Predictive Factors for Early Immune Recovery in NHL Patients after Autologous Transplantation: A Multicenter Prospective Study.

Early lymphocyte recovery as manifested by an absolute lymphocyte count at d+15 (ALC-15) ≥ 0.5 × 109/L after autologous hematopoietic stem cell transplantation (AHCT) has been associated with a better outcome. This prospective multicenter study aimed to clarify factors associated with ALC-15 ≥ 0.5 × 109/L after AHCT among 178 patients with non-Hodgkin lymphoma. The mobilization capacity, as manifested by peak blood CD34+ cell numbers > 45 × 106/L correlated with higher ALC-15 levels (p = 0.020). In addition, the amount of CD3+CD4+ T cells > 31.8 × 106/kg in the infused graft predicted ALC-15 ≥ 0.5 × 109/L (p < 0.001). Also, the number of infused graft CD3+CD8+ T cells > 28.8 × 106/kg (p = 0.017) and NK cells > 4.4 × 106/kg was linked with higher ALC-15 (p < 0.001). The two-year progression-free survival after AHCT was significantly better in patients with ALC-15 ≥ 0.5 × 109/L (74 vs. 57%, p = 0.027). The five-year OS in patients with higher ALC-15 was 78% vs. 60% in those with lower ALC-15 (p = 0.136). To conclude, the mobilization capacity of CD34+ cells and detailed measures of graft cellular content mark prognostic tools that predict ALC-15 ≥ 0.5 × 109/L, which is associated with a better outcome in NHL patients after AHCT.

CD34+ Cell Mobilization, Autograft Cellular Composition and Outcome in Mantle Cell Lymphoma Patients.

Backgound: Autologous stem cell transplantation (ASCT) is a standard treatment in transplant-eligible mantle cell lymphoma (MCL) patients after first-line chemoimmunotherapy. Study Design and Methods: This prospective multicenter study evaluated the impact of CD34+ cell mobilization and graft cellular composition analyzed by flow cytometry on hematologic recovery and outcome in 42 MCL patients. Results: During CD34+ cell mobilization, a higher blood CD34+ cell count (>30 × 106/L) was associated with improved overall survival (median not reached [NR] vs. 57 months, p = 0.04). The use of plerixafor did not impact outcome. Higher number of viable cryopreserved graft CD34+ cells (>3.0 × 106/kg) was associated with faster platelet (median 11 vs. 15 days, p = 0.03) and neutrophil (median 9 vs. 10 days, p = 0.02) recovery posttransplant. Very low graft CD3+CD8+ cell count (≤10 × 106/kg) correlated with worse progression-free survival (PFS) (HR 4.136, 95% CI 1.547-11.059, p = 0.005). On the other hand, higher absolute lymphocyte count >2.5 × 109/L at 30 days after ASCT (ALC-30) was linked with better PFS (median NR vs. 99 months, p = 0.045) and overall survival (median NR in either group, p = 0.05). Conclusions: Better mobilization capacity and higher graft CD3+CD8+ cell count had a positive prognostic impact in this study, in addition to earlier lymphocyte recovery (ALC-30>2.5 × 106/L). These results need to be validated in another study with a larger patient cohort.

Loss of CD34+ Cells and Effect of the Number of Viable Cryopreserved CD34+ Cells in the Infused Blood Grafts on Hematologic Recovery, Progression-Free Survival and Overall Survival in NHL Patients After Autologous Stem Cell Transplantation.

PATIENTS: This post-hoc study aimed to find out factors affecting graft viable CD34+ cell loss during processing and cryopreservation in 129 non-Hodgkin lymphoma (NHL) patients receiving autologous stem cell transplantation (auto-SCT) and the impact of a low (< 2.0 × 106/kg, group A) and a decent number (≥ 2 × 106/kg, group B) of viable CD34+ cells infused on the hematologic recovery, progression-free survival (PFS) and overall survival (OS) after auto-SCT. RESULTS: The median loss of viable CD34+ cells during cryopreservation was higher in group A (47% vs. 19%, p < .001). A higher yield of CD34+ cells at the first apheresis in group B (p = .002) was linked with greater loss of viable graft CD34+ cells after cryopreservation. Filgrastim (FIL) use for mobilization seemed to associate with higher viable CD34+ cell loss compared to pegfilgrastim (PEG) or lipegfilgrastim (LIPEG) in both groups (in group A FIL 66 vs. PEG 35%, p = .006; in group B FIL 37 vs. PEG 15 vs. LIPEG 13%, p < .001). Hematologic recovery after auto-SCT was faster in group B. Neither viable CD34+ cell loss during storage nor viable CD34+ cell number < 2.0 × 106/kg infused affected on PFS or OS. CONCLUSIONS: G-CSF type used in mobilization and mobilization capacity were found to correlate with viable CD34+ cell loss during processing and storage. Most importantly, low infused viable CD34+ cell count did not seem to impact on PFS or OS.

Impact of the number of cryopreserved CD34+ cells in the infused blood grafts on hematologic recovery and survival in myeloma patients after autologous stem cell transplantation: Experience from the GOA study.

BACKGROUND: Prospective data on the impact of CD34+ cell loss during cryopreservation and the amount of cryopreserved CD34+ cells infused after high-dose therapy on hematologic recovery and post-transplant outcome in multiple myeloma (MM) are scarce. PATIENTS AND METHODS: This post-hoc study aimed to investigate factors associating with CD34+ cell loss during cryopreservation and the effects of the infusion of a very low number (<1.0 × 106 /kg, group A), low number (1-1.9 × 106 /kg, group B), and optimal number (≥2 × 106 /kg, group C) of thawed viable CD34+ cells on hematologic recovery, progression free survival, and overall survival after autologous stem cell transplantation among 127 patients with MM. RESULTS: In group C, pegfilgrastim use (P = 0.001), plerixafor use (P = 0.039), and older age ≥ 60 years (P = 0.026) were associated with less loss of CD34+ cells during cryopreservation. Better mobilization efficacy correlated with greater CD34+ cell loss in group B (P = 0.013 and P = 0.001) and in group C (P < 0.001 and P < 0.001). Early platelet engraftment was slowest in group A (20 d vs 12 d in group B vs 11 d in group C, P = 0.003). The infused viable CD34+ cell count <1.0 × 106 /kg seemed not to have influence on PFS (P = 0.322) or OS (P = 0.378) in MM patients. CONCLUSIONS: Cryopreservation impacts significantly on the CD34+ cell loss. A very low number of graft viable CD34+ cells did not affect PFS or OS.

Autograft cellular composition and outcome in myeloma patients: Results of the prospective multicenter GOA study.

BACKGROUND: Autologous stem cell transplantation (auto-SCT) is a widely used treatment option in multiple myeloma (MM) patients. The optimal graft cellular composition is not known. STUDY DESIGN AND METHODS: Autograft cellular composition was analyzed after freezing by flow cytometry in 127 MM patients participating in a prospective multicenter study. The impact of graft cellular composition on hematologic recovery and outcome after auto-SCT was evaluated. RESULTS: A higher graft CD34+ cell content predicted faster platelet recovery after auto-SCT in both the short and long term. In patients with standard-risk cytogenetics, a higher graft CD34+ count (>2.5 × 106 /kg) was linked with shorter progression-free survival (PFS; 28 vs. 46 months, p = 0.04), but there was no difference in overall survival (OS) (p = 0.53). In a multivariate model, a higher graft CD34+ CD133+ CD38- (>0.065 × 106 /kg, p = 0.009) and NK cell count (>2.5 × 106 /kg, p = 0.026), lenalidomide maintenance and standard-risk cytogenetics predicted better PFS. In contrast, a higher CD34+ count (>2.5 × 106 /kg, p = 0.015) predicted worse PFS. A very low CD3+ cell count (≤20 × 106 /kg, p = 0.001) in the infused graft and high-risk cytogenetics remained predictive of worse OS. CONCLUSIONS: Autograft cellular composition may impact outcome in MM patients after auto-SCT. More studies are needed to define optimal graft composition.

Blood Graft and Outcome After Autologous Stem Cell Transplantation in Patients With Primary Central Nervous System Lymphoma.

BACKGROUND: Autologous stem cell transplantation (auto-SCT) is a treatment option for patients with primary central nervous system lymphoma (PCNSL). METHODS: In this prospective multicenter study, the effects of blood graft cellular content on hematologic recovery and outcome were analyzed in 17 PCNSL patients receiving auto-SCT upfront. RESULTS: The infused viable CD34+ cell count > 1.7 × 106/kg correlated with more rapid platelet engraftment (10 vs. 31 days, P = 0.027) and with early neutrophil recovery (day + 15) (5.4 vs. 1.6 × 109/L, P = 0.047). A higher number of total collected CD34+ cells > 3.3 × 106/kg infused predicted worse 5-year progression-free survival (PFS) (33% vs. 100%, P = 0.028). In addition, CD3+CD8+ T cells > 78 × 106/kg in the infused graft impacted negatively on the 5-year PFS (0% vs. 88%, P = 0.016). CONCLUSION: The cellular composition of infused graft seems to impact on the hematologic recovery and PFS post-transplant. Further studies are needed to verify the optimal autograft cellular content in PCNSL.

Mobilization characteristics, blood graft composition, and outcome in diffuse large B-cell lymphoma after autologous stem cell transplantation: Results from the prospective multicenter GOA study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common indication for autologous stem cell transplantation (auto-SCT). STUDY DESIGN AND METHODS: This prospective noninterventional study aimed to evaluate the impact of mobilization characteristics and graft cellular content on hematologic recovery and outcome after auto-SCT among 68 patients with DLBCL. RESULTS: Better mobilization capacity as manifested by blood CD34+ cell count >32 × 106 /L and CD34+ cell yield of the first apheresis >2.75 × 106 /kg correlated with faster neutrophil (P = .005 and P = .017) and platelet (P = .002 and P < .001) recovery. A higher number of infused CD34+ cells (> 2.65 × 106 /kg) was associated with better 5-year overall survival (OS; 95% vs 67%, P = .012). The graft CD34+ CD133+ CD38- cell count >0.07 × 106 /kg was predictive of better 5-year OS (87% vs 63%; P = .008) and higher graft CD3+ cell count (>23.1 × 106 /kg) correlated also with better 5-year OS (80% vs 40%, P = .008). In multivariate analysis only disease status of CR I at auto-SCT was associated with better progression-free survival (P = .014) and OS (P = .039). CONCLUSION: The mobilization capacity of CD34+ cells impacted on early hematologic recovery in patients with DLBCL after auto-SCT. Higher graft CD34+ cell count and both CD34+ CD133+ CD38- and CD3+ cells were also associated with better OS. The effect of optimal graft cellular composition on outcome in DLBCL should be evaluated in a randomized study.

Autograft cellular composition and outcome in NHL patients: results of the prospective multicenter GOA study.

Autologous stem cell transplantation (auto-SCT) is an established treatment option in patients with non-Hodgkin lymphoma (NHL). In this prospective multicenter study, the effect of infused blood graft cellular composition on post-transplant outcome was analyzed in 129 NHL patients. Higher graft CD34+ cell content (>2.5 × 106/kg) correlated with better progression-free survival (PFS) (p=.009) and overall survival (OS) (p=.004). Higher graft CD34+CD133+CD38- counts (>0.08 × 106/kg) were also linked with better PFS (p=.03) and OS (p=.004), and these survival benefits retained in multivariate analyses. Higher infused CD3+CD4+ cell count (>37 × 106/kg) predicted better PFS (p=.013) and OS (p=.007) in multivariate analysis. Autograft cellular composition seems to impact outcome in NHL patients. These observations regarding composition of optimal graft in autologous setting should be validated in an independent patient series or in a randomized study.

CD34+ cell mobilization, blood graft composition, and posttransplant recovery in myeloma patients compared to non-Hodgkin's lymphoma patients: results of the prospective multicenter GOA study.

BACKGROUND: Autologous stem cell transplantation is an established treatment option for patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL). STUDY DESIGN AND METHODS: In this prospective multicenter study, 147 patients with MM were compared with 136 patients with NHL regarding the mobilization and apheresis of blood CD34+ cells, cellular composition of infused blood grafts, posttransplant recovery, and outcome. RESULTS: Multiple myeloma patients mobilized CD34+ cells more effectively (6.3 × 106 /kg vs. 3.9 × 106 /kg, p = 0.001). The proportion of poor mobilizers (peak blood CD34+ cell count <20 × 106 /L) was higher in NHL patients (15% vs. 3%, p < 0.001). Plerixafor was added to rescue the mobilization failure in 17 MM patients (12%) and in 35 NHL patients (26%; p = 0.002). The infused grafts contained more natural killer (NK) and CD19+ cells in MM patients. Blood platelet and NK-cell counts were higher in MM patients posttransplant. Early treatment-related mortality was low in both groups, but NHL patients had a higher late (>100 days) nonrelapse mortality (NRM; 6% vs. 0%, p = 0.003). CONCLUSIONS: Non-Hodgkin's lymphoma and MM patients differ in terms of mobilization of CD34+ cells, graft cellular composition, and posttransplant recovery. Thus, the optimal graft characteristics may also be different.

A prospective comparison of pegfilgrastim and lipegfilgrastim combined with chemotherapy in the mobilization of CD34+ cells in NHL patients.

BACKGROUND: Autologous stem cell transplantation (auto-SCT) is a treatment approach in non-Hodgkin lymphoma (NHL) patients. The options for mobilization of CD34+ cells to support high-dose therapy are granulocyte-colony stimulating factors (G-CSFs) alone or after chemotherapy. Limited data exist on the efficacy of lipegfilgrastim (LIPEG) in the mobilization field. PATIENTS AND METHODS: The present prospective nonrandomized study compared LIPEG 6 mg (n = 40) with pegfilgrastim (PEG) 6 mg (n = 37) in the mobilization of blood CD34+ cells after chemotherapy in NHL patients with comparable mobilizing chemotherapy and disease status before auto-SCT. RESULTS: Significantly higher blood CD34+ cell (B-CD34+ ) counts were observed in the LIPEG group at the start of the first apheresis (44 vs 23 × 106 /L, P = .009), in line with a higher collection yield of the first apheresis (3.3 vs 2.1 × 106 /kg, P = .086) and total yield of CD34+ cells (4.7 vs 2.9 × 106 /kg, P = .004). LIPEG proved to be a more effective G-CSF, resulting in a higher B-CD34+ cell peak (60 vs 32 × 106 /L, P = .030) and higher proportion of excellent mobilizers (33% vs 8%, P = .008). The superiority of LIPEG was confirmed in the multivarite analysis concerning the CD34+ cell yield of the first apheresis day (P = .010) and the total yield (P = .001). CONCLUSION: The mobilization of blood grafts with LIPEG added to chemotherapy was associated with higher CD34+ cell apheresis yields than with PEG. A randomized study is warranted to verify these findings.

RVD induction and autologous stem cell transplantation followed by lenalidomide maintenance in newly diagnosed multiple myeloma: a phase 2 study of the Finnish Myeloma Group.

Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS.

Blood graft composition and post-transplant recovery in myeloma patients mobilized with plerixafor: a prospective multicenter study.

The composition of autologous blood grafts after cryopreservation, post-transplant hematological recovery up to 1 year and immune recovery up to 6 months as well as outcome was analyzed in 87 patients with multiple myeloma (MM). The patients receiving added plerixafor due to poor mobilization (11%) were compared to those mobilized with G-CSF or cyclophosphamide (CY) plus G-CSF. The use of plerixafor was found to significantly affect the graft composition as there was a significantly higher proportion of the more primitive CD34+ cells, higher number of T and B lymphocytes as well as NK cells in the grafts of patients who received also plerixafor. The hematological recovery after auto-SCT was comparable between the groups. The recovery of CD3+CD4+ T cells was faster in plerixafor mobilized patients at 1 and 3 months post-transplant. There were no significant differences in progression-free (PFS) or overall survival (OS) according to the plerixafor use.

Impact of lenalidomide-based induction therapy on the mobilization of CD34+ cells, blood graft cellular composition, and post-transplant recovery in myeloma patients: a prospective multicenter study.

BACKGROUND: Lenalidomide is an immunomodulatory drug that is also currently used in transplant-eligible patients with multiple myeloma. Previous studies have suggested a negative impact of lenalidomide on the mobilization of CD34+ cells. No data are available regarding the more detailed composition of blood grafts after lenalidomide. STUDY DESIGN AND METHODS: In a multicenter, prospective study, we analyzed the mobilization of CD34+ cells, graft cellular composition, and post-transplant hematologic recovery in 26 patients with multiple myeloma after lenalidomide-based induction and in 34 lenalidomide-naive controls with multiple myeloma. All patients were mobilized with low-dose cyclophosphamide plus granulocyte-colony-stimulating factor. The cellular composition of the grafts was analyzed from thawed, cryopreserved samples with flow cytometry. Graft function was evaluated by engraftment data and by complete blood counts until 12 months after the graft infusion. RESULTS: Patients in the lenalidomide arm had lower median peak CD34+ counts and approximately 40% lower CD34+ cell yields from the first apheresis session, but these differences were not significant. The median total number of CD34+ cells collected was comparable (6.4 vs. 7.5 × 106 /kg). The number of apheresis sessions was higher in the lenalidomide group (2 vs. 1; p = 0.039). The blood graft composition was comparable between the groups. Hematologic recovery within 12 months post-transplant did not differ between the groups. CONCLUSION: Lenalidomide-based induction seems to have an impact on the number of aphereses performed, but not on the total yields of the CD34+ cells in the graft. Neither cellular composition of the grafts nor post-transplant recovery was affected by the limited pre-transplant exposure to lenalidomide.

Cost analysis of a randomized stem cell mobilization study in multiple myeloma.

Upfront autologous stem cell transplantation (ASCT) is the standard therapy for younger multiple myeloma (MM) patients. MM patients usually undergo stem cell mobilization with cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF), or with G-CSF alone. A limited number of randomized studies are available comparing costs of different mobilization strategies. Eighty transplant-eligible patients aged up to 70 years with untreated MM were included in this prospective study. The patients were treated with RVD induction for three 21-day cycles and randomized 1:1 at inclusion into one of the two mobilization arms CY 2 g/m(2) + G-CSF [arm A] vs. G-CSF alone [arm B]. Plerixafor was given according to a specific algorithm if needed. Sixty-nine patients who received mobilization followed by blood graft collection were included in the cost analysis. The median total costs of the mobilization phase were significantly higher in arm A than in arm B (3855 € vs. 772 €, p ≤ 0.001). The cumulative median cost of the mobilization and collection phases was significantly lower in arm B than in arm A (8524 € vs. 11,622 €, p = 0.012). There was no significant difference between the arms in the total median costs of ASCT (n = 59) (34,997 € in arm A vs. 31,981 € in arm B, p = 0.118). Mobilization with G-CSF alone seems to be a preferable mobilization method for MM patients in terms of mobilization and apheresis costs. In addition, it requires less hospital resource utilization.

Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low-dose cyclophosphamide: a randomized comparison.

BACKGROUND: Autologous stem cell transplantation is a standard treatment in multiple myeloma (MM). Blood grafts are usually collected after mobilization with granulocyte-colony-stimulating factor (G-CSF) alone or in a combination with cyclophosphamide (CY). There is limited knowledge of the possible effects of different mobilization regimens on blood graft characteristics and posttransplant outcomes. STUDY DESIGN AND METHODS: Thirty-eight patients with MM were included in this study. The patients were randomly assigned at registration to mobilization with either low-dose CY plus G-CSF (Arm A) or G-CSF alone (Arm B) and received three cycles of lenalidomide, bortetzomib, and dexamethasone induction. Flow cytometry analysis of lymphocyte subsets in the blood grafts after cryopreservation was performed. Hematologic and immune recovery were evaluated up to 12 months posttransplant. RESULTS: The blood grafts in Arm A contained significantly more CD34+ cells but in Arm B there was a greater proportion of CD34+CD38- cells and higher numbers of T and B lymphocytes as well as natural killer (NK) cells. The engraftment was comparable but lymphocyte count at 15 days posttransplant was higher in Arm B (0.8 × 10(9) /L vs. 0.5 × 10(9) /L, p = 0.033). At 3 and 6 months posttransplant the total number of NK cells was also higher in G-CSF-mobilized patients. There was no difference in progression-free survival between the study arms. CONCLUSION: CY plus G-GSF yields more CD34+ cells but seems to diminish lymphocyte and NK cell counts in the grafts and hampers immune recovery after transplantation. Thus G-CSF alone might be a preferred mobilization method due to more rapid immune recovery posttransplant.

Early immune recovery after autologous transplantation in non-Hodgkin lymphoma patients: predictive factors and clinical significance.

Limited data is available about the factors affecting early immune recovery or its clinical significance after autologous stem cell transplantation (auto-SCT). We prospectively analyzed factors affecting early immune recovery and outcome among 72 non-Hodgkin lymphoma (NHL) patients. Absolute lymphocyte count 15 d after auto-SCT (ALC-15) ≥ 0.5 × 10(9)/L was associated with the use of plerixafor (p = 0.004), the number of CD34(+) cells (p = 0.015), and CD34(+) CD38(-) cells (p = 0.005) in the grafts. ALC-15 ≥ 0.5 × 10(9)/L was associated with improved overall survival (p = 0.021). In patients with aggressive histology, ALC-15 ≥ 0.5 × 10(9)/L was beneficial in regard to both progression-free survival (p = 0.015) and overall survival (p = 0.002). Early immune recovery seems to be important in transplanted patients with NHL and, therefore, an easy and affordable method for disease-related risk analysis. Patients with aggressive histology and slow immune recovery may need additional post-transplant treatment.

Blood graft cellular composition and posttransplant recovery in non-Hodgkin's lymphoma patients mobilized with or without plerixafor: a prospective comparison.

BACKGROUND: Autologous stem cell transplantation is commonly used to treat non-Hodgkin's lymphomas (NHLs). Cellular composition of the blood grafts apparently has a role in the posttransplant hematologic and immune recovery. Plerixafor increases the mobilization of CD34+ cells and higher amounts of various lymphocyte subsets have been reported in the grafts. Limited prospective data are available in regard to graft cellular composition, hematologic and immune recovery, and patient outcomes in NHL patients who receive plerixafor added to chemomobilization. STUDY DESIGN AND METHODS: Forty-one patients with NHL participated in this prospective study. All patients received chemomobilization and 15 poor mobilizers also received plerixafor. CD34+ cell subsets and lymphocyte subsets of cell grafts, posttransplant hematologic and immune recovery, and outcome were evaluated. RESULTS: Blood grafts in the plerixafor group contained a significantly higher proportion of CD34+133+CD38- cells and more lymphocytes of all major subsets except B lymphocytes. Neutrophil engraftment was comparable and platelet recovery slightly slower in the plerixafor group. Natural killer cell recovery was significantly faster in patients mobilized with plerixafor. Otherwise hematologic and immune recovery as well as short-time outcome were comparable even though there was a trend for progression-free survival and overall survival benefit in the plerixafor group. CONCLUSIONS: In poorly mobilizing NHL patients, plerixafor added to chemomobilization is safe and effective. It also modifies the blood graft composition in many ways, some of which have been linked to better outcomes in previous studies. Larger sets of patients and longer follow-up are needed to see whether plerixafor-mobilized grafts are associated with superior outcome of the patients.

Spermidine/spermine N(1)-acetyltransferase activity associates with white blood cell count in myeloid leukemias.

The metabolism of polyamines, the cationic small molecules essential for cell proliferation and differentiation, is altered in cancer cells and can be exploited in cancer diagnosis and therapy. Spermidine/spermine N(1)-acetyltransferase (SSAT), which regulates intracellular levels of polyamines by catabolizing spermidine and spermine, has a controversial role in the development of cancers. In this study, the polyamine metabolism and function of SSAT were characterized in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoid leukemia patient samples. Also, mice overexpressing SSAT and having a myeloproliferative phenotype were analyzed for their response to decitabine and histone deacetylase inhibitor trichostatin A. The presence of epigenetic factors in the bone marrow cells of SSAT mice was analyzed. Elevated levels of spermidine and spermine, as well as increased activity of SSAT, were detected in AML, CML, and acute lymphoid leukemia patients compared with the controls. However, we found SSAT activity to be associated with white blood cell count only in AML and CML patients. Decitabine treatment brought the peripheral blood and bone marrow cell counts of SSAT mice to the level of wild-type mice. Spermidine/spermine N(1)-acetyltransferase mice had increased histone methylation and an increased level of histone deacetylase 1 in their bone marrow cells. The study suggests that SSAT influences the development of myeloid malignancies, and epigenetic factors partly contribute to the SSAT overexpression-induced myeloproliferative disease in mice.

Enhanced polyamine catabolism disturbs hematopoietic lineage commitment and leads to a myeloproliferative disease in mice overexpressing spermidine/spermine N¹-acetyltransferase.

Spermidine/spermine N(1)-acetyltransferase (SSAT) regulates intracellular polyamine levels by catabolizing spermidine and spermine which are essential for cell proliferation and differentiation. Hematological characterization of SSAT overexpressing mice (SSAT mice) revealed enhanced myelopoiesis and thrombocytopoiesis leading to increased amounts of myeloid cells in bone marrow, peripheral blood, and spleen compared to wild-type animals. The level of SSAT activity in the bone marrow cells was associated with the bone marrow cellularity and spleen weight which both were significantly increased in SSAT mice. The result of bone marrow transplantations indicated that both the intrinsic SSAT overexpression of bone marrow cells and bone marrow microenvironment had an impact on the observed hematopoietic phenotype. The Lineage-negative Sca-1(+) c-Kit(+) hematopoietic stem cell (HSC) compartment in SSAT mice, showed enhanced proliferation, increased proportion of long-term HSCs and affected expression of transcription factors associated with lineage priming and myeloid differentiation. The proportions of common myeloid and megakaryocytic/erythroid progenitors were decreased and the proportion of granulocyte-macrophage progenitors was increased in SSAT bone marrow. The data suggest that SSAT overexpression and the concomitantly accelerated polyamine metabolism in hematopoietic cells and bone marrow microenvironment affect lineage commitment and lead to the development of a mouse myeloproliferative disease in SSAT mice.