightly better 5 year LFS in recipients of MA conditioning. Similar outcomes with these RIC/NMA vs. MA regimens suggest the need for prospective trials comparing these transplant intensities in patients eligible for either approach.

Impact of Comorbidity Index on Outcome with Allogeneic Hematopoetic Stem Cell Transplantation for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia, a disease that is not curable with standard therapy, is an attractive target for allogeneic (allo) hematopoetic stem cell transplant (HSCT) with demonstrated strong graft vs. leukemia effect. However, optimal selection of patients (pts) in order to maximize outcome and minimize toxicity is still under study. We hypothesized that patient co morbidity, as measured by the HSCT adapted Charlson co morbidity index (CCI) would have a strong effect in this group of patients with older median age. At the Leukemia/BMT Program of BC the CCI has been prospectively calculated for HSCT pts since 2006, and we performed chart review to calculate scores retrospectively for the remaining CLL allo HSCT patients in order to evaluate the impact of this factor on outcome following allo HSCT. Transplant specific data was collected prospectively and entered into an electronic database. Forty pts with CLL proceeded to allo HSCT between Jan 91 and Dec 07, with myeloablative (MA) (n=21) or non-myeloablative/reduced-intensity (NMA/RIC) (n=12/7) conditioning regimen. Median (range) number of prior therapies was 4 (1–7). Twenty-four pts were refractory to fludarabine. Donors were related in 25 cases, unrelated in 15. Median age (range) was 49 yrs (32–57) (MA) and 57 yrs (52–64) (NMA/RIC), with 3 and 13 patients greater than age 55 in the 2 groups respectively. Interval from dx to HSCT was 60 months (range 7–135) (MA) and 90 months (range 18–350) (NMA/RIC). Five yr OS is 55% for the whole group; 51% for the MA group at a median follow-up (med FU) of 7.2 yrs (range 2.8–14.6) and 62% for the NMA/RIC group with med FU of 4.2 yrs (range 0.1–6.8). OS did not differ between the 2 groups (p=0.56). Related and unrelated donors had similar 5yr OS at 60.6 vs. 47.1%, p=0.23. Cumulative incidence of non-relapse mortality at 100 days and 2 years is 10 and 32% for the whole group, 14 and 38% for the MA and 6 and 26% for the NMA/RIC groups. CCI was 0, 1, 2, and 3 or greater for 21, 5, 7, and 7 patients. OS by CCI 0–2 vs. >=3 was 63 vs.18% for the whole group (p=0.01), 56 vs. 0% for the MA (p=0.03), and 74 vs. 27% for the NMA/RIC groups (p=0.06). Further analyses will explore the relationship between CCI and NRM, acute and chronic graft vs. host disease, and relapse. Patient numbers in this series are insufficient to evaluate the impact of specific co morbidities. In conclusion, for patients with CLL, who are in general of older age, and who may have other therapeutic options, allo SCT is optimally performed in those with a low co morbidity score. Patients with a CCI of 3 or greater may be preferential candidates for alternate less toxic therapies.

Serious acute or chronic graft-versus-host disease after hematopoietic cell transplantation: a comparison of myeloablative and nonmyeloablative conditioning regimens

We previously reported a 25% incidence of serious graft-versus-host disease (GVHD) (that is, acute or chronic GVHD that caused death, lengthy hospitalization or disability, or resulted in recurrent major infections) among 171 hematopoietic cell transplantation (HCT) recipients after nonmyeloablative (NMA) regimen. Here we present a retrospective study applying the same criteria to 264 recipients of peripheral blood HCT after myeloablative (MA) regimen, and compare the results with the previous study after additional follow-up. The MA group was younger and had lower comorbidity scores at HCT than those in the NMA group. The overall incidence of serious GVHD was 17% (44/264) in the MA group versus 28% (48/171) in the NMA group. The adjusted hazard ratio (HR) of serious GVHD in the MA group compared to the NMA group was 0.65 (95% CI, 0.4-1.1); P=0.13, and if follow-up was censored at the onset of recurrent or progressive malignancy, HR was 0.67 (95% CI, 0.4-1.3), P=0.22. We conclude that the choice between MA and NMA regimens does not greatly affect the risk of serious GVHD as an overall indicator of outcomes related to either acute or chronic GVHD. Serious GVHD may be considered as an endpoint in clinical trials with GVHD-related outcomes.

Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia

Allogeneic conventional hematopoietic cell transplantation (HCT) can be curative treatment for lymphoid malignancies, but it has been characterized by high nonrelapse mortality (NRM). Here, we compared outcomes among patients with lymphoma or chronic lymphocytic leukemia given either nonmyeloablative (n = 152) or myeloablative (n = 68) conditioning. Outcomes were stratified by the HCT-specific comorbidity index. Patients in the nonmyeloablative group were older, had more previous treatment and more comorbidities, more frequently had unrelated donors, and more often had malignancy in remission compared with patients in the myeloablative group. Patients with indolent versus aggressive malignancies were equally distributed among both cohorts. After HCT, patients without comorbidities both in the nonmyeloablative and myeloablative cohorts had comparable NRM (P = .74), overall survival (P = .75), and progression-free survival (P = .40). No significant differences were observed (P = .91, P = .89, and P = .40, respectively) after adjustment for pretransplantation variables. Patients with comorbidities experienced lower NRM (P = .009) and better survival (P = .04) after nonmyeloablative conditioning. These differences became more significant (P < .001 and .007, respectively) after adjustment for other variables. Further, nonmyeloablative patients with comorbidities had favorable adjusted progression-free survival (P = .01). Patients without comorbidities could be enrolled in prospective randomized studies comparing different conditioning intensities. Younger patients with comorbidities might benefit from reduced conditioning intensity.

Reduced-Intensity Conditioning Is Associated with Shorter Duration of Chronic GVHD Than Myeloablative Conditioning and Provides Very Good Quality of Life for Long-Term Survivors after Allogeneic Stem Cell Transplantation.

Reduced-intensity conditioning (RIC) has been increasingly used over the last decade as a curative approach for patients (pts) not eligible for myeloablative (MA) conditioning. It is now established that RIC can allow consistent engraftment and reduce toxicity of allogeneic stem-cell transplantation (SCT). However, the long-term effects, and in particular the duration of immunosuppressive therapy (IST) needed and quality of life of long-term survivors are less defined. To explore these issues we analyzed the results of 48 pts given SCT with RIC from 1/2000 to 8/2002, such that survivors have at least 5 year follow-up, and compared them to results of 41 SCT with MA conditioning given during the same period. The RIC group included older pts than the MA group, median age 49 (range, 20–65) and 37 (range, 20–65), respectively (p=0.01). The MA group included more pts with acute leukemia/MDS (68% vs 33%, p=0.001) while pts with myeloma were only given RIC (31% of the RIC group, p< 0.001). 48% of pts in the RIC group had a prior autologous SCT compared with none in the MA group (p< 0.001). There was no difference in donor type, 26% of all pts were given SCT from unrelated donors. After a median follow-up of 6.1 years (range, 5.1–7.6) 40 pts are alive, 20 after RIC and 20 after MA conditioning with estimated survival of 42% (95ci, 28–56) and 47% (95ci, 31–63), respectively (p=NS). Long-term survival with RIC was achieved across all diagnoses including 6 of 16 pts with acute leukemia/MDS, 6 of 6 pts with CML, 3 of 11 pts with lymphoid malignancies and 5 of 15 pts with myeloma. The corresponding rates for acute leukemia/MDS, CML and lymphoid malignancies in the MA group were 13 of 28, 3 of 4 and 4 of 9, respectively. Chronic GVHD occurred in 22 pts after RIC and in 26 pts after MA conditioning with a cumulative incidence of 48% (35–65) and 66% (53–83), respectively (p=0.07). 12 of 22 pts with chronic GVHD after RIC were eventually able to stop IST, 9 died on IST (relapse-5, non-relapse mortality (NRM)-4) and only 1 of 20 long-term survivors was still on IST at last follow-up. The median duration of IST was 17 months and the cumulative probability of stopping IST after 5 years (with relapse been competing risk) was 79%. In the MA group 10 of 26 pts with chronic GVHD were able to stop IST, 8 died on IST (relapse-6, NRM-2) and 8 of 20 long-term survivors were still on IST at last follow-up. The median duration of IST was 41 months (p=0.05) and the cumulative probability of stopping IST after 5 years was 48% (p=0.001). Two women gave birth in the RIC group while 2 men in the MA group fathered children spontaneously. There was one secondary malignancy in the MA group and none in the RIC group. Two pts in the MA group sustained myocardial infarction (one fatal) compared to none of the RIC group. One pt in the RIC group had reversible nephrotic syndrome. In summary long term(>5y) survival is similar for both RIC and MA SCT, however IST is significantly shorter after RIC and quality of life seems better. Overall, all 20 pts surviving more than 5 years after RIC SCT sustained excellent quality of life and only one still required IST. The more rapid achievement of transplantation tolerance with RIC may relate to better preservation of thymic function, but this requires further investigation. These observations require further confirmation in larger registry studies.

Imatinib Combined with Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia.

Imatinib has been introduced as the most effective drug for patients with chronic myeloid leukemia (CML) in chronic and advanced phases, but allogeneic stem cell transplantation (Allo-SCT) is still regarded as the only curative treatment option. The main obstacles to successful Allo-SCT for CML in advanced phase are increased post-transplant relapse and high treatment-related mortality. Individual transplantation protocol for CML in chronic and advanced phases should be studied in the imatinib era. To evaluate the exact role of imatinib combined with Allo-SCT for CML, 35 cases of CML between May 2004 and April 2007, with 27 in chronic phases, 4 in accelerated phase and 4 in blast-crisis phase, were studied in our center. 35 patients, 26 males and 10 females with a median age of 35 years (18∼50 years), received the imatinib therapy (400∼600 mg/d) for a median of 3 months (2∼6 months) before transplantation. All of the patients achieved complete hematological remission pre-transplant. Donors were siblings (n=20) or unrelated donors (n=15), and the stem cells were collected from either mobilized peripheral blood (n=24) or bone marrow (n=11). 22 patients with CML in early chronic phases received the nonmyeloablative regimen, including fludarabine 30 mg/m2/day (days −10 to −5), oral busulfan 4 mg/kg/day, or intravenous busulfan 3.2 mg/kg/day (days −6 to −5) and ATG 5mg/kg/day (days −4 to −1). In addition, other 5 patients in chronic phases beyond one year from diagnosis, 4 patients in accelerated phase and 4 in blast-crisis phase received the myeloablative regimen with oral busulfan 4 mg/kg/day, or intravenous busulfan 3.2 mg/kg/day (days −7 to −4) plus cyclophosphamide 60mg/kg/d (days −3 to −2). Mycophenolate mofetil combined with cyclosporin A and methotrexate was used to prevent aGVHD. Engraftment of neutrophils and platelets was achieved in 33 out of 35 (93.3%) patients within a median of 12 days (8∼26 days) and 15 days (0∼35 days), respectively. In myeloablative group, all patients achieved completed engraftment. In nonmyeloablative group, graft failure occurred in two patients, and mixed chimerism occurred in 4 patients while two achieved complete chimerism by the treatment of imatinib and the other two patients by imatinib combined with donor lymphocyte infusion. aGVHD was observed in 8 patients (22.86%) while no patients developed III-IV aGVHD, and cGVHD was observed in 12 patients (37.50%). With a median follow-up of 9.5 months (2.0∼37.0 months), 2 patients relapsed and 3 patients died following transplantation. OS and DFS rates were 91.43% and 82.86%, respectively. In nonmyeloablative group, just one patient relapsed at one year post-transplantation; two patients died from transplanted related complication, one of whom died from interstitial pneumonia at 2 months post-transplantation, and the other occurred cGVHD with bronchiolitis obliterans died at 11 months post-transplantation. In myeloablative group, one in blast-crisis phase before imatinib treatment pretransplant died at 4 months post-transplantation, and the other 12 patients achieved complete molecular remission. Conclusion: Nonmyeloablative Allo-SCT combined with imatinib for CML, with the associated reduction in transplant related mortality and strong GVL effect, is an effective and safe treatment choice for patients in early chronic phase. CML in advanced phase had an excellent outcome after myeloablative Allo-SCT when performed in the phase of cytogenetic response to imatinib.

Impact of Myeloablative Versus Reduced Intensity Conditioning Regimens on Early Lymphocyte Recovery and Its Impact on Transplant Outcomes after Allogeneic Peripheral Blood Stem Cell Transplantation in Adult Patients with Hematologic Malignancies.

Background: The association between early lymphocyte recovery and improved outcomes after allogeneic (Kim et al BJH 2004) and autologous stem cell transplantation (SCT) has been established. However, the impact of conditioning regimen intensity on early recovery of absolute lymphocyte count (ALC) has not been described. The current study attempted to determine different effect of early lymphocyte recovery on transplant outcomes after allogeneic peripheral blood SCT (PBSCT) followed by myeloablative (MAC) or reduced intensity conditioning (RIC). Methods: This study retrospectively assessed 225 consecutive allogeneic peripheral blood stem cell recipients at Princess Margaret Hospital, Toronto, Canada between 2000 and 2007. All patients received related donor transplants. Myeloablative conditioning (MAC) was employed in 157 patients (TBI based regimens, n=117; Busulfan based regimens, n=40), while 68 patients received RIC excluding alemtuzumab-containing regimens. The endpoints were overall survival, non-relapse mortality (NRM) and relapse incidence after PBSCT according to the day +30 absolute lymphocyte count (ALC). Results: No difference in ALC was noted between MAC and RIC groups except at 2 (p=0.036) and 3 months (p=0.036). Eighty patients (36%) had an ALC of 0.5 x 109/L or less at 30 days after SCT. No correlation was noted between the ALC prior to SCT and post-transplant ALC. The 2-year OS was significantly better in patients with an ALC ≥0.5x109/L at 30 days compared to those with an ALC &lt; 0.5x109/L in overall group (75% vs. 48%, p=0.00008; Figure 1A) or in the MAC group (p=0.00005; Figure 1B), but not in RIC group (p=0.3; Figure 1C). The NRM at 1-year was significantly lower in the group with an ALC ≥0.5x109/L at 30 days compared to those with an ALC &lt; 0.5x109/L (14% vs. 32%, p=0.00008), especially in the MAC group (p=0.00002), but not in the RIC group (p=0.5). However, no difference in relapse incidence was noted according to the ALC count either in the overall (p=0.07), MAC (p=0.3), or RIC groups (p=0.4). The incidences of acute or chronic GVHD were not significantly different between MAC and RIC groups. Delayed lymphocyte reconstitution was noted up to 6 months for the group with ALC of 0.5x109/L or less. Conclusion: Conditioning regimen intensity did not affect day +30 lymphocyte counts. However, we demonstrated that early lymphocyte recovery may be a prognostic marker for improved OS and better NRM after myeloablative allogeneic PBSCT. Figure 1. comparison of overall survival between groups with high and low ALC counts at day 30 in overall group (A), myeloablative conditioning group (B) and reduced intenmsity conditioning group (C). Figure 1. comparison of overall survival between groups with high and low ALC counts at day 30 in overall group (A), myeloablative conditioning group (B) and reduced intenmsity conditioning group (C).

Comparison of Myeloablative and Nonmyeloablative Hematopoietic Stem Cell Transplantation for Treatment of Chronic Myeloid Leukemia

This retrospective study compared outcomes for 81 chronic myeloid leukemia patients who underwent myeloablative or nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT). Sixty-five patients received myeloablative HSCT, and 16 patients received fludarabine (Fd), low-dose busulfan (Bu), and antithymocyte globulin (ATG) in nonmyeloablative HSCT. We determined overall survival (OS) and disease-free survival (DFS), as well as the occurrence of acute and chronic graft-versus-host disease (GVHD). The incidences of acute GVHD of grades II to IV were 14.0% and 18.7% for the myeloablative and nonmyeloablative groups, respectively. The incidence of chronic GVHD was significantly higher in the nonmyeloablative group (80% versus 66%). Five-year OS and DFS rates were significantly higher in nonmyeloablative group (70% for both), compared with 56% and 54%, respectively, for the myeloablative group. A univariate analysis, however, revealed a strong but statistically insignificant trend for enhanced overall OS and DFS in the nonmyeloablative group (P = .1 and .07, respectively). A multivariate analysis with the factors of treatment, age, sex, acute and chronic GVHD, and disease status at the time of transplantation revealed that both OS and DFS were significantly higher in the nonmyeloablative group than in the myeloablative group. These findings suggest that nonmyeloablative Fd/Bu/ATG treatment is at least not inferior (and quite probably superior) in terms of patient outcome compared with standard myeloablative therapy. Further larger-scale randomized clinical trials are warranted to clarify the efficacy of this treatment regimen.

Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: A comparative clinical analysis

We evaluated the efficacy of hematopoietic stem cell transplantation (HSCT) using reduced intensity (RI) vs. myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome. Thirty two patients (median age 54) who underwent a RI HSCT (2000-2003) were compared with 187 patients (median age 39) who received a MA transplant (1990-2003). Neutrophil engraftment was more rapid in the RI group (median 11.5 vs. 21 days). Platelet recovery was similar and graft failure was infrequent. The incidence of graft-versus-host disease (GVHD) and treatment-related mortality was similar though relapse was more frequent after RI conditioning (RR 2.2 [95% CI = 1.1-4.6] P = 0.03). At 2 years, disease-free survival (DFS) (31% vs. 30%, P > 0.1) and overall survival (33% vs. 35%, P > 0.1) were comparable between RI and MA groups, respectively. We suggest that RI allografts can yield satisfactory DFS both for older as well as younger patients with pre-existing comorbidities, who are ineligible for MA allografts. Advances in GVHD management and new approaches for relapsed or refractory disease are necessary to improve these outcomes.

Prognostic factors for patients with acute myeloid leukaemia or high‐risk myelodysplastic syndromes undergoing myeloablative or non‐myeloablative allogeneic blood stem cell transplantation

In this uni-centre retrospective study, we studied 120 adults with acute myeloid leukaemia (AML) (n = 88) and myelodysplastic syndrome (MDS) (n = 32) who received first allogeneic HSCT to determine prognostic factors which are correlated with the outcome after myeloablative (MA) or non-myeloablative (non-MA) allogeneic HSCT. The median age of our cohort was 44 years. Fifty-nine per cent of the patients were transplanted in complete remission (CR) and 41% were in relapse or refractory to induction or salvage therapy. A total of 97 patients received a MA regimen and 23 were treated with a non-MA regimen. The prognostic impact for several parameters was assessed by univariate and by multivariate analyses using the Cox regression model. Three-year probabilities of non-relapse mortality (34 vs. 54%; p = 0.9) did not differ in the MA and non-MA groups, but differences were observed in the disease-free survival (DFS) (43 vs. 17%; p = 0.1) and the relapse rate (RR) (29 vs. 62%; p = 0.01). Independently from the regimen, in uni- and multivariate analysis, survival was best in those patients who were transplanted in CR and experienced cGvHD. Interestingly, outcome of patients with complex cytogenetic aberrations was identical to that of better prognostic subgroups. In this study, the clinical benefit of a lower toxicity regimen was offset by higher RR resulting in inferior results in the non-MA group, especially when no CR was achieved by prior induction or salvage therapy.

Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia

The role of chimerism analysis as a prognostic indicator of relapse after hematopoietic stem cell transplantation (SCT) is controversial. We monitored chimerism status by short tandem repeat-based polymerase chain reaction (PCR) in T- and non-T-cell subsets and retrospectively evaluated clinical outcome in 96 patients with acute myeloid leukemia after myeloablative (MA) or reduced-intensity conditioning SCT. Fifty-six percent of 80 patients in the MA group demonstrated complete donor chimerism (CC) at all time points, whereas 6% had decreasing mixed chimerism (MC), 8% stable MC, 25% increasing MC and 3% increasing and decreasing MC. In 16 RIC patients, these percentages were 12, 50, 6, 6 and 19, respectively, together with 6% nonengraftment. Forty-three out of 96 patients experienced relapse. The last chimerism evaluation before relapse revealed increasing MC in only eight patients. In samples taken between 1 and 6 months post SCT, CC/decreasing MC was significantly related with a lower risk of relapse (31 versus 83%, P<0.000) and mortality (38 versus 83%, P<0.000) than with MC/increasing MC. However, the development of relapse was very rapid. Only very frequent monitoring of chimerism status by highly sensitive methods might identify impending relapse and allow early immunological intervention.

Allogeneic Stem Cell Transplantation for Patients with Advanced Hematological Malignancies: Comparison of Fludarabine-based Reduced Intensity Conditioning versus Myeloablative Conditioning

We compared the outcomes of allogeneic hematopoietic stem cell transplantation using reduced intensity and myeloablative conditioning for the treatment of patients with advanced hematological malignancies. A total of 75 adult patients received transplants from human leukocyte antigen-matched donors, coupled with either reduced intensity (n=40; fludarabine/melphalan, 28; fludarabine/cyclophosphamide, 12) or myeloablative conditioning (n=35, busufan/cyclophosphamide). The patients receiving reduced intensity conditioning were elderly, or exhibited contraindications for myeloablative conditioning. Neutrophil and platelet engraftment occurred more rapidly in the reduced intensity group (median, 9 days vs. 18 days in the myeloablative group, p<0.0001; median 12 days vs. 22 days in the myeloablative group, p=0.0001, respectively). Acute graft-versus-host disease (≥grade II) occurred at comparable frequencies in both groups, while the incidence of hepatic veno-occlusive disease was lower in the reduced intensity group (3% vs. 20% in the myeloablative group, p=0.02). The overall 1-yr survival rates of the reduced intensity and myeloablative group patients were 44% and 15%, respectively (p=0.16). The results of present study indicate that patients with advanced hematological malignancies, even the elderly and those with major organ dysfunctions, might benefit from reduced intensity transplantation.

Co-Morbidity and Disease Status at the Time of Transplant Predict Outcome Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) for Poor Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML).

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the standard of care in poor risk myeloid malignancies. Identifying factors which predict both non-relapse mortality and relapse risk are imperative to patient selection. We report the outcome of 198 cases of poor risk MDS (n=70) and AML (n=128) who underwent allo-HSCT with either myeloablative (MA) (n=67) or reduced intensity conditioning (RIC) (n=131). A T-cell depleted regimen using Alemtuzumab was administered to all patients receiving RIC and for volunteer unrelated donor (VUD) MA transplants. 13% had a diagnosis of refractory anaemia excess blasts (RAEB I), 14% RAEB II, 15% AML with multi-lineage dysplasia, 49% de-novo AML and 9% chronic myelomonocytic leukaemia. The median age of the RIC cohort was 53years (21–72 years) compared with 31years (17–59 years) in the MA group. On comparison of RIC versus MA cohorts, 31% v 45% had a co-morbidity score of 0, 17% v 25% score 1, 17% v 16% score 2 and 35% v 14% score ≥3 (p=0.025). The Charlson co-morbidity index was used to define the pre-transplant score. No difference in disease status at time of transplant was observed between the RIC and MA groups (p=0.399) with 80% v 71% in first complete remission (CR1), 4% v 6% in second CR (CR2), 2% v 6% partial remission (PR), 9% v 9% progressive disease (PrD) and 5% v 8% dysplastic remission (DysCR). A higher number of VUD transplants 61% versus 45% (p=0.042) were observed in the RIC cohort, whereas a higher proportion of cases with poor risk cytogenetics (42% v 26%) (p=0.01) were observed in the MA group. No difference in FAB classification, prior therapy or HLA disparity was observed between the RIC and MA groups. The median follow-up for the MA and RIC groups was 1782days (50–4300days) and 1014days (168–2211days) respectively. The transplant related mortality (TRM) for the MA and RIC cohorts at day+100 was 31% v 10% and at 3years 47% v 30% respectively. The 3year overall survival (OS) was 41% v 47% (p=0.062), 3year disease free survival (DFS) 36% v 43% (p=0.156) and 3year relapse rate 34% v 40% (p=0.28) for the MA and RIC groups respectively. Multiple cox regression analysis identified co-morbidity risk score (p=0.003) disease status at time of transplant (p=0.012) and cytogenetic risk group (p=0.041) as the most significant factors affecting OS for all allogeneic HSCT. Analysis of factors affecting DFS further identified co-morbidity risk group (p=0.007) disease status at time of transplant (p=0.015) and cytogenetic risk group (p=0.022) as retaining significance. On analysis of RIC and MA cohorts separately co-morbidity and disease status remain the most significant variables affecting OS and DFS. With respect to disease status, PR and PrD consistently demonstrate significantly worse outcome than CR1, CR2, or DysCR subgroups. A co-morbidity index of ≥2 displayed inferior outcome to a score of 0 or 1. Age, sex, HLA disparity or sibling v VUD showed no effect on OS or DFS. In summary, the results demonstrate a trend towards improved OS following RIC transplantation, with no significant difference in DFS. Patient selection for allo-HSCT should not be based on age alone, whereas response to chemotherapy and the use of co-morbidity scores more accurately predict outcome following both MA and RIC regimens.

Serious Acute or Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplantation: A Comparison of Myeloablative and Non-Myeloablative Conditioning Regimens.

We have previously described serious graft-versus-host disease (GVHD) as a highly undesirable outcome after allogeneic hematopoietic cell transplantation (HCT). Serious GVHD encompasses death, lengthy hospitalization, major disability, or recurrent major infections related to either acute or chronic GVHD. In a previous study, we found a 25% incidence of serious GVHD among 171 consecutive patients who had HCT after non-myeloablative (NMA) conditioning between January 1998 and May 2002. To put this observation into perspective, we applied the same criteria for serious GVHD in a cohort of 264 consecutive patients who had HCT after myeloablative (MA) conditioning during the same period of time and compared results with those of the previous study. The overall incidence of serious GVHD was 17% (44/264) in the MA group, compared to 25% (43/171) in the NMA group. There were no statistically significant differences in the incidence of grades III–IV GVHD, extensive chronic GVHD or nonrelapse mortality between the two groups (Table). Patients in the NMA group were older and had higher comorbidity scores than those in the MA group. In the univariate analysis, the hazard ratio (HR) of serious GVHD for the NMA group compared to the MA group was 1.71 (95% C.I., 1.1–2.6) (p = 0.01). After adjusting for patient age, patient and donor gender, donor type, HLA-mismatch, aggressive versus indolent malignancy at HCT, remission versus relapse at HCT, myeloid versus non–myeloid malignancy, HCT co–morbidity index, and prior donor lymphocyte infusion, the HR of serious GVHD was 1.50 (95% C.I., 0.8–2.7) (p = 0.17). After censoring for recurrent or progressive malignancy after HCT, the cumulative incidence of serious GVHD at 3 years was 21% for the NMA group and 14% for the MA group, and the HR was 1.33 (95% C.I., 0.7–2.6) (p = 0.40). Reasons for categorization of GVHD as serious (i.e., death, lengthy hospitalization, major disability, or recurrent major infections) were similar between the MA and NMA cohorts. Among the 44 patients with serious GVHD in the MA group, 19 (43%) had serious acute GVHD, and 25 (57%) had serious chronic GVHD. Among the 43 patients with serious GVHD in the NMA group, 20 (46%) had serious acute GVHD, and 30 (70%) had serious chronic GVHD. Among the 264 MA patients, 28 (11%) had grade III–IV acute GVHD and 147 (56%) had extensive chronic GVHD that did not meet the criteria for serious GVHD, compared to 7 (4%) and 84 (49%) of the 171 NMA patients, respectively. We conclude that the type of pretransplant conditioning regimen does not have a large effect on the incidence of serious GVHD after HCT. Assessment of serious GVHD provides additional useful information to acute GVHD grades and the classification of limited and extensive chronic GVHD in describing overall GVHD-related outcomes after HCT.MANMAOutcome, n (%)n = 264n = 171Serious GVHD44 (17)43 (25)Grades III–IV acute GVHD54 (20)27 (16)Extensive chronic GVHD174 (66)114 (68)2-year nonrelapse mortality66 (25)43 (25)

Low Incidence of CMV Reactivation and Infection after Allogeneic Bone Marrow Transplantation (BMT) Incorporating Post-Transplantation Cyclophosphamide (Cy).

Cytomegalovirus (CMV) disease remains an important complication of allogeneic stem cell transplantation (SCT). A major goal has been to develop bone marrow transplant (BMT) preparative regimens that minimize the duration of post-transplantation immunosuppression, and thus the risk of severe infectious complications. Previously, we reported a low rate of CMV reactivation (17.6%, 6/34 eligible patient-donor pairs) among hematologic malignancies patients receiving partially HLA-mismatched (haploidentical) BMT after non-myeloablative conditioning including high dose, post-transplantation Cy (50 mg/kg IV on days 3 and 4). Here, we have retrospectively analyzed an additional 99 recipients of post-transplantation Cy after fludarabine/200 cGy TBI-based nonmyeloablative conditioning and haploidentical BMT (n=44) or busulfan/Cy-based myeloablative conditioning and HLA-matched BMT (n=55). After high-dose Cy, patients undergoing haploidentical BMT received mycophenolate mofetil and tacrolimus, while recipients of HLA-matched grafts received no further graft-versus-host disease (GVHD) prophylaxis. Patients did not receive CMV prophylaxis. CMV reactivation, measured weekly by quantitative PCR, occurred in 38.7% (12/31 eligible donor-patient pairs) in the mini-haploBMT trial and 31% (13/42 eligible patient donor pairs) in the myeloablative trial. CMV reactivation occurred twice in two patients in each trial. CMV disease occurred in two patients in the haploidentical BMT trial (1 retinitis, 1 pneumonia) but in no recipients of HLA-matched grafts. No deaths have been attributed to CMV infection on either trial. In the mini-haplo BMT patients, 58.3% (7/12) of those with CMV reactivation were considered high-risk (recipient CMV IgG positive, donor CMV IgG positive or negative) and 25% (3/12) were considered to be at intermediate risk (recipient CMV IgG negative and donor CMV IgG positive). Of the myeloablative BMT patients, 100% (13/13) of patients with CMV reactivation were part of the high-risk group. In addition to recipient CMV positivity, the presence of graft-versus-host disease (GVHD) was a risk factor for CMV reactivation on the myeloablative trial as 77% (10/13) of patients who reactivated their CMV had GVHD, but not on the “mini-haploBMT” trial where only 41.7% (5/12) had GVHD. The median number of days post-transplant to CMV reactivation was 49 (range 19–197) in the “mini-haploBMT” patients and 56 (range 19–140) in the myeloablative group. The median number of weeks to clear detectable CMV was 1 (range 1–11 in the mini-haploBMT group and 1–4 in the myeloablative group). These rates of CMV reactivation and infection compare favorably to the rates seen in patients receiving haploidentical and HLA-matched grafts following myeloablative conditioning without post-transplantation Cy. The low rates of CMV reactivation may be secondary to low rates of Grade 3–4 GVHD (9.1%, 4/44 “mini-haploBMT patients”; 7.3%, 4/55 myeloablative patients) and rapid immunologic recovery facilitated by the absence of prolonged pharmacologic immunosuppression, especially among recipients of HLA-matched grafts.

Comparison of Outcomes after Reduced-Intensity Versus Myeloablative Stem Cell Transplantation in 128 Patients with Acute Myeloid Leukemia: A Single-Center Analysis.

Background: It is still unclear whether the intensity of the conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) affects the overall outcome of patients with acute myeloid leukemia (AML).Patients and Methods: We retrospectively surveyed the data of 128 patients with AML who received HCT between Jan, 2000, and Mar, 2005. Cytogenetic risk groups based on the SWOG classification were favorable (n=19), intermediate (52), unfavorable (41), and unknown (16) risks. Disease status was CR1 (n=31), ≥CR2 (36), relapse (33), primary refractory (24) and untreated (4). Regimens with myeloablative conditioning (n=71) included cyclophosphamide with 12 Gy TBI (n=48) or busulfan (23), and those with reduced-intensity conditioning (RIC, n=57) included 8 mg/kg of busulfan plus 180 mg/m2 of fludarabine or 0.66 mg/kg of cladribine with or without 2–4 Gy TBI. The patients received bone marrow (n=55), G-CSF-mobilized PBSC (62) or cord blood (11) from either an HLA-matched relative (n=46), a mismatched relative (18) or an unrelated volunteer (64). For GVHD prophylaxis in the myeloablative group, 83% of the patients received cyclosporine (CyA) plus methotrexate (MTX), while the RIC group received CyA with (44%) or without (54%) MTX. The median follow-up of surviving patients was 1,347 days (423–2,282).Results: Patients who received RIC were older than those who received a myeloablative regimen (median age, 55 vs 37 years). The engraftment rates (95% vs 93%) and cumulative incidence of grade II-IV acute GVHD (39% vs 38%) were comparable between the two groups, but the incidence of grade III-IV acute GVHD was higher in the RIC group (21% vs 10%). The 3-year overall survival (OS) according to pre-transplant disease status was 58% in CR1, 53% in ≥CR2, 18% in relapse, and 25% in primary refractory. The 3-year OS according to cytogenetic risk groups was 63% in favorable, 42% in intermediate, 26% in unfavorable, and 35% in unknown risk. The 3-year OS of patients who received grafts from an HLA-matched relative was 52%, and this was 31% in those who received grafts from an alternative donor (unrelated or HLA-mismatched related donor). The 3-year OS and relapse rate were essentially comparable between the two groups, i.e. 33% and 35% for the RIC group and 44% and 47% for the myeloablative group, respectively. Unexpectedly, the 3-year non-relapse mortality (NRM) was higher in the RIC group (52% vs 28%). In a multivariate analysis, pre-transplant non-remission disease status (HR: 3.0 [95% CI, 1.9–5.0] p<0.0001) and transplantation from an alternative donor (HR: 2.4 [95% CI, 1.4–4.2] p=0.0006) were associated with poor OS. The intensity of the conditioning regimen was not a risk factor for poor OS.Conclusions: Our data showed that OS and relapse rate were comparable between the RIC and myeloablative groups, although the RIC group was predominantly composed of older patients. In contrast to our expectation, our data showed higher NRM after RIC, which might be due to a higher incidence of grade III-IV acute GVHD in this group as a result of the intentional induction of a graft-versus-leukemia effect by the rapid tapering of immunosuppresion. To improve survival, GVHD prophylaxis should be optimized in older patients undergoing HCT with a RIC regimen.

Long-Term Survival of Patients with Myelofibrosis Treated with Allogeneic Hematopoietic Stem Cell Transplantation.

Myelofibrosis with myeloid metaplasia (MMM) is a disorder characterized by clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis and bone marrow fibrosis. Between 4/1998 and 1/2006, 17 patients with MMM were treated with allogeneic hematopoietic stem cell transplantation. Patients included 8 males and 9 females with a median age of 51.8 years (range 37–66). All patients were transfusion-dependent at the time of transplantation, 3 (18%) had abnormal cytogenetics and 4 (24%) had a prior splenectomy. Six patients (35%) received a reduced intensity conditioning regimen consisting of either fludarabine and busulfan (1 pt), fludarabine and low dose total body irradiation (1 pt), fludarabine and melphalan (3 pts) or fludarabine and cyclophosphamide (1 pt). Eleven patients (65%) received an ablative regimen of either busulfan and cyclophosphamide (10 pts) or cyclophosphamide and total body irradiation (1 pt). Patients with unrelated donors also received ATG as part of their conditioning. The hematopoietic cell source was peripheral blood in 12 pts (71%) and bone marrow in 5 pts (29%). Six pts (35%) received cells from an HLA-identical sibling, 1 pt (6%) had a 1 Antigen mismatch sibling and 10 pts (59%) received stem cells from an unrelated donor. Graft-versus-host disease prophylaxis consisted of tacrolimus in 15 pts (88%) and cyclosporine in 2 pts (12%). Transplant-related mortality was 17% (sepsis 1 pt, VOD 1 pt, acute GVHD 1 pt) all occurring in the group treated with a myeloablative regimen. Of the remaining 14 patients, all achieved hematological recovery and transfusion independence. There were 2 relapses and one patient died of disease recurrence; both relapses occurred in the group receiving a reduced intensity regimen. The other 12 patients remain alive and in remission. The 6-year actuarial survival is 67% with no statistical difference between the groups who received a reduced intensity versus a myeloablative regimen. In conclusion, Myelofibrosis with Myeloid Metaplasia can be successfully treated with allogeneic hematopoietic stem cell transplantation with a significant proportion of patients achieving long-term survival. Hematopoietic recovery can be achieved despite the presence of marrow fibrosis. The optimal preparative regimen remains to be determined with more relapses observed in the reduced intensity regimen group and a higher mortality seen in the myeloablative group. A risk-stratification strategy for regimen selection should be considered in future studies.