Haploidentical Transplantation Using Double Source of Hematopoietic Stem Cells and Post-Transplant Cyclophosphamide for Acute Leukemias

Allogeneic stem cell transplantation (allo-SCT) represents a curative option for intermediate- and high-risk acute leukemias (AL). The number of unmanipulated haploidentical allo-SCT (haplo-SCT) is increasingly used with favorable outcomes. Incidence of graft-versus-host disease (GvHD) in haploidentical bone marrow (BM) transplants using post-transplant cyclophosphamide (PTCy) is low, counterbalanced by an excess in disease recurrence; and acute GvHD using mobilized peripheral blood stem cells (PBSC) ranges between 30% and 40%. The ultimate choice of graft source depends on the design of the full transplantation package based on transplantation center experience. We conducted a retrospective analysis of 32 patients (59% male), who received an haplo-PTCy with double source of stem cells, G-CSF primed bone marrow plus G-CSF-mobilized PBSC, for high-risk or advanced acute leukemia in two Brazilian centers, Hospital Santa Marcelina (n=23) and Hospital São Paulo (n=9), from 2013 to 2019. The median age patients were 27.5 years (range 17-60 years). Median disease time before haplo-PTCy was 8.9 months (3.6-108). There were 13 acute myeloid leukemia (AML), 17 acute lymphoblastic leukemia (ALL), one mixed phenotype acute leukemia and one dendritic cell leukemia. 6/17 ALL were Ph1 positive. 34% of the patients received 2 treatment protocols to achieve CR and 12.5% had submitted to more than two treatments. So, at the time of transplant 75% (n=24) was in first CR (CR1) although one (3%) patient was minimal residual disease (MRD) positive and six (18.7%) there were no MRD available. The others patients (n=8, 25%) were on second or third CR. The HCT-CI comorbidities was ≥ 3 in two patients, and there were 15 patients (46%) with carbapenem-resistant gram-negative bacilli (CRGNB) colonization before transplant. Panel reactive antibody was positive in two patients. The donor was a sibling in 68.7% (n=22), father, mother and child in two (6%), three (9%) and five (15%) patients, respectively. The conditioning was reduced intensity (RIC) in 87.5% (n=28) patients, with fludarabine, cyclophosphamide and total body irradiation (TBI) 200 cGy. After conditioning, patients received G-CSF primed bone marrow grafts in combination with PBSC no ex-vivo T cells depleted, and cyclophosphamide 50 mg/Kg/day IV on days +3 and +4 post-transplant, as well as GVHD prophylaxis. Six (18.7%) patients died for sepsis before 60 days (10 to 58 days), all had had CRGNB before transplant, four those ones with no grafting, died from days +10 to +19. Acute GvHD grade III-IV was observed in two patients, who died at +48 and +95 days. High mortality related to transplant (TRM) was observed considering all patients. CRGNB was a determining factor in these early deaths. If we excluded all CRGNB patients of this study the mortality could be 11% (2 patients with GVHD in 17 patients transplanted). Four patients (16%) has severe cGvHD. Nine patients (37%) relapsed in two years. Two years OS and DFS were 40% and 37.5%, respectively. In conclusion, with a median follow-up of 2 years, haplo-PTCy with double source leads to 40% overall survival in 32 patients with high-risk advanced acute leukemia, with 16% (n=2) being in treatment for cGvHD. The causes of death were relapse 43% (n=7), early sepsis in patients with CRGNB colonization 37.5% (n=6), grade IV acute GvHD in 12,5% (n=2), and one patient died for pneumonia community at D+285. Our data suggests that haplo-PTCY double source is a feasible option in these cases. However, CRGNB colonization in aggressive disease is the main factor that should be considered as exclusion for haplo-SCT in development countries. Disclosures No relevant conflicts of interest to declare.

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Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia

Blood ◽

10.1182/blood.v86.1.60.bloodjournal86160 ◽

1995 ◽

Vol 86 (1) ◽

pp. 60-65 ◽

Cited By ~ 14

Author(s):

JT Holden ◽

RB Geller ◽

DC Farhi ◽

HK Holland ◽

LL Stempora ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Acute Leukemia ◽

Lymphoblastic Leukemia ◽

Blast Crisis ◽

Myelogenous Leukemia ◽

Acute Leukemias ◽

Hematopoietic Stem

Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

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Hematopoietic Stem Cell Transplantation (HSCT) from Alternative Donors for Acute Leukemia at High-Risk of Relapse. The Haploidentical Option.

Blood ◽

10.1182/blood.v106.11.441.441 ◽

2005 ◽

Vol 106 (11) ◽

pp. 441-441

Author(s):

Franco Aversa ◽

Antonio Tabilio ◽

Adelmo Terenzi ◽

Stelvio Ballanti ◽

Alessandra Carotti ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Acute Leukemia ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Prognostic Features ◽

Post Transplant ◽

Leukemia Relapse

Abstract Despite advances in chemotherapy for acute leukemia, survival is poor when patients have unfavourable prognostic features at diagnosis, when they do not achieve CR after the first induction cycle and when they are in second or later remission. In these circumstances an allogeneic HSCT is preferred. The chance of finding a matched unrelated donor depends on the HLA diversity and although molecular analysis achieves closer matches it reduces the probability of finding a donor. Furthermore, many patients relapse while waiting for transplant. Transplantation of HSCs from a one-haplotype mismatched family member offers an immediate source of HSCs to almost all leukemia patients who urgently need an allogeneic transplantation because of the high-risk of leukemia relapse and who do not have a matched, either related or unrelated, avaible donor. Over the past decade, our group has shown the two major obstacles to mismatched transplants, that is severe acute GVHD in T-cell-replete transplants and graft rejection in T-cell-depleted transplants, can be overcome by infusing a megadose of extensively T-cell-depleted HSCs after an immuno-myelo-ablative conditioning regimen. Since our first reports (Aversa et al. Blood 1994 and NEJM 1998), the main modifications to our original approach were: a) in October 1995, fludarabine was substituted for cyclophosphamide in our TBI-based conditioning regimen; b) peripheral blood cells were positively selected by using initially the Ceprate device and then, since January 1999, the Clinimacs instrument which ensures a 4.5 log T-cell depletion in a one-step procedure with no E-rosetting; c) in the 138 patients transplanted since January 1999 post-transplant G-CSF administration was stopped so as to improve immune recovery. The patient population included 90 AML and 48 ALL, median age 28 years (range 9–62), 40 (29%) in bad-risk CR I, 43 (31%) in second or later CR and 55 (40%) in relapse at transplant. Primary full-donor engraftment was achieved in 125/134 evaluable patients (93%); 8 patients engrafted after second transplants. Overall engraftment was achieved in 133 patients (96%). Without any post-transplant immunosuppressive prophylaxis, grade II-IV acute GvHD occurred in 7/133 evaluable patients and 5/106 developed chronic GvHD. Cumulative incidence (C.I. 95%) of non-leukemia mortality was 36% (19%–53%) and 40% (19%–66%) for patients who were respectively in CR or in relapse at transplant. 38/51 deaths were infection-related. Disease status was the major risk factor for relapse and EFS. Cumulative incidence of leukemia relapse was 27% (12%–45%) and 60% (30%–80%), p=0.006, for ALL patients in CR and relapse respectively; 17% (8%–29%) and 46% (29%–61%), p=0.0001, for AML in CR and relapse respectively. ALL and AML patients transplanted in relapse have, respectively, a 6% and 13% probability of surviving event-free. For those transplanted in remission, EFS is respectively 38% and 50% for ALL and AML patients in any CR at transplant. These results indicate the mismatched transplant should be offered to high-risk acute leukemia patients without a HLA-identical donor not as a last resort, but as a viable option in the early stages of the disease.

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Disease Propagating Blasts in Standard and High Risk Acute Lymphoblastic Leukemia Are Frequent and of Diverse Immunophenotype.

Blood ◽

10.1182/blood.v114.22.1421.1421 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1421-1421 ◽

Cited By ~ 1

Author(s):

Klaus Rehe ◽

Kerrie Wilson ◽

Hesta McNeill ◽

Martin Schrappe ◽

Julie Irving ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

High Risk ◽

Cancer Stem Cells ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Color Flow ◽

Nsg Mice ◽

Limiting Dilution

Abstract Abstract 1421 Poster Board I-444 Conflicting results in the field of cancer stem cells have reignited debate regarding the frequency and identity of cells with the ability to self renew and to propagate the complete phenotype of the malignancy. Initially it was suggested by different studies that cancer stem cells represent only a small minority of the malignant population and that the immunophenotypes of these cells resemble a rather immature type in the cell hierarchy. More recent data from our own and other groups have challenged these findings by demonstrating that cells at different maturity levels within the leukemic hierarchy have cancer stem cell abilities and that the frequency of the leukemia maintaining cell is higher than previously thought (Cancer Cell 2008, 14(1), p47-58). We use an in vivo NOD/scid IL2Rγnull (NSG) mouse intra-femoral transplant model to determine the clonogenicity of sorted candidate leukemic stem cell populations, characterized by specific immunophenotypes. We selected the surface markers CD10 and CD20, in order to differentiate between rather immature and more mature cells. Furthermore we carried out limiting dilution experiments on sorted (CD20) and unsorted leukemic blasts to investigate the frequency of the proposed leukemic stem cells. Flow sorted ALL blasts of CD19+CD20low and CD19+CD20high as well as of CD19+CD10low and CD19+CD10high immunophenotype were transplanted into NSG mice. Sorts were performed on primary patient material and on leukemic blasts that had been harvested following prior passage in mice. Different subtypes of ALL were included (high risk: BCR/ABL (t9;22) positive (patients L4967, L4951, L49101, L8849, L2510), high hyperdiploid/MRD positive high risk (L754, L835), intermediate risk: high WBC/MRD negative (L736, L784), age >10 years (L803)). CD20 sorts were performed on primary patient material (L4951, L49101, L754, L835 and L776), on secondary samples harvested from engrafted primary mice (L4967, L4951, L2510, L736 and L754) and on tertiary samples harvested from engrafted secondary mice (L4967 and L736). In total 151 mice were transplanted, with 122 showing engraftment in consecutive bone marrow punctures or in bone marrow harvests. CD10 sorts were performed on primary patient material (L784 and L49101) and on secondary samples harvested from engrafted primary mice (L4951, L8849, L2510 and L803) with 31 out of 52 mice transplanted with sorted material showing engraftment as seen with CD20 sorted cells. Blasts of all selected immunophenotypes were able to engraft the leukemia in unconditioned NSG mice as determined by 5 color flow cytometry. In particular, sorted cells of both fractions were able to reconstitute the complete phenotype of the leukemia. Harvested cells from engrafted mice could then be re-sorted into high and low antigen expressing fractions and successfully re-engrafted on secondary and tertiary mice. Cell purities of transplanted cells were usually higher than 90% (range 67-100%). The ability of all populations to serially engraft mice demonstrates long-term self-renewal capacity. Two additional patients were used in the limiting dilution assays (high WBC/t(4;11) high risk (L826); low WBC/MRD negative low risk (L792)) and experiments were performed on primary unsorted and secondary sorted material. Cell numbers necessary for ALL engraftment differed between individual leukemias but as little as 100 cells proved to be sufficient in one unsorted and in both the CD19+CD20low and CD19+CD20high fractions (Table 1). Mice transplanted with 10 cells only are still under observation. Table 1 Patient Transplant Population Cell dose Mice engrafted/transplanted L4951 Secondary CD20 high 500 3/3 CD20 low 3/3 CD20 high 100 3/3 CD20 low 3/3 L2510 Secondary CD20 high 3,000 2/4 CD20 low 4/4 CD20 high 300 0/4 CD20 low 1/4 L49101 Primary Unsorted 500 3/4 100 0/4 L792 Primary Unsorted 1,000 5/5 100 1/5 L826 Primary Unsorted 1,000 3/4 100 0/4 In conclusion we present strong evidence that leukemia-propagating cells are much more prevalent than previously thought and that blasts of diverse immunophenotype are able to serially reconstitute the complete leukemia in immune-deficient mice. Disclosures: No relevant conflicts of interest to declare.

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Application of Mesenchymal Stem Cells Derived From the Umbilical Cord Instead of Bone Marrow In Hematopoietic Stem Cells Transplantation.

Blood ◽

10.1182/blood.v116.21.4544.4544 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4544-4544

Author(s):

Ching-Tien Peng

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Proliferative Potential ◽

Hematopoietic Stem ◽

Cell Based Therapy

Abstract Abstract 4544 Bone marrow-derived mesenchymal stem cells (BMMSCs) have been found to enhance engraftment of hematopoietic stem cell transplantation (HSCT), plus show effect against graft-versus host disease (GVHD) because of their immunosuppressive properties. However, harvesting these cells is an invasive and painful procedure. To substitute BMMSCs from alternative sources is necessary. We intravenously infused ex vivo-expanded third-party umbilical cord-derived mesenchymal stem cells (UCMSCs) obtained from a bank 8 times in 3 patients who developed severe, steroid-resistant acute GVHD after allogeneic HSCT. The acute GVHD improved with each infusion of UCMSCs. Besides, after cotransplantation of cord blood and UCMSCs in 5 patients, we found UCMSCs enhanced absolute neutrophil counts and platelet counts recovery. No adverse effects after UCMSCs infusions were noted. We also found that UCMSCs had superior proliferative potential and greater immunosuppressive effects than BMMSCs in vitro. This is the first report of UCMSCs in human clinical application. These findings suggest UCMSCs are effective in treating aGVHD and can enhance hematopoiesis after HSCT. Considering that they are not only easy to obtain but also proliferate rapidly, UCMSCs would be the ideal candidate for cell-based therapy, especially for diseases associated with immune responses because of their immunosuppressive effects. Disclosures: No relevant conflicts of interest to declare.

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Nelarabine-Based Salvage Therapy in Adult Patients with T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (T-ALL/LL) Relapsing After Allogeneic Stem Cell Transplantation: A French Experience on Behalf of the Group for Research in Adult Lymphoblastic Leukemia (GRAAL),

Blood ◽

10.1182/blood.v118.21.4095.4095 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4095-4095

Author(s):

Edouard Forcade ◽

Thibaut Leguay ◽

Norbert Vey ◽

Andre Baruchel ◽

Jacques Delaunay ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

High Risk ◽

Salvage Therapy ◽

Acute Gvhd ◽

Response Rate ◽

Lymphoblastic Leukemia ◽

Unrelated Donor ◽

Cell Transplant ◽

Hematopoietic Stem

Abstract Abstract 4095 Backgroud: The prognosis of patients with T-ALL/LL has been recently re-assessed, based on monitoring of minimal residual disease (MRD) levels and new insights in pathogenesis (NOTCH1 pathway mutations). To date, allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR) remains the standard option in patients identified with a high risk of relapse. In this context, patients relapsing after HSCT represent a very difficult challenge to get a second CR. Nelarabine, a pro-drug of Ara-G, has been associated with a high response rate in relapsing ALL (Gökbuget N et al., Blood 2011), but very few data are available on its efficacy and safety in the post-HSCT setting. Patients: Medical records of 11 T-ALL/LL patients who received nelarabine-based salvage therapy for a relapse after HSCT were retrospectively reviewed. These patients were treated with nelarabine alone (1,5g/m2/day (D) D1, D3, D5, every 28 days) (N=5) or nelarabine associated with hyperfractionated cyclophosphamide (HyperC; N=6). Results: Ten patients had T-ALL and one had T-LL. Median age was 23 years (14–62) at time of diagnosis. Ten patients underwent HSCT in first CR (median time between diagnosis and HSCT: 141 days). HSCT conditioning regimen was myeloablative for 7 patients including Total Body Irradiation for 6 of them (reduced intensity conditioning for 4 patients). Source of stem cells was hematopoietic peripheral blood stem cells in 6 patients, bone marrow in 4 patients and unrelated cord blood in one patient. Four patients received a transplant from an HLA matched sibling donor and 7 from an unrelated donor (HLA-matched 10/10 in 3 patients). GVHD prophylaxis consisted in ciclosporine for all patients, either associated with methotrexate for 8 patients, mycophenolate for 2 patients or alone for one patient. Eight patients presented grade I-II acute GVHD (no patient had grade III-IV). Two patients developed chronic GVHD (1 extensive). Relapse occurred with a median duration of 199 days (119–2099). Six patients were still under immunosuppressive agents, because of slow tapering off or context of GVHD, which was stopped quickly. One patient presented a relapse in the context of cGVHD. Of the 11 patients treated with nelarabine-based salvage therapy, 81% achieved hematological CR within a median delay of 48 days. At one year, disease-free and overall survivals were 56% and 90%, respectively. Eight patients received additional nelarabine consolidation cycles (median, 4 cycles) and 2 CR patients received Donor Lymphocytes Infusion (1 complete molecular CR). One patient presented acute GVHD following nelarabine-based first cycle, requiring immunosuppressive treatment. Main toxicity was neurological (Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events), with 2 patients presenting sensitive neuropathy and cerebellar ataxia. Conclusion: In patients with T-ALL/LL relapsing after allogeneic HSCT, nelarabine-based salvage therapy was well tolerated with 2 neurological complications grade 2 and one acute GVHD. Moreover, this treatment was associated with a very high (81%) response rate with some patients experiencing prolonged remission. Post-HSCT nelarabine maintenance might thus be a valuable option to investigate in high-risk patients, possibly driven by MRD detection. Assessing immune responses in this particular setting could also be of particular interest. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

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Unmanipulated Graft Transplantation From Family Haploidentical Donors: A Survey On 183 Adult Patients with Acute Leukemias On Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v120.21.1987.1987 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1987-1987

Author(s):

Fabio Ciceri ◽

Myriam Labopin ◽

Paolo Di Bartolomeo ◽

William Arcese ◽

Stella Santarone ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Acute Leukemia ◽

Advanced Disease ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Treatment Algorithm ◽

Working Party ◽

Acute Leukemias

Abstract Abstract 1987 Background. Allogeneic stem cell transplantation from an haploidentical family donor has been recently developed through unmanipulated graft platforms. Methods. We collected in 57 EBMT centers 183 haploidentical transplants (haploSCT) from unmanipulated peripheral blood (PB) and bone marrow (BM) graft in adults patients (pts) with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) reported to EBMT registry from 2007 to 2010 and analysed the outcome according to the known risk factors. Results. Overall, 120 AML patients underwent transplantation in CR1 (39), CR2 (22) or in advanced disease (54). Overall, 63 ALL pts underwent transplantation in CR1 (26), CR2 (14) or in advanced disease (22). Median age was 42y (18–75). Graft composition was based on non ex-vivo T-cell depleted BM in 52 (28%) or PB in 131 (72%). Conditioning regimen was myeloablative (MAC) in 95 and reduced-intensity (RIC) in 88 pts. Primary engraftment was documented in 160 pts (88%), with ANC 0.5 ×109/L in a median of 19 days (BM) and 16 days (PB). Graft-versus-Host Disease (GvHD) prophylaxis was based on Anti-thymocyte globulins (ATG) + cyclosporine-methotrexate (24%) or cyclosporine-mycophenolate (18%), rapamycine-mycophenolate (25%), tacrolimus-mycophenolate (15%), others (7%). The cumulative incidence of acute GvHD >=II was 26%. With a median follow-up of 13 months (1–49), the estimated leukemia-free survival (LFS) at 1 years i was 53 +/−7%, 36 +/−8% and 22 +/−5% for CR1, CR2 and advanced patients respectively. In multivariate analysis for competing risks, relapse incidence (RI) at 1 y was 23 +/−5%, 20 +/−7%, 48 +/−6% for CR1, CR2 and advanced. The non-relapse mortality (NRM) at 1 y was 23 +/−6%, 43 +/−5%, 29 +/−6% for CR1, CR2 and advanced patients. On multivariate analysis, the only factor relevant for LFS was disease status at transplant. Conclusion. EBMT registry analysis of haploidentical transplantation from unmanipulated donor graft confirms relevant LFS for patients with high risk acute leukemia. These results suggest that this procedure should be considered prospectively int treatment algorithm for high risk adults patients in early stages. Disclosures: No relevant conflicts of interest to declare.

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Unsuccessful Cytogenetics and Outcomes in Acute Leukemia

Blood ◽

10.1182/blood-2018-99-110470 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2673-2673

Author(s):

Lauren Lee ◽

Helene Bruyere ◽

Michael J Barnett ◽

Raewyn Broady ◽

Donna L. Forrest ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

White Blood Count ◽

Prognostic Impact ◽

Intermediate Risk ◽

Steroid Use ◽

High Risk Disease

Abstract Introduction: Cytogenetic features at diagnosis have significant independent prognostic impact in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Failed or unsuccessful cytogenetics (UC) is estimated to occur in 10% of AML cases and 25-30% of ALL cases (Grimwade, 2010; Pullarkat, 2008). Previous studies suggest worse outcomes in AML patients (pts) with UC, similar to pts with unfavorable karyotype with lower response rates to induction chemotherapy and poor 5-year (yr) survival rates (Medeiros, 2014; Lazarevic, 2015). Hydroxyurea (HU) and steroids are often given urgently for cytoreduction prior to obtaining cytogenetics. The effects of such pretreatment on rates of UC have not been studied previously. In this study, we compared clinical outcomes of acute leukemia pts with UC versus successful cytogenetics (SC) and determined whether the use of HU or steroids affects cytogenetics success rates. Methods: All pts <70 yrs with de novo acute leukemia (AML or ALL) with available diagnostic bone marrow and cytogenetics testing seen at the Leukemia/Bone Marrow Transplant (BMT) Program of British Columbia between January 2010 and December 2016 were included. Pertinent information was reviewed from the program database. Cytogenetic failure was defined by the presence of <10 metaphases with a normal karyotype in the absence of a clinically actionable FISH abnormality. Pts with SC were risk stratified based on NCCN guideline criteria (NCCN, 2018). Baseline features of pts with SC and UC were compared using Chi-squared and two-tailed t-testing. Overall survival (OS) was calculated from the date of initial diagnosis to the date of death from any cause. Disease free survival (DFS) was calculated from the date of attaining first complete remission (CR1) to the date of relapse or death from any cause. Survival outcomes were estimated using the Kaplan-Meier method, with p values determined using the log rank test. A p < 0.05 was considered significant. Results: We identified 654 cases of acute leukemia (AML N=515; ALL N=139). Of these, 39 (6%) had UC (AML N=16, 3%; ALL N=23, 17%). There was no difference in age at diagnosis between groups (UC vs SC, 46 vs 51 yrs, p=0.08). AML pts with UC had higher initial white blood count (WBC) at diagnosis (71 vs 34, p<0.001). No effect of WBC was seen in ALL pts with UC versus SC. HU and/or steroid use prior to cytogenetics was similar between UC and SC groups in both AML and ALL pts (UC vs SC, HU: 8% vs 12%, p=0.61; steroids: 5% vs 1%, p=0.07. Therapy with intensive induction was also similar between groups (UC vs SC, 92% vs 90%; p=1.00). 137 (27%) of AML pts with SC had favorable risk disease, 182 (37%) intermediate, and 180 (36%) high risk. In ALL pts with SC, 32 (28%) had standard risk, and 84 (72%) had high risk disease. Follow up time in UC and SC groups was similar (32 vs 27m, p=0.18). CR rates in AML pts with UC was 81%, which was similar to pts with intermediate risk disease (84%, p=0.72) and better than CR rates of 39% observed in high risk pts (p=0.03). Compared to pts with SC, AML pts with UC had similar 5-yr OS and DFS as pts with intermediate risk disease (5-yr OS 25% vs 37%, p=0.45; 5-yr DFS 28% vs 28%, p=0.84), superior survival to high risk pts (5-yr OS 25% vs 17%, p=0.01; 5-yr DFS 28% vs 13%, p=0.036), and inferior survival to favorable risk pts (5-yr OS 25% vs 68%, p=0.07, 5-yr DFS 28% vs 52%, p=0.008), Figure 1. CR rates in ALL pts with UC was 83% and not significantly different than standard (94%, p=0.22) or high risk pts (86%, p=0.74). Compared to pts with SC, ALL pts with UC had similar 5-yr OS and DFS to pts with standard and high risk disease (UC vs standard vs high; 5-yr OS 58% vs 51% (p=0.93) vs 55% (p=0.85); 5-yr DFS 50% vs 37% (p=0.86) vs 36% (p=0.27)). Subgroup analysis of UC pts demonstrated no difference in survival in UC pts receiving BMT (N=12) vs no BMT (N=27). UC pts with high WBC >20 (N=14) had inferior survival compared to those with WBC ≤ 20 (N=25) (5-yr OS 60% vs 29%, p=0.025; 5-yr DFS 52% vs 12%, p=0.013). Conclusions: Unsuccessful cytogenetics was more frequently observed in ALL as compared to AML pts, though at lower rates than reported in previous studies. HU and steroid use had no effect on the rates of cytogenetic success. In comparison to previous reports, UC in AML was not associated with inferior outcomes, and survival was similar to intermediate risk pts. High initial WBC count was prognostic in pts with UC, and further studies are warranted to evaluate factors that affect outcomes in pts with UC. Disclosures No relevant conflicts of interest to declare.

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High Ferritin Level Is High Risk Factor of II-IV Acute Gvhd or Severe Cytopenia Post-Transplant in Thalassemia HSCT

Blood ◽

10.1182/blood.v124.21.2680.2680 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2680-2680

Author(s):

Jianyun Liao ◽

Jianyun Wen ◽

Chunfu Li

Keyword(s):

Risk Factor ◽

High Risk ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Ferritin Level ◽

Hematopoietic Stem ◽

Post Transplant ◽

High Risk Factor ◽

Group 2 ◽

Group 1

Abstract Purpose: To find out causes of II-IV acute graft-versus-host disease (GVHD) or severe cytopenia after hematopoietic stem cell transplantation (HSCT). Methods: Sixty-four children with thalassemia major underwent HSCT from fifty-seven 7/8 (at allele of A, B, C, or DRB1) matched donors and seven 7/8 match associated with a DQB1 or DPB1 allele mismatched donors from January 2009 to September 2013. Thirty-three patients suffered from II-IV acute GVHD or severe cytopenia beyond day 28 post-transplant (SCB-28PT, WBC < 2G/L for 4 sequence weeks after HSCT, Group 1). The remains (n=31) associated with well status (Group 2). Current study focus on effect of ferritin, recipient age and donor age on the Group 1. Results: Ferritin was significant higher in Group1 than Group 2 (4178.3 vs.3033.8 ng/ml, p=0.042). Ferritin was also proved as the dangerous cause by multi-factor binary regression analysis (p=0.017). There were insignificant in comparison of Group 1 and Group 2 in donor’s age (30.2 vs.30.4, p=0.939) and receptor’s age (6.3 vs. 6.4,p=0.889), respectively. Conclusions: The current study showed high ferritin level is a high risk factor of II-IV acute GVHD or SCB-28PT. Disclosures No relevant conflicts of interest to declare.

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A Clinical Study of 15 Acute Leukemia Patients with Plasmacytoid Dendritic Cells Expansion

Blood ◽

10.1182/blood-2021-149623 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4468-4468

Author(s):

Ya-Lan Zhou ◽

Yan Wei ◽

Xiaohong Liu ◽

Jing Wang ◽

Jinsong Jia ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Dendritic Cells ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Plasmacytoid Dendritic Cell ◽

Plasmacytoid Dendritic Cells ◽

Ras Signaling ◽

Hematopoietic Stem

Abstract Objective: To improve the understanding of acute leukemia with plasmacytoid dendritic cells (pDCs) expansion. Method: Bone marrow smears and flow cytometry immunophenotyping results of patients with acute leukemia and pDCs expansion at diagnosis in our clinical center from August 2018 to January 2021 were retrospectively analyzed. The clinical and biological characteristics were analyzed. Results: Among the 1039 patients with acute leukemia, 15 (1.4%) had pDCs expansion at diagnosis, with a median age of 55 (28-99) years old. The ratio of men to women was 3 to 2. The median proportion of pDCs accounting for all the nucleated cells in bone marrow smear and flow cytometry immunophenotyping were 12.0% (6.0%-50.0%) and 16.6% (4%-28%), respectively. There were 12 cases of acute myeloid leukemia (AML), 11 of them had mutations in RUNX1 and 10 were morphologically classified as AML-M4 or M5. Notably, CD56 was mostly negative (only 1 of the 15 patients expressed CD56 antigen partially) and one of these 15 patients had definite skin lesions, which were significantly different from Blastic plasmacytoid dendritic cell neoplasms. 3 cases were diagnosed as acute lymphoblastic leukemia (ALL), of which 2 cases had mutations in NOTCH1 and RAS signaling pathways. 9 out of the 15 cases had consecutive prognostic information and the median follow-up time was 14.9 (2.1-31.9) months, of which 6 received allogeneic hematopoietic stem cell transplantation(allo-HSCT) and all were in continuous remission. However, among the 3 non-transplanted patients 2 cases relapsed. Conclusion: Acute leukemia with pDCs expansion is a group of patients with characteristic mutation profiles and relatively poor prognosis, more common in AML with abnormal expansion of the mononuclear system. Allo-HSCT may improve the clinical outcomes of these patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Second Allogeneic Bone Marrow Transplantation in Acute Leukemia: Results of a Survey by the European Cooperative Group for Blood and Marrow Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.16.3675 ◽

2001 ◽

Vol 19 (16) ◽

pp. 3675-3684 ◽

Cited By ~ 139

Author(s):

Alberto Bosi ◽

Daniele Laszlo ◽

Myriam Labopin ◽

Josy Reffeirs ◽

Mauricette Michallet ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Leukemia ◽

Marrow Transplantation ◽

Chronic Gvhd ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone ◽

Cooperative Group ◽

Hematopoietic Stem ◽

Blood And Marrow Transplantation

PURPOSE: Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. PATIENTS AND METHODS: One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. RESULTS: Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade ≥ 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. CONCLUSION: Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.

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