Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1111-1111
Author(s):  
B. Oran ◽  
A. Aleman ◽  
E. J. Shpall ◽  
C. Hosing ◽  
M. Korbling ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Stem Cell ◽  
Median Time ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Lymphoid Malignancies ◽  
Gvhd Prophylaxis

Abstract TTP is one of the complications of allogeneic hematopoietic stem cell transplantation (HSCT). In contrast to idiopathic cases, post-transplantation TTP may not be associated with severe von Willebrand factor-cleaving protease deficiency but rather a diffuse endothelial injury. Our aim was to define incidence, risk factors and mortality of TTP following allogeneic HSCT. 1312 patients with lymphoid malignancies (n=605), myeloid malignancies (n=688) or aplastic anemia (AA, n=18) who were treated with ablative preparative regimens (n=614) or reduced intensity regimens (n=697) followed by HSCT from an HLA matched related (MRD, n=694) or unrelated donor (MUD; n=461) and 1–3 antigen mismatched related (MMR, n=99) or unrelated donor (MMUD, n=57) between December 1997 and December 2004 were studied. Patients with prior allogeneic HSCT or graft failure were excluded. GVHD prophylaxis was tacrolimus-based in 1276 (97.3%) and cyclosporine based in 15 (1.1%) patients. Twenty patients did not receive GVHD prophylaxis per protocol. Anti-thymocyte-globulin (ATG) was added in 350 patients. Stem cell sources were bone marrow (n=626), peripheral blood (n=635) or cord blood (n=50). The following variables were evaluated: age, gender, primary diagnosis, disease status before HSCT, intensity of preparative regimen, stem cell source and acute GVHD(aGVHD) grade ≥2 (time dependent variable). Of the 1312 patients with a median follow-up from transplantation of 11.4 months (range, 5 days-7.2 years), 77 developed TTP (6%). The actuarial risk of developing TTP was 6.5% at 1 year. The median time of the onset of TTP was 67 days post HSCT (range, 11–1812) with 27 cases (35%) presenting after day 100. Female gender, lymphoid malignancies, unrelated or antigen mismatched related donor and aGVHD grade ≥2 were found to be independent risk factors. (Table1). Among the patients who had aGVHD grade≥2, the median time of interval between the onsets of two events was 25 days (range, 2–335 days). All patients were treated with therapeutic plasma exchange (PE). Of the 77 patients only 1 died of TTP (intracranial hemorrhage). The overall one-year survival after TTP was 29% and the most common cause of death were acute or chronic GVHD (n=35, 55%) and primary disease progression (n=10, 16%). Stem cell donors other than MRD, lymphoid malignancies and aGVHD≥2 have been established as risk factors associated with development of TTP and therapeutic PE has been shown to decrease TTP related mortality. Risk factors for TTP after allogeneic HSCT Variables sample size events HR 95% CI p Male 793 33 1.0 Female 518 44 2.2 1.3–3.6 0.002 Myleoid malignancy 688 33 1.0 Lymphoid malignancy 605 42 1.9 1.1–3.3 0.03 AA 18 2 1.3 0.2–8.0 0.75 MRD 694 28 1.0 MUD 461 40 2.9 1.6–5.1 &lt;0.001 MMR 99 7 2.4 0.9–6.0 0.06 MMUD 57 2 1.7 0.4–7.6 0.5 aGVHD ≥2 370 39 3.3 2.0–5.5 &lt;0.001

Amelioration of Late Complications Following Unrelated Donor Bone Marrow Transplantation When Anti-Thymocyte Globulin Is Used as a Part of Conditioning.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5319-5319
Author(s):  
Matthew E. Adess ◽  
Patrick Stiff ◽  
Tulio Rodriguez ◽  
John Norton ◽  
Mala Parthasarthy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Graft Rejection ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Donor Bone Marrow ◽  
Number Of Patients ◽  
Significant Difference ◽  
Unrelated Donors ◽  
The Impact

Abstract Polyclonal anti-thymocyte globulin (ATG) reduces the risk for primary graft rejection as well as acute graft-versus-host disease (GVHD) by depleting T cells in both the host and the infused allograft. However, the impact of ATG on late outcomes is less certain. We report the results of a retrospective landmark analysis of consecutive patients who underwent an unrelated donor bone marrow transplant at our center between January 2001 and October 2005 (n=45) and survived at least 90 days following transplant. We compared late outcomes in patients who either recieved ATG (n=25) or did not (n=20) as a part of their conditioning regimen. Conditioning was with either busulfan and cyclophosphamide (n= 28; 17 without ATG) or BCNU, etoposide, cytarabine, and melphalan (n=18; 3 without ATG). Most patients (20) received rabbit ATG at a median dose of 3 mg/kg (range: 1.5–9 mg/kg) on day -4 and -3. Others were given equine ATG. GVHD prophylaxis consisted of tacrolimus + methotrexate in both groups. Median age was 42 years (range 18–65; 14 female). Bone marrow from unrelated donors matched at HLA-A, B, C, and DRB1 (7/8 and 8/8 matches) was used as the stem cell source. Diseases treated were CML (11), HD (9), AML (8), MDS (6), NHL (3), MM (3), and other (5). A median of 3 prior therapies had been given before transplant (range 1–5). There was no significant difference (Pearson χ2) in the number of patients beyond CR1/CP1 (n=25) and those having failed a prior autograft (n=17) between the two groups. The median overall survival in the recipients of ATG was 1382 days (95% CI: 373– 2391 days) as opposed to 364 days (95% CI: 0–851) in those not receiving ATG (P=0.125 by Log-Rank test); with a 1-year overall survival of 76% (59%–93%) vs. 50% (28–72) in the ATG vs. no ATG cohorts respectively, and 69% (49–89) vs. 44% (22–66) at 2-years. The 1-year progression free survival was 84% (69–98) vs.90% (77–100) in the ATG vs. no ATG cohorts, and 84% (69–98) vs. 67% (37–97) at 2 years. Chronic GVHD developed in 15/20 (75%) patients not receiving ATG (45% extensive), and in 12/25 (48%) in those recieving ATG (16% extensive) (P=0.06 Pearson χ2). Graft rejection was seen in 2/20 patients in the non-ATG arm and 1/25 patients in the ATG arm. Despite a lower incidence of chronic GVHD, the relapse rate was similar in the two groups (16% in the ATG group vs. 20% in the non-ATG group; P=0.73). Lymphoid recovery was similar in the two groups. The absolute lymphocyte counts at day-90 and day-180 post transplant were 680 vs 800/microL and 1100 vs. 1500/microL in the no ATG vs. ATG cohorts (P=0.275 repeated measures ANOVA). Serious late infections requiring parenteral antimicrobial treatment occured in 8 patients (32%) receiving ATG, and in 9 patients (45%) in the non-ATG arm ((P=0.248). CMV reactivation was seen in 8 patients (32%) receiving ATG, and 7 (35%) in the non-ATG arm. Eleven patients (55%) have died in the no ATG cohort from either relapse (2), GVHD (4) or infection (5); whereas in the ATG cohort 9 (36%) have died of either relapse (4), GVHD (3) or infection (2). In conclusion, ATG appears to reduce delayed transplant related complications, such as chronic GVHD and infections, in patients receiving bone marrow from unrelated donors. This may lead to a favorable trend towards improved survival in patients recieving ATG as a part of non-total body irradiation based conditioning.

scholarly journals Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2354-2363 ◽  
Author(s):  
J Casper ◽  
B Camitta ◽  
R Truitt ◽  
LA Baxter-Lowe ◽  
N Bunin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Significant Difference ◽  
Matched Sibling

Allogeneic bone marrow transplantation is the treatment of choice for many childhood leukemias. The donor of choice-an HLA matched sibling-is only available about 30% of the time. Unrelated donors are an alternative choice. In this report, we describe the results of unrelated donor bone marrow transplants (BMT) in 50 children with leukemia (25 acute lymphoblastic leukemia [ALL], 3 acute myeloid leukemia [AML], 3 juvenile chronic myelogenous leukemia [JCML], 10 chronic myeloid leukemia [CML]) or myelodysplastic syndrome (MDS; 9). The median age of the 31 male and 19 female patients was 9 years (range 2 to 18). Only 13 patients were serologically matched at HLA-A, B, DR, and DQ with their donors; 6 of these were reactive in mixed lymphocyte culture. The other 37 patients were mismatched for one (36 patients) or more (1 patient) HLA antigens. Pretransplant conditioning included cytosine arabinoside, cyclophosphamide, fractionated total body irradiation (TBI) (with lung, liver, and more recently, kidney shielding), and methylprednisolone. High-risk patients also received busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of T- cell depletion with IgM monoclonal antibody T10B9 plus complement and posttransplant cyclosporine-A. Forty-nine patients (98%) engrafted. Median times to greater than 500 polymorphonuclear leukocytes (PMN)/microL and greater than 25,000 platelets/microL were 18 and 20 days, respectively. Acute GVHD > or = grade II occurred in 16 patients (33%); 13 (81%) of these died. Chronic GVHD developed in 30 of 40 patients at risk, but was extensive in only 5. Event-free survival (EFS) for all patients was 44% +/- 7% (median follow-up was 49 months), and overall survival was 50 +/- 7%. Patients with low-risk disease (ALL or AML in first or second remission and CML in chronic phase) had a better EFS than children with high-risk disease (60% v 34%, P = .07). There was no significant difference in EFS between patients who were serologically matched with their donors (46%) and those who were partially mismatched (43%) (P = .97). These data compare favorably with published reports for children transplanted with HLA-matched sibling donors and should encourage earlier consideration of unrelated donor BMT in children with leukemia or myelodysplasia.

Quadruple Therapy with CsA, MTX, MMF and ATG and Triple Therapy with CsA, MTX and ATG for Preventing Graft-Versus-Host Disease in Unrelated Donor Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5296-5296 ◽  
Author(s):  
Zhiping Fan ◽  
Zhengshan Yi ◽  
Qifa Liu ◽  
Jing Sun ◽  
Dan Xu ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Genetic Loci ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Disease Free

Abstract Objective To explore the effective protocol for graft-versus-host disease (GVHD) prophylaxis in unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Methods 31 patients with leukemia received URD-HSCT, of whom 16 received quadruple therapy (quadruple group) with CsA, MTX, MMF and ATG for GVHD prophylaxis and 15 received triple therapy (triple group) with CsA, MTX and ATG. 22 patients were matched in all HLA genetic loci with donors, seven were mismatched in one HLA genetic locus, 1 in two HLA genetic loci, and 1 in three HLA genetic loci. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 17 cases and modified BuCY conditioning regimen (hydroxyurea, busulfan, Ara-C, Cyclophosphamide) in the other 14 cases. Immune reconstitution of quadruple group and triple group at 1,3, 6, 9,12 month after transplantation were examined by flow cytometer, and the diference of the two group were estimated with Independent-Samples T test. The incidence of GVHD of the two group was esitimated with Mann-Whitney Test. Kaplan-Meier survival analysis model was used to estimate the overall survival and the disease-free survival (DFS). Results Immune reconstitution after transplantation of quadruple group and triple group have no significant difference (P&gt;0.05). Acute GVHD (aGVHD) occurred in 9 patients (56.25%) of the quadruple group and in 11 (73.33%) of the triple group, respectively. The incidence of acute GVHD (aGVHD) differed little between the two group (P=0.238). The incidence ofIII~IV°aGVHD in the two group were 6.30% and 26.67%, respectively, and there was no significant difference (P=0.122). 6 patients had chronic GVHD (cGVHD), in the16 cases who could be followed up in quadruple group, 3 of the 11 patients who could be followed up in triple group developed cGVHD postoperatively (P=0.580). Four patients of quadruple group died of hemorrhagic cystitis, mycotic pneumonia, tuberculosis and relapse, respectively. 3 patients of triple group died of GVHD, and the other 3 died of GVHD associated interstitial pneumonia, cytomegalovirus (CMV) pneumonia and pneumocystis carinii infection. The lethality of GVHD of quadruple group and triple group were 0%,26.7%, respectively, and there was significant difference(P=0.027). The one-year disease-free survival rate was 75% and 60% in patients of the quadruple and the triple group, respectively, and significant difference was not noted (P= P=0.188). Conclusion Compared with triple therapy with CsA, MTX and ATG, CsA+MTX+MMF+ATG procedure dose not worsen the immune reconsititution after transplantation. It can’t decrease the incidence and severity of aGVHD, but can lower the lethality of GVHD in URD-HSCT. The quadruple procedure may lead to higher relapse rate after URD-HSCT.

Allogeneic Bone Marrow Transplantation From HLA Mismatched Family Donors in Children with Aplastic Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 831-831 ◽  
Author(s):  
Hideki Muramatsu ◽  
Hiromasa Yabe ◽  
Ryoji Kobayashi ◽  
Akira Kikuchi ◽  
Kazuko Kudo ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Secondary Malignancy ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Unrelated Donors ◽  
Related Donor ◽  
Family Donor

Abstract Abstract 831 The first-line therapy for children with severe aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-matched family donor, and immunosuppressive therapy (IST) is indicated for patients without HLA-matched family donors. While the standard therapy for children who fail to respond to IST is allogeneic HSCT from an HLA-matched unrelated donor, HSCT from an HLA-mismatched family donor has also been indicated. Compared with unrelated donors, an HLA-mismatched family donor has some advantages especially for children who need urgent transplantation. We analyzed the clinical outcome of 578 children (325 boys and 253 girls) with AA (age, <20 years) who received allogeneic BMT between 1990 and 2009 in Japan, and registered to the Transplant Registry Unified Management Program (TRUMP). The median age at transplantation was 11 years (0–19), and the donors were serological 6/6 HLA-matched related donors (MRD) (n = 312), 1 locus-mismatched related donor (1MMRD) (n = 44), 2–3 loci-mismatched related (haploidentical) donors (n = 9), and HLA-matched unrelated donors (MUD) (n = 213). Causes of deaths were as follows: acute graft-versus-host disease (GVHD) (n = 4), chronic GVHD (n = 4), acute respiratory distress syndrome (n = 2), severe hemorrhage (n = 7), engraftment failure (n = 5), infection (n = 18), idiopathic pneumonia (n = 8), organ failure (n = 19), secondary malignancy (n = 4), and others (n = 4). The probability of severe acute GVHD (grade III–IV) in patients transplanted from 1MMRD (26.9% ± 7.4%) was significantly higher than that in patients transplanted from MRD (4.9% ± 1.3%) (p < 0.001). The probability of 5-year overall survival (5y OS) of patients transplanted from 1MMRD (93.1% ± 3.9%) was comparable to that of patients transplanted from MRD (93.1% ± 1.5%) (p = not significant, NS), but it was significantly better than that of patients transplanted from haploidentical donors (66.7% ± 15.7%, p =.016) and MUD (79.0% ± 2.9%, p =.014). In the subgroup analysis of 1MMRD, no significant difference was observed between HLA class I-mismatched (n = 32) and class II-mismatched patients (n = 12) (5y OS; 93.8% ± 4.3% vs. 91.7% ± 8.0%, p = NS). Comparison of the survival outcome based on the transplant period (1990–1999 vs. 2000–2009) revealed that the probability of 5y OS of patients transplanted from 1MMRD was not significantly different (92.3% ± 5.2% (n = 26) vs. 94.4% ± 5.4% (n = 18), p = NS), while that of patients transplanted from MUD significantly improved in the same period as we reported previously (67.1% ± 5.5% (n = 73) vs. 86.1% ± 3.1% (n = 140), p =.001)(Yagasaki et al., Blood 2011). In multivariate analysis, haploidentical donors (p <.001), MUD (p <.001), age ≥ 10 years (p <.001), and transplant period (1990–1999 vs. 2000–2009, p =.006) were identified as independent covariates associated with unfavorable OS. In summary, our analysis revealed that an HLA-mismatched related donor, especially 1MMRD, could be selected as a donor candidate for children with AA who need urgent transplantation. Disclosures: No relevant conflicts of interest to declare.

Favorable Results of Allo-HSCT from MRD in Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5934-5934
Author(s):  
Miroslaw Markiewicz ◽  
Monika Dzierzak-Mietla ◽  
Patrycja Zielinska ◽  
Agata Wieczorkiewicz-Kabut ◽  
Sylwia Mizia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Collagen Type ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Graft Loss ◽  
Chronic Phase ◽  
Curative Treatment ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Introduction: Myelofibrosis (MF), chronic myeloid malignancy associated with shortened survival, in majority of patients develops de novo as Primary MF, but also polycythemia vera (PV) or essential thrombocythemia (ET) may progress into post-PV or post-ET MF. Although management of MF includes several treatment options, the only potentially curative treatment approach in MF is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aim of this study was to evaluate the results of allo-HSCT in patients with MF treated in Katowice, Poland. Material and Methods: 27 pts (14 male and 13 female) with median age 51 years (range 21–63) were treated with allo-HCT due to PMF (20), post-PV (4) or post-ET (3) MF. 11,7,11,26 and 41% of pts had DIPSS 0,1,2,3 and 4, respectively. Median bone marrow cellularity was 70% (10-100%), fibrosis was collagen-type (14 pts including 2 with osteosclerosis), reticulin (10) or it was not specified (3). Splenomegaly was present in all pts: 13-20 cm (14 pts), > 20 cm (13 pts). JAK2V617F point mutation was present in 18 pts. Karyotype was available in 14 pts: in 9 normal, in 5 with variable abnormalities. Median time from diagnosis to allo-HCT was 1.5 (0.4–9.5) years. 16 pts (59.3%) received cells from HLA-matched related donor (MRD), 11 pts (40.7%) from unrelated donor: 10/10 (9) or 9/10 (2) HLA-A,B,C,DR,DQ alleles matched. Reduced intensity conditioning (RIC) was used in 26 pts, 1 patient received myeloablative conditioning (MC). Sources of stem cells were: peripheral blood (21), bone marrow (4) and both (2). All pts but one had chronic phase of MF at time of transplantation. Results: 14/27 (52%) pts are alive at median 3.4 (0.4-5.4) years after allo-HSCT: 11/16(69%) from MRD and 3/11(27%) from MUD, p=0.032. Graft failure, graft loss or PRCA were observed in 3, 5 and 1 pt, respectively. Absolute neutrophil count >0.5×109/L and platelet count >50×109/L were achieved at median 16 and 28 days, respectively. 12/27 (44%) pts reached complete blood count of Hb>10 g/dl, Plt>100 G/l and WBC>3.5 G/l; 11 of them (92%) are alive. 6/27 (22%) pts remained either RBC or PLT transfusions dependent post-transplant; 3 of them (50%) died. 9/27 (33%) pts remained both RBC and PLT transfusion dependent and all of them died. JAK2V617F mutation was completely eradicated in 11/16 evaluated previously positive patients (69%), decreased in 4 (25%) and stable in 1(6%) pt. Acute graft-versus-host disease (aGVHD) III-IV developed in 5/27 (19%) and extensive chronic GVHD in 5/19 (26%) pts. Relapse occurred in 4 pts and was treated with subsequent second transplant (in 1 pt thereafter by 3-rd allo-HSCT). Spleen length decreased at median by 5 (0.3-9.2) cm. Out of 7 pts with initial collagen fibrosis who were evaluated post-transplant, 1 had no fibrosis, 5 reticulin type and only in 1 pt collagen fibrosis was stable. Out of 3 pts with initial reticulin fibrosis it disappeared in 2 and progressed to collagen type in 1. Causes of death were GVHD (5 pts: 3 aGVHD, 2 cGVHD) and pancytopenia with either infection (7 pts) or CNS hemorrhage (1 pt). Conclusions: Allo-HSCT, the only curative treatment of myelofibrosis, provides chance of long survival, regression of the disease (lower stage of fibrosis, JAK2V617F eradication) and improved quality of life (transfusion independency, decreased splenomegaly). Transfusion independency may indicate good outcome. Favorable results are observed after allo-HSCT from MRD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Race as a Factor in Donor Selection and Survival of Children with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplant in Florida

2021 ◽  
Author(s):  
Biljana Horn ◽  
Deepak Chellapandian ◽  
Nikhil Lamba ◽  
Gauri Sunkersett ◽  
Jorge GalvezSilva ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hla Matching ◽  
Hematopoietic Cell Transplant ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Related Donor ◽  
The Impact ◽  
To Receive

Background Previous studies have explored post-hematopoietic cell transplant (HCT) outcomes by race in adults; however, pediatric data addressing this topic are scarce. Procedure This retrospective registry study included 238 White (W) and 57 Black (B) children with hematologic malignancies (HM) receiving first allogeneic HCT between 2010 and 2019 in one of five Florida pediatric HCT centers. Results We found no differences between W and B children by transplant characteristics, other than donor type. There was a significant difference in use of HLA-mismatched donors (HLA-MMD) (53% W, 71% B, p=0.01). When comparing HLA-MMD use to fully HLA-matched donors, B had RR of 1.47 [95% CI 0.7-3] of receiving a mismatched unrelated donor (MMUD), RR of 2.34 [95% CI 1.2-4.4] of receiving a mismatched related donor (MMRD), and a RR of 1.9 [95% CI 0.99-3.6] of receiving a mismatched cord blood donor (MMCBD) HCT, respectively. There was no significant difference in the incidence of aGVHD (48% W, 35% B), p=0.1 or cGVHD (19% W 28% B, p=0.1), or primary cause of death. Overall 24-month survival was 61% [95% CI 54-68%] for W, and 60% [95% CI 38-68] for B children, log-rank p=0.72. While HLA matching improved survival in W children, the number of B children receiving HLA-matched HCT was too small to identify the impact of HLA matching on survival. Conclusions In this contemporary cohort of children with HM we found that B children were more likely to receive HLA-MMD transplants, but this did not adversely affect survival or GVHD rates.

scholarly journals Therapy for AML with Myelodysplasia-Related Changes (AML-MRC)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1340-1340
Author(s):  
Taiichi Kyo ◽  
Kouhei Kyo ◽  
Takeshi Okatani ◽  
Tetsuro Ochi ◽  
Kayo Toishigawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Survival Rate ◽  
Maintenance Therapy ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Hematopoietic Stem ◽  
Elderly Aml ◽  
Significant Difference ◽  
Blast Count ◽  
Bone Marrow Blasts

Abstract Introduction Patients with AML-MRC are almost older and highly resistant to chemotherapy, so that they are thought to be not eligible for intensive chemotherapy (IC) compared with de novo AML. Reduced intensity chemotherapy, such as low-dose cytarabine and azacitidine (AZA), are used for AML-MRC therapy, but their overall survival (OS) is not satisfactory. Although chemotherapies for AML (except for M3) have not improved for 30 years, several supportive cares for IC have shown a great progress. In this background, we have used IC as induction, consolidation, and maintenance therapies, including AZA, for elderly AML-MRC to avoid relapses and obtain longer survivals. For patients, whose age are under 65 years, hematopoietic stem cell transplantations (HSCT) were mainly considered after IC treatments. Methods Between March 2012 and April 2015, 62 newly diagnosed AML-MRC were treated with idarubicin (IDR) 12 mg/m2 on days 1, 3, 5, 8, and enocitabine (BH-AC) 350mg/m2 on days 1-10 as an induction chemotherapy (IDR+BH-AC). Over 70 years patients, IDR and BH-AC were reduced to 10 mg/m2 and 300 mg/m2, respectively. On day 15, if bone marrow blasts were over 5%, etoposide 100 mg/m2 was additionally treated on days 16-19. Some fit patients, who reached complete remission (CR), were received cytarabine (Ara-C) 1 g/m2 on days 1-5 (bid) and mitoxantrone (MIT) 7 mg/m2 on days 2-4, as a consolidation therapy (Ara-C+MIT). As a maintenance therapy, AZA 75mg/m2 days 1-5 (i.v.) and IDR day1 + BH-AC days 1-4 (or aclarubicine 14 mg/m2 days 1-6 + BH-AC days 1-4) were sequentially treated for one year. If a relapse was observed, mainly AZA was treated to keep a good quality of life. Results Total number of patients was 62 (44 were male) and median age at diagnosis was 71 years (range 36-86). Median WBC was 3,800 x 109/L (600-129,200), median peripheral blast count was 16% (0-96), and median bone marrow blast count was 57% (22-95). Thirty-five patients had intermediate cytogenetics and 27 adverse. Twenty-nine patients, who had >5% bone marrow blasts on day 15, were additionally treated with etoposide. Median follow-up time was 25 months. After the induction therapy, 54 patients (87%) achieved CR, 5 (8%) partial remission, 2 (3%) were refractory, and 1 (2%) died. The CR rate of male was 82% (36/44) and female 100% (18/18). The CR rate of patients with intermediate cytogenetics was 86% (30/35), adverse 89% (24/27), <70 years 83% (20/24), and ≥70 years 89% (34/38). There were no significant differences between CR rates and gender, cytogenetics, or age, respectively. The CR rate of patients treated with etoposide after IDR+BH-AC was 83% (24/29) and without etoposide 91% (30/33). There was no significant difference between the two groups. Among patients with adverse cytogenetics, 67% (18/27) patients treated with etoposide, and intermediate 31% (11/35) (p=0.00983), so that patients with adverse cytogenetics tended to be resistant to IDR+BH-AC and needed the additional etoposide treatment. By Kaplan-Meier method, two year survival of 62 patients was 50.1% (95% CI, 33.9-64.3) and 53.2% (95%CI, 35.0-68.4) in patients achieving CR (n=53, excluding one withdrawn patient). The rate of CR duration for 2 years was 48.2% (95% CI, 30.7-63.7). The median survival with adverse cytogenetics in CR was 18 months (95% CI, 11-25) and that of intermediate was not reached (95% CI, 18-NA). There was a significant difference between OS with adverse cytogenetics in CR and intermediate (p=0.00463). Thirty-two patients in CR received the consolidation therapy, median age was 70 years (range 36-82), 2 patients died due to fungal infection. On the other hand, 21 patients in CR, median age was 77 years (range 59-86), did not have the consolidation, but the maintenance therapy. The survival rate of two groups were almost the same. Ten patients underwent HSCT, 8 in CR and 2 in refractory or relapse, and 2 patients died due to HSCT-related events. HSCT did not influence on OS and CR duration. Conclusions Our intensive chemotherapy for AML-MRC showed a great efficacy and a good tolerability. The additional treatment with etoposide after IDR+BH-AC was especially effective for patients with adverse cytogenetics. Although the 2-years survival rate of elderly AML-MRC was 50% in our study, further efforts are needed to obtain a longer survival, especially for patients with adverse cytogenetics. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2301-2301 ◽  
Author(s):  
Raajit K. Rampal ◽  
Roni Tamari ◽  
Nan Zhang ◽  
Caroline Jane McNamara ◽  
Franck Rapaport ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Triple Negative ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Disease Characteristics ◽  
Donor Type ◽  
The Impact ◽  
Reduced Intensity

Abstract Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

No Significant Benefit of Marrow and Blood HLA-Haploidentical Stem Cell Transplantations Given by Mothers with Long-Term Fetomaternal Microchimerism.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5452-5452
Author(s):  
Ying Wang ◽  
De Pei Wu ◽  
Aining Sun ◽  
Zhengming Jin ◽  
Huiying Qiu
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Chronic Gvhd ◽  
Rank Test ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Standard Intensity ◽  
Significant Difference ◽  
Cell Source

Abstract Non-T-cell-depleted maternal HLA-haploidentical hematopoietic stem cell transplantations(SCT) have been reported feasible based on the hypothesis that long-term fetomaternal microchimerism(FMC) is linked with hyporesponsiveness to inherited paternal antigens(IPAS),but the hypothesis is still in debate due to lack of direct evidence. To determine whether the existence of such microchimerism affect the outcome of maternal HLA-haploidentical SCT, we investigated the outcomes of 18 patients (median age 19) with hematologic malignancies (ALL 8, AML 6, CML 3, NHL 1) who underwent haploidentical SCT from mothers with the same regime from July 2003 to January 2005. Donor was treated with granulocyte colony stimulating factor subcutaneously at a dose of 300μg per day for 5 days before bone marrow harvesting. Leukaphereses were performed using a continuous-flow blood cell separator if CD34+ cells in the bone marrow harvest were less than 4.0×106 cells/kg. Patients with CML or AML in CR received 7.5Gy TBI based standard-intensity regimen combined with cyclophosphamide plus cytarabine. The remaining received non-TBI standard-intensity regimen consisting of cytarabine, busulfan and cyclophosphamide. Antithymocyte globulin(ATG) at a dosage of 2.5mg/kg/day on days −5 to −3 was given as an additional immunosuppressive measure in all patients. To prevent GVHD, patients also received cyclosporin at a dose of 3mg/kg/day as a continuous infusion from day −10, 30mg/kg/day mycophenolate mofetil starting on day −10, and short-term methotrexate administered on days 1, 3, 6, 11 at doses of 15, 10, 10, and 10mg/m2. Among all these patients, microchimerism were confirmed with nested polymerase chain reaction using sequence-specific primers(PCR-SSP) typing for HLA in 10 donor-recipient pairs. In the 2 categories as to whether the microchimeric status of the donor is positive or negative, they had similar characteristics in the background factors such as recipient sex, type of conditioning regime, stem cell source, and disparity of HLA except recipients of positive group had more CML. Engraftment was obtained in all patients. As of august 1, 2005, 5 patients died (1 of relapse, 4 of complication), other 13 patients were alive and free of disease. The 2-year overall survival for the whole cohort was 58%. Although there was a survival advantage for pairs with microchimerism over pairs without it, the influence on outcome was not statistically significant (P=0.9, log-rank test). The cumulative incidences of grade Ò/Ô acute graft-versus-host disease (GVHD) were 39% (95%CI, 17%–64%). Also no significant difference was observed between the two groups. Extensive chronic GVHD developed in 5 of 13 patients who could be evaluated. These results indicate maternal HLA-haploidentical hematopoietic SCT is a acceptable option for patients who lack immediate access to a conventional stem cell source, but the presence of fetomaternal microchimerism may not correlate to the existence of immunological tolerance between mother and offspring.

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