scholarly journals Hematopoietic Cell Transplantation for Children with Acute Megakaryoblastic Leukemia without Down Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4671-4671
Author(s):  
Asahito Hama ◽  
Takashi Taga ◽  
Daisuke Tomizawa ◽  
Hideki Muramatsu ◽  
Daiichiro Hasegawa ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Down Syndrome ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cord Blood Transplantation ◽  
Hematopoietic Cell ◽  
Complex Karyotype ◽  
Acute Megakaryoblastic Leukemia ◽  
Monosomy 7 ◽  
Megakaryoblastic Leukemia

Abstract Acute megakaryoblastic leukemia (AMKL) accounts for 10% of childhood acute myeloid leukemia. Although AMKL patients with Down syndrome (DS-AMKL) have an excellent survival rate, patients with non-DS-AMKL experience poor outcomes. Despite therapeutic advances, including use of intensified treatment protocols, there is no consensus on the optimal treatment strategy for non-DS-AMKL. Some study groups recommend hematopoietic cell transplantation (HCT) for patients with non-DS-AMKL in the first complete remission (CR1); however, it is unclear whether HCT in CR1 improves outcomes of these patients. To assess outcomes and risk factors of HCT for patients with non-DS-AMKL, we retrospectively analyzed 203 patients with non-DS-AMKL (male, 95; female, 108) who underwent first HCT between 1986 and 2015 using data from the Japan Society for Hematopoietic Cell Transplantation. The median age at the time of HCT was 2 years (range, 0-16). Out of 203 patients, 12 had translocation t(1;22)(p13;q13), 18 had monosomy 7, 21 had complex karyotype, and 109 had other chromosomal abnormalities. Bone marrow transplantation (BMT) was performed for 114, cord blood transplantation (CBT) for 74, and peripheral blood stem cell transplantation (PBSCT) for 15 patients. Seventy-eight patients underwent HCT from related (HLA-matched, 43; HLA-mismatched, 35), 108 from unrelated (HLA-matched, 56; HLA-mismatched, 52), and 17 from autologous donors. Ninety-two patients underwent HCT in CR1, 21 in the second CR (CR2), and 90 in non-CR. Myeloablative conditioning (MAC) regimen was defined as the use of total body irradiation (TBI) ≥8 Gy, administration of busulfan >8 mg/kg or melphalan >140 mg/m2. All other regimens were included in reduced intensity conditioning (RIC) regimen. MAC regimen was used for 192 and RIC regimen for 11 patients. Median duration of follow-up after HCT was 713 days (range, 3-10008). Out of 203 patients, 183 (90%) exhibited engraftment. Sixteen out of 20 patients who did not exhibit engraftment underwent HCT in non-CR. In the entire cohort, 5-year overall survival (OS) and event free survival (EFS) rates were 43% and 38%, respectively. Seventy-two patients died of disease relapse and 42 died of transplantation-related complications. Five-year OS/EFS rates were not significantly different between BMT (48%/43%), CBT (35%/31%), and PBSCT (31%/27%) (p = 0.221/p = 0.087). In allogeneic HCT, 5-year OS/EFS rates were significantly lower in patients who underwent HCT from HLA-mismatched donors (27%/22%) than those from HLA-matched donors (52%/47%) (p < 0.001/p < 0.001). Five-year cumulative incidence (CI) of relapse after HLA-mismatched HCT (64%) was significantly higher than that after HLA-matched HCT (45%) (p = 0.006). Five-year OS/EFS rates were not significantly different between patients with translocation t(1;22)(p13;q13) (50%/42%), those with monosomy 7 (65%/59%), and those with complex karyotype (61%/52%) (p = 0.094/p = 0.111). Five-year OS/EFS rates of patients who underwent HCT in CR1 (72%/64%) were significantly higher than those of patients who underwent in CR2 (23%/13%) and non-CR (16%/16%) (p < 0.001/p < 0.001). Five-year CI of relapse was significantly lower in CR1 (28%) than in CR2 (73%) and non-CR (73%) (p < 0.001). Five-year non-relapse mortality was significantly higher in non-CR (27%) than in CR1 (15%) and CR2 (14%) (p = 0.022). Among the 92 patients who underwent HCT in CR1, 3-year CI of relapse in patients who received RIC (67%) was significantly higher than that in patients who received MAC regimen (25%) (p = 0.021). Five-year OS/EFS rates associated with HCT from HLA-mismatched (70%/63%) and HLA-matched donors (77%/59%) were not significantly different (p = 0.609/p = 0.761). In the multivariate analysis for 5-year OS, HCT in CR2 and non-CR was found to be a significant risk factor (hazard ratio, 5.16; 95% CI, 3.36-7.92; p < 0.001). In conclusion, multivariate analysis confirmed that HCT in CR1 was a good prognostic factor for 5-year OS. Risk stratification in patients with non-DS-AMKL should be established to determine the indication for HCT in CR1. Disclosures No relevant conflicts of interest to declare.

Establishment of Trichimerism in the Dog Leukocyte Antigen (DLA)-Identical Canine Hematopoietic Transplant Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3193-3193
Author(s):  
Scott S. Graves ◽  
William Hogan ◽  
George E. Georges ◽  
Christian Kuhr ◽  
Razvan Diaconescu ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cord Blood Transplantation ◽  
Variable Number Tandem Repeat ◽  
Hematopoietic Cell ◽  
Solid Organ ◽  
Kidney Graft ◽  
Blood Transplantation ◽  
Cell Counts

Abstract Although hematopoietic cell transplantation is generally accomplished utilizing a single donor and recipient pair, multiple donors have been used to mediate engraftment, particularly in the case of low donor cell counts as in umbilical cord blood transplantation. The general engraftment outcome of HLA nonidentical cord blood transplantation is the predominance of one of the units over the other. Here we pose the question whether in the canine hematopoietic cell transplantation model, can we establish multiple donor chimerism using two DLA-identical donors and a single recipient. We identified 8 triplets of DLA-identical littermates by matching highly polymorphic microsatellite markers within DLA class I and class II regions and confirmed by DLA-DRB1 gene sequencing. The marrow recipients received 2 Gy total body irradiation followed by intravenous infusions of marrow cells from both donors 1 and 2. The median number of donor cells injected was 4.1 (range = 2.0–7.0) X 108 cells/kg. Post grafting immunosuppression consisted of cyclosporine (CSP) and mycophenolate mofetil (MMF) given for 35 and 28 days, respectively. The median time to hematological recovery (blood counts equivalent to pre-HCT levels) was 38 (range = 30–42) days. The degrees of chimerism were determined using variable number tandem repeat-polymerase chain reaction (VNTR-PCR) methods. As shown in the Table, sustained trichimerism occurred in 4 out of 8 dogs with engraftment for a period grater than 26 weeks. For G631, both donor grafts were rejected shortly following discontinuation of CSP and MMF. Dog G513 developed graft versus host disease (GvHD) which was successfully treated with a short course of CSP. Five dogs received kidney allografts from one of the respective HCT donors 6 months after HCT to assess donor specific immune tolerance. Chimerism Analysis of Dogs Receiving Marrow from Two Donors Duration of Engraftment in Weeks (% Chimerism) Recipient Donor 1 Donor 2 Recipient GVHD Accept Donor 1 Kidney Graft (wks) ND = not determined; [R] = rejection G158 >43 (5%) 37 (0%) [R] >43 (95%) No Yes (20) G193 >44 (72%) 16 (0%) [R] >44 (28%) No Yes (10) G362 >47 (28%) >47 (55%) >47 (17%) No Yes (16) G513 >47 (53%) >47 (22%) >47 (25%) Yes Yes (16) G551 >32 (35%) >32 (20%) >32 (45%) No ND G631 8 (10%) [R] 8 (12%) [R] 8 (>88%) No ND G643 >30 (28%) >30 (40%) >30 (23%) No Yes (4) G664 >26 (50%) 6 (2%) [R?] >26 (48%) No ND Kidney allografts were found to be essentially free of inflammation when assessed histologically on biopsy. Dog G643, was tested for immune function by a mixed leukocyte reaction and found to be competent against DLA nonidentical stimulator cells but nonresponsive against either of the donor stimulator cells. In summary, following nonmyeloablative conditioning, simultaneous administration of marrow stem cells from two DLA-identical littermates can result in trichimerism. Furthermore, immunological tolerance to multiple hematopoietic cell donors can include a solid organ graft from one of the marrow donors.

High Frequency of GATA1 Mutations in Childhood Non-Down Syndrome Acute Megakaryoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 888-888 ◽  
Author(s):  
Katarina Reinhardt ◽  
C. Michel Zwaan ◽  
Michael Dworzak ◽  
Jasmijn D.E. de Rooij ◽  
Gertjan Kaspers ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Mutation Screening ◽  
Study Group ◽  
Acute Megakaryoblastic Leukemia ◽  
Monosomy 7 ◽  
Megakaryoblastic Leukemia ◽  
Exon 1 ◽  
Gata1 Mutation

Abstract Abstract 888 Introduction: Pediatric acute megakaryoblastic leukemia (AMKL) occurred in 6.6% (84/1271) of the children enrolled to the AML-BFM98 and 2004 studies. Despite a similar phenotype in morphology and immunophenotype, AMKL shows a heterogenous cytogenetic distribution (normal karyotype 23%, complex karyotype 21%, t(1;22) 9%; MLL-rearrangement 8%; monosomy 7 5%, trisomy 8 5%; other aberrations 29%). Mutations of the hematopoietic transcription factor GATA1 have been identified in almost all children suffering myeloid leukemia of Down syndrome (ML-DS). In addition, GATA1 mutations (GATA1mut) could be identified in children with trisomy 21 mosaic. Here, AMKL without evidence of Down syndrome or Down syndrome mosaic were analyzed for mutations in exon 1, 2 or 3 of the transcription factor GATA1. Patients: Seventy-one children from the AML-BFM Study group (n=51; 2000–2011), the Netherlands (n=10), France (n=3) and Scandinavia (n=7) were included. Within the AML-BFM Group the 51 analyzed patients showed similar characteristics compared to the total cohort of 84 children with AMKL of the AML-BFM 98 and 2004 studies. AMKL was confirmed according to the WHO classification by genetics (t(1;22)); morphology and immunophenotyping. Table 1a) summarizes the patientxs characteristics and b) the cytogenetic results. Methods: For GATA1 mutation screening genomic DNA was amplified by PCR reaction for exon 1, 2, and 3. PCR amplicons were analyzed by direct sequencing or following denaturing high-performance liquid chromatography (WAVE). Results: Seven different GATA1 mutations were detected in 8 children (11.1%; table 2). In all GATA1mut leukemia, a trisomy 21 within the leukemic blasts could be detected. Seven out of these 8 children and all other 64 AMKL patients have been treated with intensive chemotherapy regimens according the study group protocols. The results are given in table 2. All achieved continuous complete remission (CCR; 0.4 to 4.2 years). In one newborn with typical morphology and immunophenotype a GATA1mut associated transient leukemia was supposed. The child achieved CCR (follow-up 6 years). In total, allogeneic stem cell transplantation in 1st CR was performed in 6 children with AMKL (GATA1mut leukemia n=1). Conclusions: GATA1 mutations occurred in 11% of children with AMKL without any symptoms or evidence of trisomy 21 or trisomy 21 mosaic. GATA1 mutations are associated with a trisomy 21 within the leukemic blasts. Although non-response occurred, prognosis was significant better compared to other AMKL. Therefore, analysis of GATA1 mutation in infant AMKL is strongly recommended. Whether treatment reduction similar to ML-DS Down syndrome is feasible needs to be confirmed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Haploidentical Hematopoietic Cell Transplantation Using Posttransplant Cyclophosphamide for Sézary Syndrome

2020 ◽  
Vol 13 (2) ◽  
pp. 1053-1058
Author(s):  
Madoka Kanda-Kato ◽  
Satoshi Yoshioka ◽  
Takayuki Ishikawa
Keyword(s):  
Cell Transplantation ◽  
Bacterial Infections ◽  
Hematopoietic Cell Transplantation ◽  
Cord Blood Transplantation ◽  
Infectious Complications ◽  
Hematopoietic Cell ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Blood Transplantation ◽  
Unrelated Cord Blood

Patients with advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment option; however, since most patients with MF/SS are elderly, they often have difficulty in finding HLA-matched donors. In recent years, HCT from HLA-haploidentical donors (haplo-HCT) using posttransplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis has been conducted for patients without HLA-matched donors. Infectious complications, particularly cutaneous bacterial infections, are common among patients with MF/SS. The lower incidence of severe infectious complications after haplo-HCT than after an unrelated cord blood transplantation could lead to lower transplant-related mortality. Here, we report on a patient with SS who was treated successfully with haplo-HCT with PTCy. The patient has remained in complete remission for more than 24 months.

scholarly journals Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1490-1494 ◽  
Author(s):  
Min Fang ◽  
Barry Storer ◽  
Elihu Estey ◽  
Megan Othus ◽  
Lisa Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Hazard Ratio ◽  
Hematopoietic Cell ◽  
Complex Karyotype ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Monosomal karyotype (MK), defined as ≥ 2 autosomal monosomies or a single monosomy in the presence of other structural abnormalities, was confirmed by several studies to convey an extremely poor prognosis in patients with acute myeloid leukemia (AML) with a 4-year overall survival after diagnosis of < 4%. A recent investigation by the Southwest Oncology Group found that the only MK+ patients alive and disease free > 6 years from diagnosis received allogeneic hematopoietic cell transplantation (HCT). To expand this observation, we retrospectively analyzed 432 patients treated with HCT at the Fred Hutchinson Cancer Research Center, 14% of whom were MK+. The 4-year overall survival of patients after HCT was 25% for MK+ AML and 56% for MK− AML (adjusted hazard ratio = 2.29, P < .0001). Among the MK+ patients, complex karyotype was associated with a significantly worse outcome than patients with noncomplex karyotype (adjusted hazard ratio = 2.70, P = .03). Thus, although the prognosis of MK+ patients remains worse than that for MK− patients in the transplantation setting, HCT appears to improve the overall outcome of MK+ patients, especially patients without a complex karyotype. However, the 28% of MK+ patients > 60 years had only a 6% 4-year survival rate after HCT, stressing the need for new approaches in these patients.

The Hematopoietic Cell Transplantation Comorbidity Index: No Effect on Outcome of Reduced-Intensity Allografts.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1119-1119
Author(s):  
O. Frankfurt ◽  
J. Altman ◽  
J. Krishnamurthy ◽  
Andrew M Evens ◽  
L. Gordon ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Performance Status ◽  
Univariate Analysis ◽  
Hematopoietic Cell ◽  
Refractory Disease ◽  
Score Distribution ◽  
Comorbidity Index ◽  
Reduced Intensity

Abstract The hematopoietic cell transplantation-comorbidity index (HCT-CI) has been proposed as a means to estimate the risk of transplant-related mortality (TRM) and the likelihood of overall survival (OS) after allogeneic HSCT. However, its value and applicability remain unclear; in a 2-center study, it was predictive of outcome at one but not at the other in multivariate analysis (Blood2007;110:4606). We investigated the effect of HCT-CI in 130 adult patients with hematologic malignancies undergoing reduced-intensity HSCT after 100 mg/m2 melphalan (+ 50 mg/kg cyclophosphamide if no prior autograft). GVHD prophylaxis comprised cyclosporine/tacrolimus and MMF. 18% of the donor-patient pairs were 1 antigen/allele-mismatched. 57% had refractory disease. 45% had failed an autograft. ECOG performance status (PS) was 0–34%, 1–48%, 2–14%, and 3–4%. The HCT-CI score distribution was 0–10%, 1–4%, 2–28%, 3–24%, 4–15%, 5–10%, 6–8%, and ≥7–2%. Overall, the patient population had higher HCT-CI scores than described in other studies (Cancer2008;112:1992). In multivariate analysis, TRM was higher with HLA mismatch and PS 2-3, and OS was lower with PS 2-3, HLA mismatch, refractory disease, donor age &gt;45 y, elevated LDH, and platelets &lt;100. HCT-CI 0 vs 1-2 vs ≥3 had no effect on TRM or OS. HCT-CI 0-2 vs ≥3 had a borderline effect on TRM (P=0.09) and OS (P=0.15) in univariate analysis, but no effect in multivariate analysis when forced into the model with factors known to be significant. No significant correlation was seen between HCT-CI and any of the factors found to be predictive of outcome. Figure Figure Because serum albumin is a powerful non-specific predictor of general health and outcome in all clinical situations, we hypothesized that it would correlate with the PS. As shown in the figure below, it did. We expected that it would correlate with HCT-CI because increasing comorbidity should theoretically be associated with declining albumin. However, it did not. Figure Figure In our experience, HCT-CI does not correlate with outcome – especially when other pertinent factors are taken into account. Since most data supporting HCT-CI have originated from a single center, it is possible that its applicability depends on individual centers and the treatment protocols employed. However, lack of correlation of HCT-CI with albumin does call its biological plausibility into some question. HCT-CI cannot be employed unless refined and validated prospectively in multi-center studies.

Reduced Intensity or Non-Ablative Hematopoietic Cell Transplantation in Older Patients with Non-Hodgkin Lymphoma (NHL): Encouraging Survival for Patients ≥55 Years

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1015-1015
Author(s):  
Brian McClune ◽  
Tanya L. Pedersen ◽  
Kwang W Ahn ◽  
Erica D Warlick ◽  
Joseph Pidala ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cell Transplantation ◽  
Older Patients ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Hematopoietic Cell ◽  
Age Cohorts ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Abstract 1015 Non-Hodgkin lymphomas (NHL) disproportionately affect older patients. Hematopoietic cell transplantation (HCT) with non-ablative conditioning regimens is increasingly used to treat this population. We analyzed data reported to the CIBMTR on 1248 patients receiving either non-myeloablative (NMA) or reduced-intensity conditioning (RIC) HCT from 2001–2007 for both aggressive (n=668) and indolent (n=580) NHL testing the association of age on transplant-related mortality (TRM), relapse, engraftment, acute and chronic graft-versus-host disease (GVHD), progression-free (PFS) and overall survival (OS). Patients were stratified into 3 age cohorts: 40–54, 55–64, and ≥65 years. Clinical characteristics were mostly well-matched across age cohorts, but more frequent aggressive NHL histologies occurred in the oldest age group [67% vs. 49% (age 40–54) and 57% (age 55–64); p=0.0008] and fewer patients ≥65 years had prior autografts (9% vs. 26% and 24% in the younger groups; p=0.002); 30% of those ≥65 had resistant disease at HCT (vs. 25% and 23% in younger cohorts; p=0.79). Univariate analysis demonstrated no statistically significant differences in the incidence of relapse, acute or chronic GVHD across age cohorts (Table 1). We observed lower 1 year TRM for the youngest group, but TRM was similar in the two older cohorts. PFS and OS were also inferior in the two older cohorts, but no differences between those aged 55–64 and ≥65 were noted. Multivariate analysis (Table 2) revealed no independently significant impact of age on the incidence of acute (p=0.91) or chronic GVHD (p=0.66), or on relapse (p=0.06). Older age ≥55 years, lower Karnofsky performance status (KPS), and human leukocyte antigen (HLA) match disparity adversely impacted TRM, PFS, and OS. Advanced disease status (CR1/2 vs. PR1/2, or resistant) at HCT also significantly worsened TRM, relapse (p<0.0001), PFS and OS. Histology (aggressive vs. indolent) did not impact any multivariate model of outcomes. Compared to NMA regimens RIC worsened acute (p=0.007) and chronic (p=0.002) GVHD and OS (p=0.03), but not TRM or PFS. We conclude that patients ≥55 receiving non-ablative HCT for NHL have only modestly worse outcomes with no further decrement in those ≥65 years. These results are, however, influenced by KPS and disease status at time of HCT, and by HLA donor/recipient mismatch. Despite higher risk characteristics, 3 year survival still approached 40% for even the oldest groups making HCT a worthwhile option for these patients. Future work should focus on refining techniques for patient selection and optimizing conditioning regimens to improve these already encouraging results.Table 1.Univariate probabilities of patients receiving HCT for NHLN40–54N55–64N≥ 65P61455282TRM, 1 year22 (19–26)%27 (23–31)%34 (24–44)%0.05Relapse, 3 years28 (24–32)%33 (29–37)%33 (23–44)%0.22PFS, 3 years44 (39–48)%32 (28–36)%27 (17–37)%<0.0001OS, 3 years54 (50–58)%40 (36–44)%39 (28–50)%<0.0001Follow-up, median (months)56 (3–111)47 (2–111)47 (2–96)Table 2.Factors affecting multivariate analysis in patients receiving HCT for NHLAgeTRMPFSOSHRPHRPHRP    40–541.01.01.0    55–641.52<0.00011.37<0.00011.47<0.0001    65+1.570.021.330.041.470.01KPS    ≥ 801.01.01.0    < 801.87<0.00011.63<0.00011.87<0.0001HLA match    Identical sib1.01.01.0    URD well matched1.36<0.011.130.151.300.004    URD partial match2.30<0.00011.390.0031.90<0.0001    URD mismatch2.9<0.00012.28<0.00012.210.0001Disease Status    CR1/CR21.01.01.0    PR1/PR21.270.061.45<0.00011.290.01    Resistant1.90<0.00012.28<0.00011.97<0.0001 Disclosures: No relevant conflicts of interest to declare.

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