Days For Absolute Neutrophil Count Research Articles

Development of ALL-Hematotox (ALL-HT): predicting post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia

Immune effector cell–associated hematotoxicity (ICAHT) is a major B-cell targeted chimeric antigen receptor (CAR) T-cell related toxicity. Although ICAHT incidence and severity is documented in large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), and multiple myeloma (MM), ICAHT has not been described in B-cell acute lymphoblastic leukemia (B-ALL). Similarly, the CAR-HEMATOTOX (CAR-HT) model, designed to predict severe prolonged neutropenia (>14 days of absolute neutrophil count [ANC] <500/μl), has been validated in LBCL, MCL, and MM, but not in B-ALL. As B-ALL bone marrow (BM) infiltration can impact cytopenias, we sought to describe ICAHT and assess CAR-HT for predicting hematotoxicity in B-ALL. In a cohort of 156 children and young adults with relapsed/refractory B-ALL, the median duration of severe neutropenia (ANC <500/μl) was 13 days (95% confidence interval, 10-16 days), with 83 (53%) experiencing grade >3 ICAHT. Applying CAR-HT, nearly 90% were classified as high risk, demonstrating limited discriminative power and prompting further development. Using the association identified between BM disease burden and postinfusion neutropenia (r = 0.64, P < .0001), we developed the ALL-Hematotox (ALL-HT) score, which substitutes BM disease burden for ferritin in CAR-HT. The ALL-HT score associated with severe prolonged neutropenia (area under the curve = 0.84, P < .0001), and appropriately discriminated high-risk patients (47%) who had more cumulative days of neutropenia (26 vs 4 days; P < .0001), fewer rates of complete response (88% vs 98%; P = .03), and shorter median overall survival (9.8 vs 24 months; log-rank P = .0002). ALL-HT was also validated in 2 independent cohorts. The ALL-HT score refines a widely accepted predictive model of postinfusion hematotoxicity, applicable in B-ALL.

Comparable Survival Following Allogeneic Haematopoietic Stem Cell Transplant Utilising HLA-Matched Versus Alternative Donors: A Single-Centre Retrospective, Consecutive Cohort Analysis

Introduction: Allogeneic haematopoietic stem cell transplant (alloHCT) is a potentially curative therapy for many serious haematological disorders. The advent of alternative donor alloHCT, such as umbilical cord blood unit (CBU) and haploidentical (HAPLO), greatly widened the donor pool for recipients without HLA (human leukocyte antigen)-matched donor (MD), providing near universal donor availability. Although survival outcome of MD and alternate donor is considered to be similar, there is ongoing debate about preference of CBU and HAPLO (Wagner et al Blood Adv 2021; Wieduwilt et al Blood Adv 2022). Increased relapse after HAPLO versus increased non-relapse mortality with CBU makes selection of alternative donors difficult, with minimal supporting evidence. Hence, we compared single-centre outcomes of MD versus alternative donor alloHCT. Method: We performed a retrospective, consecutive cohort review of all patients who underwent alloHCT between 1st Jan 2010 and 30th Jun 2021 at our centre. Donors matched with recipients at HLA-A, HLA-B, HLA-C and HLA-DRB1, HLA-DQB1 loci (10/10) were considered MD, HAPLO (5/10) and CBU matched (5 - 6/8). Graft versus Host Disease (GVHD) prophylaxis for MD and CBU was calcineurin inhibitor, whereas HAPLO utilised post-HCT cyclophosphamide. Unrelated MD recipients also received rabbit anti-thymoglobulin (rATG) for in vivo T cell depletion. Neutrophil engraftment was defined as first of three consecutive days of absolute neutrophil count (ANC) > 0.5x109/L. Platelet (PLT) engraftment was defined as first of three consecutive days of PLT count > 20x109/L, unsupported for ≥7 days. Overall survival (OS) was assessed by Kaplan Meier (KM) method. Cumulative incidence (CI) of GVHD and relapse (REL) were estimated as competing events. Univariate and multivariate analysis (U/MVA) was conducted via Cox regression model. Statistical significance was defined as P<0.05. Results: Four-hundred and sixteen alloHCT were performed at our centre: 354 (85.10%) MD (41% related and 59% unrelated), 44 (10.58%) CBU and 18 (4.33%) HAPLO. Median follow up was 65.12 months. CBU recipients were significantly younger than other MD or HAPLO (median age 52 vs 45 vs 61 years, respectively: P=0.0001). Primary indication for transplant of total cohort was myeloid malignancy (64%) with majority in complete remission (68%) at transplant - there was no significant difference between donor groups. MD alloHCT utilised myeloablative conditioning significantly more than CBU and HAPLO (57% vs 23% vs 11%, respectively: P<0.0001). Median CD34 dose infused was 5.02 (4.28 - 5.98), 0.29 (0.24 - 0.36) and 4.98 (4.37 - 5.00) x106/kg for MD, CBU and HAPLO, respectively (P=<0.0001). There was no difference in ANC recovery (median D+19 vs 19 vs 25 for MD, CBU and HAPLO, respectively: P=0.2) between donor groups. PLT recovery was significantly faster for MD than CBU and HAPLO (median D+23 vs 41 vs 38, respectively: P=0.0139). Cumulative incidence of Grade II - IV acute GVHD (aGVHD) by D+100 was significantly higher in CBU than MD (48.46% vs 23.06%: P<0.001) and HAPLO (48.46% vs 34.81%: P=0.001). There was no difference of aGVHD CI between MD and HAPLO (P=0.2). Cumulative incidence of relapse was significantly higher following HAPLO versus CBU (3yr CI 52% vs 23%: P=0.025). However, there was no difference in REL between MD and CBU (32% vs. 23%; P=0.1) or MD and HAPLO (32% vs. 52%; P=0.3). Median and 3-year OS in our total cohort was 40.1 months and 51.8% (95% CI 0.570), respectively. We did not observe OS difference according to donor groups. Three-year OS was 51%, 63% and 45% for MD, CBU and HAPLO, respectively (P=0.4). UVA did not identify OS difference between donor groups. However, UVA revealed significant difference in other variables that were reassessed by MVA, per Table 1. Interestingly, MVA demonstrated significantly lower OS in fresh versus cryopreserved (cryo) alloHCT (HR fresh vs cryo 0.33, 0.15 - 0.72, P=0.005). Conclusion: Overall, we observed higher rates of aGVHD with CBU, versus higher rates of REL for HAPLO. However, the overall survival was comparable. Our results demonstrate that with careful patient selection and optimal management, alternative donor alloHCT have comparable outcomes to MD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Delayed Neutrophil Engraftment in Autologous Transplant Patients with Very High CD34+ Cell Collections in a Single Apheresis

Background: The number of CD34+ cells infused during autologous hematopoietic stem cell transplantation (auto-HSCT) is the most important determinant of the speed of engraftment and neutrophil recovery. Increasing the infused CD34+ cell doses results in faster neutrophil recovery, but infusion of more than 5-10 x 106/kg CD34+ cells typically does not hasten engraftment any further. In contrast, we have noticed cases of delayed engraftment when the number of CD34+ cells collected has been extraordinarily high. We report a single center experience of engraftment in auto-HSCT patients with very high CD34+ cell numbers collected in a single apheresis session (typically 20 L blood volume). Methods: Utilizing the database of the Stem Cell Transplantation and Cell Therapy Program and the Mathews Center for Cellular Therapy, we studied apheresis and engraftment data on patients undergoing auto-HSCT for hematologic malignancies at Northwestern Memorial Hospital from January 2000 through June 2022. Inclusion criteria were age ≥18 years, ≥20 x 106/kg CD34+ cells collected in a single aphaeresis session, and available neutrophil engraftment data. Time to neutrophil engraftment was defined as days from stem cell infusion to the first of three consecutive days of absolute neutrophil count ≥0.5 x 109/L. Delayed engraftment was defined as ≥20 days to neutrophil recovery. Fisher's exact test of independence was utilized to determine the statistical significance of the difference between variables. Results: We identified 214 patients with a yield of ≥20 x 106/kg CD34+ cells in one apheresis session. Patients were divided into two groups depending on the number of CD34+ cells collected; ≥20 but <50 (group A; n=93) and ≥50 (group B; n=121). Group A had a median collection of 31.1 x 106/kg CD34+ cells and group B had 66.8 x 106/kg. For group A, the median time to neutrophil recovery was 12 days, compared with 11 days for group B. Zero out of 93 patients in group A had delayed engraftment compared with 7 of the 121 patients (6%) in group B (P=0.022). All 7 patients with delayed engraftment were mobilized with single-agent granulocyte-colony stimulating factor. Four patients had myeloma, 2 acute promyelocytic leukemia (APL), and 1 Waldenstrom's macroglobulinemia (WM) (Table 1). Patients with myeloma and WM (all in first partial remission) received high-dose melphalan conditioning and patients with APL (both in second complete remission) received busulfan-cyclophosphamide. For the 7 patients with delayed engraftment, the median number of CD34+ cells infused was 14.5 x 106/kg (range 9.5-19.6) with a median time to neutrophil engraftment of 24 days (range 20-38). Conclusions: We describe an uncommon phenomenon of delayed engraftment in some patients with very high CD34+ cell yields in a single apheresis. Additional studies on stored autologous stem cells are needed to elucidate the cause of this peculiar finding. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, Ex Vivo, CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction

Introduction: Increased levels of fetal hemoglobin (HbF; encoded by γ-globin [HBG1/HBG2]) are protective against complications of sickle cell disease (SCD). BCL11A is a transcription factor that binds to HBG1/HBG2 promoters and produces a γ-to-β globin (fetal-to-adult hemoglobin) switch. Inhibiting BCL11A binding to its target can reverse the switch and induce HbF expression in adult red blood cells (RBCs). OTQ923 is an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product with a targeted disruption of the HBG1/HBG2 promoters on chromosome 11. Targeting this region in preclinical models led to HbF induction, phenotypically recapitulating hereditary persistence of fetal hemoglobin (a naturally occurring condition whose co-inheritance ameliorates SCD severity). This approach is more targeted than complete elimination of BCL11A expression in erythrocyte precursors for treating hemoglobinopathies. Additionally, unlike lentiviral vector gene addition, induction of endogenous γ-globin transcription could concur with reduction of βS-globin expression to avoid α- and β-like globin chain imbalance. Methods: Subjects with severe SCD, defined by a history of stroke, recurrent vaso-occlusive events (VOE), acute chest syndrome (ACS), chronic transfusions, recurrent priapism or red cell alloimmunization, were eligible to participate in the adult cohort (≥18-≤40 years old) of this clinical trial (NCT04443907). OTQ923 was manufactured from cryopreserved, peripheral blood derived CD34+ cells, collected after plerixafor mobilization. Prior to infusion, participants received myeloablative busulfan. Primary endpoints are to evaluate engraftment, long-term safety, and efficacy of HbF expression. Results: As of the data cut-off (July 8, 2022), 2 participants had received OTQ923, with follow-ups of 9 months (mos) and 3 mos, respectively. Here, we present initial clinical data from these 2 participants; additional data will be presented at the meeting. Both participants were homozygous for the sickle mutation. Participant 1 is a 22-year-old male with a history of silent cerebral infarcts, ACS, and priapism. At study entry, he was receiving chronic transfusions. He received 2.8x106 CD34+ cells/kg of OTQ923 (2 combined manufacturing batches). Participant 2 is a 21-year-old male with a history of ACS, and a silent cerebral infarct and was receiving hydroxyurea. He received 5.99x106 CD34+ cells/kg of OTQ923 (3 combined manufacturing batches). Time to neutrophil engraftment (the first of 3 consecutive days of absolute neutrophil count above 500 cells/mL after cell infusion) was 26 and 20 days for Participants 1 and 2, respectively. No OTQ923-related adverse events (AEs) were reported in either participant. All observed AEs were consistent with busulfan conditioning. Participants received RBC transfusions around conditioning and have received none after engraftment. For Participant 1, HbF level increased in the 6 mos after infusion and was stable at data cut-off (22.1% HbF at 9 mos after infusion). Induction of HbF was pancellular, with an F-cell percentage around 91% at 6 mos after infusion (Fig. 1A). Participant 2 had achieved an HbF level of 15.9% at 3 mos after infusion, the latest evaluable timepoint at data cut-off. Neither participant had any SCD-related VOEs after infusion of the cellular product. The proportion of edited alleles in the peripheral blood of Participant 1 was maintained at over 60% until Mo 6, which was the last evaluable timepoint (Fig. 1B). The indels were diverse, except for a predominant, large 5 kb deletion arising from simultaneous double-stranded DNA cleavage at HBG1 and HBG2 on-target sites, similar to previous reports. Conclusion: Preliminary data demonstrate clinically meaningful increases in HbF and evidence of benefit for both Participants 1 and 2 after OTQ923 infusion. Edited alleles were stable and maintained in the peripheral blood for >6 mos. The safety profile of OTQ923 was as expected after myeloablative busulfan and autologous hematopoietic stem cell transplantation. Taken together, these data suggest that this approach is safe and offers a potentially curative option for patients with severe SCD. Using cryopreserved, CD34+ cells as a starting material offers the advantage of centralizing manufacturing, scaling up the process to allow for improved patient access around the globe. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-241 Sequential Venetoclax and FLT3 Inhibitors in Combination With Hypomethylating Agents or Low-Dose Chemotherapy in Newly Diagnosed, Unfit, FLT3-Mutant Acute Myeloid Leukemia Patients

Targetable mutations such as FLT3, a receptor tyrosine kinase, are present in 30% of cases with acute myeloid leukemia (AML). Direct inhibitors of FLT3 are promising therapeutic agents such as midostaurin and gilteritinib. The use of FLT3 inhibitors as single agents remains to be limited with short-lived responses. For treatment-naïve AML patients with FLT3 mutation, the standard treatment entails induction with intensive chemotherapy in physically fit or younger patients and in combination with an FLT3 inhibitor. There is no approved targeted therapy option for treatment-naïve patients with AML harboring an FLT3 mutation ineligible for intensive therapy. To assess the efficacy and feasibility of sequential administration of venetoclax, a selective inhibitor of Bcl-2, and midostaurin in addition to induction chemotherapy in unfit newly diagnosed FLT3-mutant AML patients. This is a case series reviewing the clinical data of four consecutive patients with FLT3-mutant AML, ineligible for standard induction chemotherapy, who received induction treatment consisting of low-dose chemotherapy or hypomethylating agents (HMA) with the sequential use of venetoclax for 10 days followed by midostaurin for 14 days, treated at the American University of Beirut Medical Center. Between November 2021 and February 2022, four patients were included in our study. The median age was 68 years (range 66-70). All patients had FLT3 mutation (three with ITD, one with TKD), and three patients had concomitant NPM1 mutation. One patient had trisomy 8 and another patient had deletion 7 on cytogenetics. All patients achieved complete remission on day 21 and day 28. One patient with underlying myelodysplastic syndrome remained to have detectable FLT3 with deletion 7 at day 28 evaluation and had the longest time for absolute neutrophil count (ANC) and platelet count recovery. The median number of days for ANC and platelet count recovery was 40 days (range 27-59) and 34 days (24-not reached) respectively. The main toxicity was febrile neutropenia in 3 out of 4 patients. The sequential use of venetoclax followed by midostaurin in combination with low dose chemotherapy or HMA for newly diagnosed AML, FLT3-mutant patients who are unfit for intensive chemotherapy seems to be a promising approach with an acceptable toxicity profile.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin‐6 (IL‐6), soluble IL‐6 receptor, and C‐reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single‐dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target‐mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7‐15 days for CRP and 3‐5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Graft Purity and Composition Significantly Impact the Engraftment of Autologous Stem Cell Transplants

Background: Autologous stem cell transplantation (ASCT) has been widely used in the treatment of hematological malignancies over the last two decades. Despite its broad use, some characteristics that might influence engraftment have not been exhaustively investigated, particularly graft purity with respect to contamination by platelets (PLTS) and White Blood Cells (WBC). Here we report collection characteristics and engraftment kinetics of a single Center consecutive series of 510ASCTs.Methods: We retrospectively collected clinical records of patients who underwentleucapheresis procedures (LA; followed or not byASCT) at our Institution over 16 years (2000-2016): 290 patients collected peripheral blood stem cells (PBSC) (80 Multiple Myeloma MM, 133 Non Hodgkin Lymphoma NHL, 22 Hodgkin Lymphoma HL, 32 Acute Myeloid Leukemia AML, 23 other diseases) for a total of 481LAs. Mobilizing regimens are described in Table 1.We considered the number of harvested CD34+ cells *106/kg the first day of LA. Data on 458 patients (191 MM, 190 NHL, 45 HL, 19 AML and 13 other diseases) for a total of 510 ASCTs were acquired. The impact on engraftment kinetics of conditioning chemotherapies, amount of infused CD34+ cells and WBC/PLTS graft contamination were analyzed. Absolute neutrophil count (ANC) engraftment was defined as the duration of neutropenia (from day 0 to the first of 3 consecutive days of ANC>500/ul post ASCT).Results: Regarding CD34+ cell collection, no impact of mobilizing regimens and WBC count during LA was observed. On the other hand, we observed a difference in the number of total CD34+ cells collected among different diagnoses: the median overall collection was 7.2 (0.65-64.06)*106/kg CD34+ cells for NHL patients, 5.66 (0.71-23.31)*106/kg for MM patients, 6.15 (0.51-23.24) *106/kg for HL patients and 3.56 (0.64-20.3)*106/kg for AML patients) (p = 0.001). Considering CD34+ cells/kg harvested on the first day of LA, 59.2% of NHL and HL, 57.5% of MM patients and 34% of AML patients harvested ³ 5*106/Kg CD34+ cells. Of note, among AML patients, 40.6% collected less than 2.5*106/kg. The differences were statistically significant (p = 0.003) (Tab. 2). Moreover, an inverse correlation between collected CD34+ cells and age was shown (p = 0.001) (Fig.1).ANC recovery after ASCTwas not influenced by conditioning regimen whereas diagnosis impacted on the duration of neutropenia (AML patients displayed a longer aplasia, p < 0.01). We observed that the median days with ANC<500/ul were 10, 11 and 12 in patients who received >5.3*10^6/kg, 3.5-5.3*10^6/kg and <3.5*10^6/kg CD34+ cells, respectively (p <0.0001) (Fig 2a). Furthermore, the same finding was observed considering the duration of thrombocytopenia (median number of days with PLTS <50000/ul: 15, 18 and 20 in patients who received >5.3*10^6/kg, 3.5-5.3*10^6/kg and <3.5*10^6 CD34+ cells, p<0.0001) (Fig.2b).Looking at the apheresis product, we analyzed the impact of harvest contaminating WBC and PLTSon engraftment kinetics. Notably, when the ASCTcollection contained >100*103/ul WBC, ANC engraftment (days with ANC < 500/ul) lasted longer (median days 11) compared to patients who received a graft with lower WBC count (p < 0.0001) (Fig. 3a). A faster ANC engraftment was also observed in patients receiving harvests with PLTS levels >600*103/ul compared to those who infused a collection bag with PLTS <600*103/ul (p = 0.005) (Fig.3b,c).Conclusions: Herein, we confirmed that the disease and the amount of infusedCD34+ cells significantly influence time of ANC andPLTS engraftment; furthermore, we observed for the first time that quality and purity of the graft have a substantial impact on engraftment kinetics. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Comparative Study of Biosimilar Filgrastim Versus Originator G-CSF for CD34+ Cells Mobilization and Autografting in Hematological Malignancies

INTRODUCTION: Autografting (auto-HSCT) is widely used for the treatment of hematological malignancies. Since 2010, Biosimilar Filgrastim (Nivestim™, Pfizer Inc.) (BioG-CSF) has been approved and introduced into clinical practice to mobilize hematopoietic stem cells (CD34+cells) and to reduce the duration of chemo-induced neutropenia. This single institution study was designed to evaluate its safety and efficacy in the setting of "real life" medical practice.METHODS: We designed a "mixed retrospetive-prospective study" to evaluate the impact of BioG-CSF on CD34+ cells collections and engraftment kinetics after autografting. Patients who received BioG-CSF were compared with a historical cohort treated with Originator G-CSF (Filgrastim or Lenograstim). Primary endopoints were CD34+ mobilizations and post auto-HSCT engraftment kinetics. Secondary objectives included transfusions requirements, duration of hospitalization and 1-year overall survival (OS). Leukapheresis (LA) was initiated when circulating CD34+ count was at least 20/uL. Day of neutrophil engraftment was defined as the first of 3 consecutive days of absolute neutrophil count (ANC) ≥ 500/ul whereas day of platelet engraftment was defined as the first of 7 consecutive days without transfusion support.RESULTS: Initially,187 patients (137/187 affected by multiple myeloma) have been enrolled in the cohort under evaluation for CD34+ mobilization kinetics. Overall, 138 and 49 patients received originator and BioG-CSF (5-10 ug/kg/day) to collect CD34+cells. All but two patients underwent chemotherapy for mobilization (high-dose cyclophosphamide in 157/187 patients). Less than 3% of patients were poor mobilizers in both cohorts. No differences between Originator and BioG-CSF cohort were observed in time from chemotherapy to first day of LA (median day 11 vs day 11 p=0.473), CD34+/ul (mean 157.3/ul vs 166.2/ul, p=0.59) and CD34+*10^6/kg recipient harvested on the first day of LA (mean 10.5*10^6/kg vs 11.1*10^6/kg, p=0.323). A higher count of white blood cells on the first day of LA was observed in patients treated with BioG-CSF (mean originator 18.6*10^9/L vs BioG-CSF 27.1*10^9/L, p=0.001).A further analysis was conducted on 175 patients (126/175 affected my multiple myeloma) for a total of 220 auto-HSCTs, evaluable for hematological recovery and clinical outcomes. Overall, 137 and 83 patients received Originator and BioG-CSF, respectively. All patients were hospitalized and prepared for the autograft with a high-dose conditioning (Melphalan 200mg/sqm in 171/220 auto-HSCTs). Infused CD34+ cells were 5*10^6/kg recipient (IQR 3.8-5.1) and 4.1*10^6/kg recipient (IQR 3.5-5.3) in the Originator and BioG-CSF cohorts. After the autograft, patients were prescribed 30-34 milliion units (MU) of Originator G-CSF and 30 MU dose of BioG-CSF starting on day +1/+3. Day +25 cumulative incidences of ANC and platelets recovery were 99.3% and 98.5% and 97.6% and 90.2% in the Originator and BioG-CSF groups, respectively (p=0.786, p=0.006). Of note, by Mann-Whitney test, no differences between cohorts were found in a)median duration of neutropenia (median 7 and 6 days, p=0.355), platelets (median 1 pool/patient in both, p=0.894) and red blood cells (median 0/patient in both, p=0.704) transfusion requirements, hospital stay (median 20 days and 21 days, p=0.33). Serial measurements of complete blood counts were performed from discharge to day +90 post auto-HSCT; no significant differences were found at any time point between the two groups. No severe adverse reactions attributable to G-CSFs were documented. Thrombocytopenia lasted longer for patients treated with BioG-CSF, however this finding did not translate into a higher transfusion requirement or bleeding episodes. Finally, 1-year OS was comparable between cohorts (p=0.699).CONCLUSIONS: In this sizable study, BioG-CSF was as effective as Originator G-CSF in mobilizing CD34+ cells as well as in treating post-transplant neutropenia in patients with hematological malignancies. Moreover, the extensive use of BioG-CSF led to a significant cost containment. DisclosuresMassaia:Janssen: Other: advisory board; Gilead: Other: advisory board; Roche: Other: advisory board, research support. Cavallo:JANSSEN: Honoraria; CELGENE: Honoraria; ONYX: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; Abbivie: Honoraria; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

Combination chemotherapy of intermediate-dose cytarabine, idarubicin, plus etoposide and subsequent mobilized donor leukocyte infusion for relapsed acute leukemia after allogeneic bone marrow transplantation

The efficacy and side effects of intermediate-dose cytarabine, idarubicin plus etoposide and subsequent donor leukocyte infusion (DLI) were investigated in patients with acute leukemia who relapsed after allogeneic bone marrow transplantation (BMT). Patients were given cytarabine continuous i.v. (1 g/m 2 per day×5), idarubicin i.v. (12 mg/m 2 per day×3), and etoposide i.v. infusion (150 mg/m 2 per day×3). Two days later, G-CSF mobilized donor leukocytes were infused for 2 days. No graft-versus-host disease (GVHD) prophylaxis was given. Between August 1997 and February 2000, 13 patients enrolled (eight acute myeloid leukemia (AML) and five acute lymphoblastic leukemia (ALL)). All patients finished chemotherapy and DLI. Eleven patients (85%) achieved complete remission (CR) at median 27 days after DLI. After median follow up of 10.9 months (2.5–33.3), five of 11 patients who achieved CR relapsed. Overall, six of 13 patients were surviving (6/8 AML and 0/5 ALL, P=0.059). Marrow recovery after chemotherapy and DLI was rapid (12 days for absolute neutrophil count (ANC)>500/μl). Side effects included fever with neutropenia (100%), pneumonia (46%), grade II–IV mucositis (69%), grade III–IV acute GVHD (45%), and extensive chronic GVHD (64%). One patient died from chronic GVHD. Chemotherapy containing intermediate-dose cytarabine and DLI produced a high CR rate in acute leukemia in relapse after allogeneic BMT. A fraction of patients are surviving long term. Side effects were substantial but manageable.

A randomized, double-blind, placebo-controlled trial of prophylactic recombinant human granulocyte-macrophage colony-stimulating factor to reduce nosocomial infections in very low birth weight neonates

Objective: We carried out a randomized placebo-controlled trial in very low birth weight neonates (VLBWNs), comparing the incidence of nosocomial infections after the prophylactic use of recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) versus placebo in VLBWNs. Study design: VLBWNs (n = 264), weighing 501 to 1000 g, ≤72 hours of age were randomly assigned to receive rhu GM-CSF (8 μg/kg/d), administered intravenously (n = 134) over 2 hours daily × 7 days and every other day for 21 days, or placebo (n = 130). The safety, incidence of nosocomial infections, days of absolute neutrophil count ≥4000/mm, 3 peripheral blood progenitor studies, and 24-hour polymorphonuclear leukocyte C3bi receptor expression were compared between the 2 treatment groups. Results: No (grade III/IV) toxicity or adverse events were associated with rhu GM-CSF. The absolute neutrophil count and absolute eosinophil count were significantly elevated in the rhu GM-CSF group on days 7 ( P = .001), 14 ( P = .001), and 21 ( P = .007) and on days 7 and 28 ( P = .012 and P = .001, respectively). However, there was no difference in the incidence of confirmed nosocomial infections between the 2 treatment groups in this trial (40% vs 39%, rhu GM-CSF vs placebo; P = NS). Conclusion: In a large randomized placebo-controlled trial, prophylactic administration of rhu GM-CSF in VLBWNs does not appear to decrease the incidence of nosocomial infections. (J Pediatr 1999;134:64-70)

Double dose-intensive chemotherapy with autologous marrow and peripheral-blood progenitor-cell support for metastatic breast cancer: a feasibility study.

Twenty-seven percent of responding metastatic breast cancer patients remain progression-free a median 29 months following one intensification course of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). European investigators report high complete response (CR) rates with melphalan for breast cancer. This trial studied the feasibility of two tandem high-dose intensification therapies in an attempt to optimize disease response and duration. Women with at least partial responses (PRs) to induction therapy received melphalan (140 to 180 mg/m2), followed 24 hours later by chemotherapy and granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral-blood progenitor cells (PBPCs) and subsequent G-CSF until WBC recovery. The women were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. Twenty women were assessable. Fourteen (70%) required admission for fever (10% infection) or mucositis (35%) after melphalan (median stay, 5 days). Median days of absolute neutrophil count (ANC) less than 500/microL and platelet count less than 20,000/microL were 6 and 5.5, respectively. Patients received CTCb 25 days after starting melphalan and had a hospital stay of 25 days. After CTCb, median days of ANC less than 500/microL and platelet count less than 20,000/microL were 11.5 and 24, respectively. Grade 3 toxicities included venoocclusive disease (VOD) (10%), mucositis (45%), and infection (20%). Toxicities were reversible without mortality. With mobilized PBPCs and growth factors, double dose-intensive chemotherapy is feasible with acceptable toxicity. When compared with trials using marrow alone, these supportive adjuncts decrease sepsis and organ toxicity. The concepts of dose and dose-intensity may now be more effectively and safely studied in chemosensitive tumors, including breast cancer.