Iron Metabolism before Allo-HSCT in Patients with Acute Leukemia and Impact of Iron Overload on Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2461-2461
Author(s):  
Jimin Shi ◽  
Xuying Pei ◽  
Yi Luo ◽  
Yamin Tan ◽  
Yanmin Zhao ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Increased Risk

Abstract Objective: Iron overload is common in patients with acute leukemia who undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). We performed a comprehensive analysis of iron parameters to assess these patients' iron metabolism, and studied the prognostic impact of pretransplant iron overload on the outcome of transplantation. Methods: In this retrospective study, we studied 124 patients undergoing myeloablative allo-HSCT between 2012 and 2014. Serum iron (SI), serum ferritin (SF), hepcidin (Hepc) and soluble transferrin receptor (sTfR) were measured before transplant. We analyzed the effect of elevated pretransplant ferritin on acute graft versus host disease (aGVHD), infectious complications, overall survival (OS) and non-relapse mortality (NRM). Results: Date of 124 patients (including 56 cases of acute lymphocytic leukemia and 68 cases of acute myeloid leukemia) were analyzed. Median SI, SF, Hepc and sTfR values were 12.15 umol/L, 667.05 ng/ml, 369.50 ng/L and 7.69 ng/ml, respectively. Iron overload (defined as SF>1000 ng/ml) were observed in 27.42% of patients. Pretransplant iron overload was significantly associated with increased risk of bacterial infections during the early post-transplant period, and with reduced risk of aGVHD. Pretransplant iron overload increased NRM and reduced OS, but there were no significant differences. Conclusion: Patients with acute leukemia regularly develop iron overload before they undergoing allo-HSCT. Pretransplant iron overload was correlated with transplantation outcome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4586-4588 ◽  
Author(s):  
Philippe Armand ◽  
Haesook T. Kim ◽  
Corey S. Cutler ◽  
Vincent T. Ho ◽  
John Koreth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Iron Overload ◽  
Cell Transplantation ◽  
Serum Ferritin ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Increased Risk

Abstract Iron overload could be a significant contributor to treatment-related mortality (TRM) for patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). We studied 590 patients who underwent myeloablative allogeneic HSCT at our institution, and on whom a pretransplantation serum ferritin was available. An elevated pretransplantation serum ferritin level was strongly associated with lower overall and disease-free survival. Subgroup multivariable analyses demonstrated that this association was restricted to patients with acute leukemia or myelodysplastic syndrome (MDS); in the latter group, the inferior survival was attributable to a significant increase in TRM. There was also a trend toward an increased risk of veno-occlusive disease in patients with high ferritin. Our results argue that iron overload plays an important role in transplantation outcome for patients with acute leukemia or MDS, as it does in thalassemia. They also suggest future prospective trials to examine the potential benefit of chelation therapy in this setting.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

The Transcription Factor ELF4 Promotes Survival of Myeloid Leukemic Stem Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1209-1209
Author(s):  
Chun Shik Park ◽  
Koramit Suppipat ◽  
H. Daniel Lacorazza
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem

Abstract Abstract 1209 Chronic myeloid leukemia (CML) is a myeloproliferative disease that originate in hematopoietic stem cells (HSCs) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and BCR-ABL oncoprotein. Although treatment of CML patients with tyrosine kinase inhibitor can efficiently eliminate most leukemic cells, chemoresistant leukemic stem cells (LSCs) can survive and drive recurrence of CML in these patients. A number of genes have been described to promote or inhibit proliferation of LSCs. Some of them have similar roles in normal HSCs. The transcription factor ELF4 promotes cell cycle entry of quiescent HSCs during homeostasis (Lacorazza et al., 2006). Thus, to investigate the function of ELF4 in CML initiation and maintenance, we developed a BCR-ABL-induced CML-like disease using retroviral transfer of BCR-ABL in Elf4-null bone marrow (BM) cells. We first investigated whether ELF4 is required for the induction of CML. Recipient mice of BCR-ABL-transduced WT BM cells developed CML and died with a latency 16–23 days, whereas recipient mice of BCR-ABL-transduced Elf4-/- BM cells showed longer latency of 45–47 days (n=20; p<0.0005). Progression of leukemia was monitored in peripheral blood, BM and spleen by flow cytometry. In mice transplanted with BCR-ABL-transduced Elf4-null BM cells, Gr-1+ leukemic cells expanded the first two weeks after BM transplantation followed by a decline at expense of a secondary expansion of B220+ cells. In contrast, Gr-1+ leukemic cells continuously expanded in mice receiving BCR-ABL-transduced WT BM cells. These results suggest that loss of ELF4 causes a profound abrogation in BCR-ABL-induced CML, while allowing progression of B-cell acute lymphocytic leukemia. Since loss of Elf4 led to impaired maintenance of myeloid leukemic cells, we postulated that ELF4 may affect survival of LSCs. Thus, we analyzed the frequency of Lin-c-Kit+Sca-1+ (LSK) cells that are BCR-ABL positive in BM and spleen. We found that BCR-ABL+ LSK cells were significantly reduced in recipients of BCR-ABL-transduced Elf4-/- BM cells. These studies indicate that ELF4 is essential to maintain the LSC pool in CML acting as a molecular switch between myeloid and lymphoid blast crisis. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of a Novel Biomarker, Serum Soluble LR11 on Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2717-2717
Author(s):  
Chikako Ohwada ◽  
Masahiro Takeuchi ◽  
Shio Sakai ◽  
Daijiro Abe ◽  
Yusuke Takeda ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Laboratory Data ◽  
Type I ◽  
Prognostic Impact ◽  
Soluble Lr11

Abstract Abstract 2717 Introduction: LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding. LR11 plays a key role in the migration of undifferentiated vascular smooth muscle cells, and circulating sLR11 is known to be a biomarker of carotid intima-media thickness. Along with the fact that circulating sLR11 levels represent the accumulation of vascular immature cells, human CD34+CD38− immature hematopoietic precursors have been reported to express high levels of LR11 mRNA. We have recently found that LR11 is specifically and highly expressed on cell surface of acute leukemia cells in addition to normal leukocytes (unpublished data). These facts prompted us to evaluate the serum sLR11 level in patients with acute leukemia and other hematological malignancies to validate sLR11 as a novel circulating marker for treatment outcome and prognosis. Patients and Methods: Serum sLR11 levels were measured by ELISA method in 139 patients with acute leukemia and other hematological malignancies treated at a single institution from 1999 to 2010. Patients' laboratory data and treatment outcome were collected retrospectively in 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Results: sLR11 levels of acute leukemia patients were significantly increased [ALL, 73.5±93.5 ng mld−1 (range, 5.7–407.0), P<0.0001; AML, 26.8±29.1 ng ml−1 (range, 5.0–157.5), P<0.0001] in comparison to the control subjects (9.2±3.3 ng ml−1), while sLR11 levels in patients with chronic myeloid leukemia (17.9±11.1 ng ml−1), chronic lymphocytic leukemia (12.7±11.6 ng ml−1), multiple myeloma (10.5±4.8 ng ml−1), and POEMS syndrome (9.0±2.7 ng ml−1) were not significantly different from controls. sLR11 levels were significantly higher in ALL than those in other leukemias. Paired sample analysis of patients with AML and ALL at complete remission (CR) after chemotherapy showed significantly decreased sLR11 levels compared to the time of diagnosis (AML: 30.9±37.5 ng ml−1 vs. 10.4±4.3 ng ml−1, P=0.015, ALL: 39.1±126.0 ng ml−1 vs. 11.2±5.0 ng ml−1, P=0.0029). The multiple stepwise liner regression analysis showed that the peripheral blast proportion in both ALL and AML patients were independently associated with sLR11 at diagnosis (AML: r2= 0.21, P=0.0026, ALL: r2= 0.34, P=0.0043). Among 42 AML patients, sLR11 levels of subjects in the highest tertile of peripheral blast proportion (>67.5% of WBC) were 2.44- and 3.05-fold higher than those in the middle (23.0-64.0% of WBC) and lowest tertiles (<20.0% of WBC), respectively. Twenty out of 21 AML patients with <20 ng ml−1 sLR11 at diagnosis achieved CR after induction chemotherapy, and the CR rate was significantly higher in patients with <20 ng ml−1 sLR11 than in patients with ≥20 ng ml−1 (95.2% vs 65.5%, P=0.02). The probability of overall 5-year survival was significantly lower in AML patients with ≥20 ng ml−1 sLR11 at diagnosis than in those with <20 ng ml−1 [Figure1, 36.8% vs 63.7%, P = 0.04; hazard ratio (HR): 2.74; 95% confidence interval (CI): 1.04–8.01]. Conclusions: Serum sLR11 levels in patients with acute leukemia were significantly elevated and were associated with the peripheral blast population but not in other chronic proliferative hematological malignancies. These findings suggest that the serum sLR11 levels are predictive for pathogenic properties of immature blasts, including their migration and attachment activities, rather than simply associating with proliferating cell numbers. Especially in AML patients, serum sLR11 levels at diagnosis significantly affect CR rate and OS. Although larger scale studies including karyotype or FAB classification would be required for its patho-clinical significance, serum sLR11 is a promising novel biomarker for acute leukemia and it could play an important role as prognostic factor. Disclosures: No relevant conflicts of interest to declare.

Cytogenetic Evolution (CE) In Patients (pts) with Low and Intermediate Risk Myelodysplastic Syndromes (MDS) Is Associated with Poor Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2941-2941
Author(s):  
Liunan Li ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cytogenetic Analysis ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Significant Difference ◽  
The Impact ◽  
Cytogenetic Evolution

Abstract Abstract 2941 Introduction: MDS is a spectrum of abnormalities in the proliferation and differentiation of hematopoietic stem cells that result in peripheral cytopenias, bone marrow dysplasia and increased risk of transformation to acute myelogenous leukemia (AML). Cytogenetic abnormalities occur in more than 50% of patients (pts) and have an impact on survival and risk of transformation to AML. CE, or acquisition of additional clonal chromosomal abnormalities, has been reported to occur in 30 to 50% of primary MDS pts. Their impact on prognosis and transformation into AML among pts with low and intermediate risk MDS is not known. In this study, we analyzed the impact of CE on prognosis in lower risk MDS. Methods: we reviewed 722 pts clinic records of low and intermediate risk MDS pts at MD Anderson Cancer Center (MDACC) from 2000–2010 and conducted a retrospective analysis of all MDS pts with at least two consecutive cytogenetic analysis (365 patients, 50.6%) and compared the cytogenetic evolution group (CE group) with the group without cytogenetic changes (no CE group). Cytogenetic analysis was performed in the Cytogenetics Laboratory at MDACC. Results: CE was detected in 200 pts (55%). Characteristics of patients with CE are: median age 65 years (23-91), IPSS int-1 79%, diploid CG 42%, excess blasts 25%. Pts with CE were more frequently female (p=0.005), and had more frequently abnormalities of chromosome 5 and 7 (p<0.001) at baseline. There were no statistically significant difference between these two groups (p>0.05) regarding age, WBC, platelet, hgb, ANC, BM blasts percent, diagnosis (RA or RAEB), and IPSS score. There were more chr.-5/-7, insufficient metaphases, and other abnormalities, but less diploid cases in CE group compared with no CE group (p<0.001). History of malignancy (p=0.001) and prior chemotherapy exposure were also associated with CE (p=0.001), but this was not as strong for radiation exposure (p=0.066). Also, more CE patients required therapy for MDS compared to no CE patients (p=0.039). Progression free survival was significantly extended in no CE patients (p=0.02). Overall survival was a longer in no CE (34.1months), compared with CE group (26.2 months), although this was not statistically significant. Conclusion: CE is more commonly observed among pts with high-risk features, and is usually associated with disease progression and resistance. Also, prior malignancy and chemotherapy exposure were associated with CE in this study. This data indicates that genomic instability has a role in disease progression in MDS. Further analysis of CE in MDS is needed. Disclosures: No relevant conflicts of interest to declare.

Outcome of Patients with Relapsed/Refractory AIDS-Related Lymphoma In the AIDS Malignancy Consortium (AMC) 1997–2008

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3569-3569
Author(s):  
Ariela Noy ◽  
Ulas Darda Bayraktar ◽  
Neel Gupta ◽  
Adam M. Petrich ◽  
Page Moore ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Infectious Complications ◽  
High Dose ◽  
Hiv Diagnosis ◽  
Curative Intent ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Aids Related Lymphoma

Abstract Abstract 3569 Introduction: High dose therapy (tx) with autologous hematopoietic stem cell transplantation (AHSCT) in (rel/rfr) lymphoma is the standard of care in the general population with chemosensitive disease. The feasibility of second line therapies (Tx) and AHSCT in (rel/rfr) AIDS related lymphoma (ARL) has been shown in a number of trials. However, the true impact of 2nd line tx and AHSCT is unknown, as nearly all studies focus on those already with disease sensitive to 2nd therapy going onto transplantation. The only recent study capturing patients (n=50) before 2nd line tx showed 49% progression-free survival (Re et al. Blood 2009). Here, we retrospectively analyzed the outcome of patients (pts) presenting at 13 US AIDS Malignancy Consortium sites with (rel/rfr) ARL in the HAART era. Patients and Methods: HIV-positive pts initiating tx for (rel/rfr) ARL between 1997–2008 were included. Overall survival (OS) was calculated from the initiation of 2nd line tx. Results: A total of 126 pts received 2nd line tx. Only those 88 pts who received 2nd line with curative intent to treat (ITT) were included in the analysis. Baseline and selected clinical characteristics are summarized in the table. Median CD4 at HIV diagnosis was 110 (n=37) with a range of 12 to 1000. At ARL dx, median CD4 was 152 (5-803). 47% had an opportunistic infection (OI) prior to ARL. 2nd line tx were: ICE (n=34), EPOCH (n=16), ESHAP (n=11), High-dose MTX variants (n=10), Hodgkin's specific tx (n=5), DHAP (n=4) and others (n=8). Thirty-two (36%) had a response to 2nd line tx (CR, n=21; PR, n=11). Of 50 pts with grade ≥3 toxicities, the most common were thrombocytopenia (46%) and neutropenic fever (44%). Six pts died during 2nd line tx due to infectious complications, with 1 aspergillosis. Best response to 2nd line tx: Thus, CR/PR was 32/88 (36%) in ITT analysis. Only 10/32 CR/PR pts went onto AHSCT due to availability and changing treatment paradigms. Conditioning was BEAM (n=9) and Bu/Cy (n=7). No pt went onto allotransplant. At AHSCT day +90, 10 pts were in CR. For all pts, median follow-up was 122 weeks (range, 8–597), median OS was 38 weeks (95% CI, 27–63). Reflecting the 65% prevalence of pts refractory to 2nd line tx in the non-AHSCT group, OS was longer in pts who underwent AHSCT compared to those who did not (2-year OS: 55.3% vs. 31.0%). Surprisingly, 1-year OS in the CR/PR pts was 87.5±12.5% for AHSCT and 81.8±8.2% for non-AHSCT. One Burkitt pt survived a year without AHSCT. Discussion: Rel/rfr ARL was treated aggressively in this largest ever reported cohort, but CR/PR was only 32/88 (36%) in ITT analysis. Not all CR/PR pts went onto AHSCT due to changing treatment paradigms and regional availability. Aggressive 2nd line tx and ASHCT was feasible despite prior low CD4 and OI, but DFS may be possible without transplant. We cannot draw conclusions about the impact of AHSCT from this retrospective cohort. Similarly, it is not known whether survival in (rel/rfr) ARLs is equivalent to the HIV negative population. The current paradigm is to offer pts with rel/rfr ARLs AHSCT if disease is chemosensitive and no contraindication exist. New strategies are needed for 2nd line therapy, particularly in rel/rfr BL. Disclosures: No relevant conflicts of interest to declare.

Rituximab In Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Chronic Lymphocytic Leukemia with Fludarabine + Total Body Irradiation Conditioning: Results of a Phase II Prospective Multicenter Study (ITAC 02-02)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3520-3520
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Mohamad Mohty ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Median Time ◽  
Total Body Irradiation ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Positive Trend ◽  
Hematopoietic Stem ◽  
Total Body

Abstract Abstract 3520 Background: CLL remains incurable with standard therapies. Myeloablative allogeneic SCT (allo-HSCT) is still associated with high TRM and few late relapses. Recently, the major focus of transplantation in CLL has been with reduced-intensity conditioning (RIC) allo-HSCT, which is applicable to the more elderly patient population and which attempts to exploit the graft-versus-leukemia (GVL) effect that was proved in CLL Objective: To evaluate the efficacy and toxicity a RIC regimen including fludarabine and total body irradiation (TBI) with the introduction of rituximab for allo-HSCT in patients with a CLL stage B or C diagnosis. Materials and methods: This prospective study included adult CLL patients with age < 65 years in stage B or C in response after a salvage treatment either following at least 2 treatment lines (1 including fludarabine) or after a progressive disease after auto-HSCT, having a HLA identical sibling donor and a good performance status (Karnfosky >70%). Donors were mobilized by G-CSF and in case of collection failure, bone marrow aspiration was authorized. The conditioning included: rituximab 375mg/m2 on day -5, fludarabine 30 mg/m2 from day-4 to day-2, TBI 2grays (6-7 cGrays/minute) on day 0 and rituximab 500mg/m2 on day1 and day8. GVHD prophylaxis used cyclosporine A (IV 3mg/kg/day) from day-2 and mycomofetil fenolate oral (2g/day) from day 1. Results: Between April 2003 and December 2008, 40 patients were included, 34 (85%) males and 6 females with a median age of 54 years (35-65), 38 (95%) were in B stage at diagnosis and 2 in stage C. Among 23 explored for cytogenetics, 8 were abnormal (3 del17, 1 trisomy12, 1 t(8-11) & 1 del13). Before transplantation, 17 patients received 2 lines treatment, 10 three lines, 5 four lines, and 8>4. Only 1 patient received a previous auto-HSCT. Among 18 explored for Matutes status, 1 was in score 1, 1 in score 2, 3 in score 3, 5 in score 4 & 9 in score 5. At time of allograft, 7 (17%) patients were in complete response (CR), 29 (73%) in partial response (PR) and 4 (10%) < PR. For sex-matching, 59% were mismatched (27%of them were F>M). For ABO matching, 68% were compatible, 19% major incomp. & 13% minor incopm. The median interval diagnosis-allo-HSCT was 58 months (6-177). Median CD34+ number was 7.64 (3.1-18.7). Seven (17%) patients did not receive rituximab during conditioning because the protocol did not include it at the beginning and has been amended later. Thirty-nine (98%) patients engrafted with a median time to neutrophils recovery of 20 days (11-70), 79% of patients reached a total donor chimerism at day 90. Seventeen patients developed aGVHD grade ≥II (8 grII, 8 grIII & 1 grIV) with a cumulative incidence at 3 months of 44% (36-52). The cumulative incidence of cGVHD was, at 12 months: 29% (21-36) for limited and extensive; at 18 months: 32% (24-40) limited and 42% (34-50) extensive. After a median follow-up of 28 months (3-71), the median OS was not reached with 3 and 5-years probability of 55%(41-74). The median time of EFS was 30 months (15 - 70) with a 5-years probability of 46%(33-66). The cumulative incidence of relapse at 1 and 3 years was 17% (11-23) and 22% (15-29) respectively. The cumulative incidence TRM at 1 and 3 years was 10% (5-15) and 27% (20-35) respectively. At the last follow-up, 17 patients died, 6 due to relapse and 11 due to TRM. We noticed a high severe infection rate (56%) and 4% of deaths related only to infection. The univariate analysis showed a positive trend of rituximab on OS and relapse, and a significant protective effect on aGVHD>=2 (p=0.02). The multivariate analysis studying age, interval diagnosis-allo-HSCT, ABO and sex matching, disease status at allo-HSCT, CD34+ number, and rituximab, showed a positive significant impact of this last factor (rituximab) on OS and EFS [HR=0.1 [0-0.6] p=0.02 & HR=0.1[0-0.4] p=0.035 respectively]. Conclusion: We showed interesting results in terms of OS, relapse and TRM in patients with advanced CLL after Fludarabine/TBI allo-HSCT. The introduction of rituximab allowed a better outcome especially a significant reduction of incidence and severity of acute GVHD. Nevertheless there was still a high incidence of cGVHD, already known following the Fludarabine/TBI conditioning, leading us to propose either to increase the number of rituximab injections after allo-HSCT, or to test Fludarabine/busilvex/ATG associated to rituximab. Disclosures: No relevant conflicts of interest to declare.

Impact of Rapid Lymphocyte and Monocyte Recovery on Overall Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine/Melphalan Conditioning

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3040-3040
Author(s):  
Lori DeCook ◽  
Mary Thoma ◽  
Tanya Huneke ◽  
Nicole Johnson ◽  
Robert Wiegand ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Positive Impact ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Absolute Lymphocyte Counts ◽  
Complete Blood Counts

Abstract Abstract 3040 We have previously shown that both lymphocyte and monocyte recovery are strongly associated with improved survival post-myeloablative allogeneic hematopoietic stem cell transplant for acute leukemia (Thoma et al, Biology of Blood and Marrow Transplantation, in press). We hypothesized that rapid lymphocyte and monocyte recovery would have a similarly positive impact on overall survival in reduced intensity conditioning (RIC) HSCT with fludarabine/melphalan. To test our hypothesis, we analyzed 118 consecutive patients who underwent allogeneic HSCT with fludarabine/melphalan conditioning for AML (n=49) and MDS/MPN (n=38), ALL (n=7) and other lymphoid malignancies (n=24) at our institution from 2001–2010. The absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) derived from routine complete blood counts were determined longitudinally at days +15, +30, +60, +100 and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC > 0.3 × 10(9) cells/L were strongly associated with improved survival (OS 29.6 months vs. 5.4 months, p=0.006 and 25.3 months vs. 5.1 months, p=0.01 respectively), a pattern that continued through the day +100 evaluation. Multivariate analysis including age, CD34+ cell dose, unrelated vs. related HSCT, presence of aGVHD, remission status, and longitudinal hematologic parameters revealed that day +100 ALC (RR 0.21, 95% CI 0.07–0.66, p= 0.0096) and day +100 AMC (RR 0.41, 95% CI 0.2–0.9, p=0.047) were the only independent predictors of survival in the model. Pairwise correlations showed moderate negative associations between aGVHD and day +60 and day +100 ALC and AMC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort and identified four clusters of patients, clusters A-D. Patient clusters A and C both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters B and D (not reached for A and C vs. 54.9 and 22.3 months, respectively, p<0.001). No patient in cluster D had a day +100 AMC > 0.3 × 10(9) cells/L, and these patients experienced more acute GVHD (p=0.006) and relapse (8 of 14 patients, p=0.002) compared with clusters A, B, and C (p=0.002). 29 patients who were unable to be clustered with this algorithm, predominantly due to early toxic deaths, had a median survival of 6 months. Consistent with previous observations in our myeloablative cohort, both lymphocyte and monocyte recovery are predictive of overall survival post-RIC HSCT. However, compared to the myeloablative cohort, monocyte recovery in this series appears slightly less strongly associated with survival. Our results also extend the observation of improved survival of ALC and AMC recovery post-HSCT to diseases beyond acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Acute Lymphocytic Leukemia and Down Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-8-SCI-8
Author(s):  
Shai Izraeli
Keyword(s):  
Down Syndrome ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mtor Inhibitors ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Childhood All ◽  
Increased Risk ◽  
The Common

Abstract SCI-8 Children with Down syndrome are at a markedly increased risk for acute lymphoblastic leukemia (DS-ALL). These leukemias are exclusively of the B lymphoid precursor phenotype and occur in a similar age to “common” sporadic ALLs with the striking absence of infant ALL. Recent studies reveal that DS-ALLs are heterogeneous and differ from sporadic ALLs. Only about a fifth of DS-ALLs carry the common cytogenetic aberrations typical to childhood ALL. Genomic rearrangements leading to the expression of a cytokine receptor, CRLF2, are detected in 60% of DS-ALL in comparison with up to 10% of sporadic ALLs. CRLF2 heterodimerizes with Interleukin 7 receptor-α (IL7R) to form the receptor to thymic stromal lymphopoietin (TSLP). This receptor is usually present in macrophages, dendritic cells, and some T lymphocytes and participates in allergic and inflammatory processes. The aberrant expression of the TSLP receptor is DS-ALL (and sporadic ALL) is often associated with additional mutations that cause constitutive activation of the downstream JAK-STAT and mTOR growth signaling pathways. These are either lymphoid specific activating mutations of JAK2 or JAK1 or mutations in CRLF2 or IL7R that cause ligand-independent receptor dimerization. The role of the trisomy in selecting these somatic abnormalities is presently unknown. Clinically, the prognosis of DS-ALL is inferior to sporadic ALL mainly because of increased treatment toxicity. However, recent data suggest that the inferior outcome may also be related to the genetic properties of the leukemic cells and that excessive chemotherapy dose reduction may not be appropriate for these patients. Therefore increased vigilance for infectious complications and optimal supportive care are required during periods of intensive chemotherapy. The common activation of the TSLP signaling pathway in DS-ALLs suggests a future for targeted therapy with JAK and/or mTOR inhibitors. Importantly, research of DS-ALL has proven relevant for the general patient population with ALL, as somatic mutations in the TSLP pathway have been discovered in children and adults with sporadic ALL. A major research challenge is the elucidation of the roles of constitutional and somatic trisomy 21 in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

Family History Of Hematologic Malignancies and Disorders In a Population Based Study Of Myelodysplastic Syndromes (MDS)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1541-1541
Author(s):  
Angela R. Smith ◽  
Erica D. Warlick ◽  
Rachel K. Fonstad ◽  
Michelle A. Roesler ◽  
Jenny N. Poynter ◽  
...  
Keyword(s):  
Family History ◽  
Conflicts Of Interest ◽  
Positive Family History ◽  
Hematologic Malignancies ◽  
Population Based ◽  
Newly Diagnosed ◽  
Population Based Study ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
History Of

Abstract Background MDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. Methods Newly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom’s macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. Results A total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). Discussion In this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document