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Relapsed or refractory (r/r) Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) still represent an unmet clinical need despite the new immune therapies available for these patients. We report the case of a Ph + ALL relapsed one year after allogeneic stem cell transplant. After one DLI was started CAR‐T program with brexucabtageneautoleucel, using as bridging treatment ponatinib, vincristine and prednisone. Brexu‐cel infusion was performed in 2023, without CRS or ICANS onset. One month after Brexu‐cel infusion BM aspirate and CT‐PET showed recovery of full donor chimerism, MRD negativity and complete metabolic remission. Subsequently was started maintenance with ponatinib: at last follow‐up, the patient persisted in leukemia‐free status. CAR‐T cells represent the most powerful treatment for r/r Ph + ALL but there is no consensus about the optimal bridging strategy and also regarding the management algorithm during "post CAR‐T phase". Here, we report the efficacy of ponatinib as a bridge to anti‐CD19 CAR‐T cell therapy and as post CAR‐T maintenance. Our experience suggests that a preserving approach with TKI associated to low‐dose chemotherapy can be the optimal bridging therapy prior to CAR‐T and that an "MRD‐guided" and "TKI‐based" maintenance strategy can represent the best choice for Ph + ALL which satisfactorily responds to CAR‐T. [ABSTRACT FROM AUTHOR]

Background: Autologous stem cell transplantation (ASCT) is a potential consolidation therapy for acute myeloid leukemia (AML). This study was designed to develop a prediction model for leukemia-free survival (LFS) in a cohort of patients with de novo AML treated with ASCT during their first complete remission.Methods: This was a registry study of 956 patients reported to the European Society for Blood and Marrow Transplantation. The primary outcome was LFS. Multivariate Cox regression modeling with backward selection was used to select variables for the construction of the nomogram. The nomogram's performance was evaluated with discrimination (the area under the receiver operating characteristic curve [AUC]) and calibration.Results: Age and cytogenetic risk (with or without FMS-like tyrosine kinase 3 internal tandem duplication) were predictive of LFS and were used for the construction of the nomogram. Each factor in the nomogram was ascribed points according to its predictive weight. Through the calculation of the total score, the probability of LFS at 1, 3, and 5 years for each patient could be estimated. The discrimination of the nomogram, measured as the AUC, was 0.632 (95% confidence interval [CI], 0.595-0.669), 0.670 (95% CI, 0.635-0.705), and 0.687 (95% CI, 0.650-0.724), respectively. Further validation with bootstrapping showed similar AUCs (0.629 [95% CI, 0.597-0.657], 0.667 [95% CI, 0.633-0.699], and 0.679 [95% CI, 0.647-0.712], respectively), and this suggested that the model was not overfitted. Calibration was excellent. Patients were stratified into 4 incremental 5-year prognostic groups, with the probabilities of LFS and overall survival ranging from 25% to 64% and from 33% to 79%, respectively.Conclusions: The Auto-AML nomogram score is a tool integrating individual prognostic factors to provide a probabilistic estimation of LFS after ASCT for patients with AML. [ABSTRACT FROM AUTHOR]

BACKGROUND Although the mobilization of hematopoietic progenitor stem cells from healthy donors (HDs) using granulocyte-colony-stimulating factor is widely used, the ideal method for the administration of the cytokine has not yet been determined. STUDY DESIGN AND METHODS Seventy-five consecutive HDs received lenograstim (LENO) as mobilization agent. LENO was given subcutaneously at a dose of 10 µg/kg in a once-daily dose (ODD) every 24 hours. Results were compared with a historical control group of 181 HDs treated with 5 µg/kg LENO twice-daily dose (TDD) with a time interval of 12 hours. RESULTS CD34+ cell concentrations evaluated on Day 4 and on Day 5 were 45 × 106 (range, 6 × 106-217 × 106)/L and 75 × 106 (range, 7 × 106-279 × 106)/L with ODD versus 36 × 106 (range, 3 × 106-200 × 106)/L and 55 × 106 (range, 3 × 106-738 × 106)/L with TDD (p = 0.067 and p = 0.001). The collected CD34+ cell counts in first apheresis procedure were 5.6 × 106 ± 2.9 × 106 and 5.7 × 106 ± 3 × 106/kg donor and recipient body weight in the ODD versus 5.4 × 106 ± 3.8 × 106 and 5.3 × 106 ± 3.5 × 106/kg in the TDD cohort, respectively (p = 0.08 and p = 0.02). Five HDs (6.7%) mobilized CD34+ cells of fewer than 2 × 106/kg recipient body weight in the ODD group compared with seven HDs (3.9%) in the TDD group (p = 0.3). CONCLUSIONS Once-daily administration of LENO is at least as effective as twice-daily administration for the mobilization of CD34+ cells in HDs. [ABSTRACT FROM AUTHOR]

Background Peripheral blood ( PB) hematopoietic progenitor cells ( HPC) collected by apheresis are the first-choice source for allogeneic stem cell transplantation. The target HPC dose is usually considered to be 4 × 106 CD34+ cells/kg of the recipient, but higher doses are required in reduced-intensity conditioning and haploidentical transplants. Thus, prolonged stimulation and repeated collections or failure to reach HPC target may occur, increasing risks for donors and recipients. We carried out a retrospective multicenter study on healthy donors, to identify donor variables which may correlate with HPC mobilization. Study Design and Methods HPC allogeneic donations from sibling and unrelated donors performed in two centers from 1995 to 2012 were analyzed. We defined a mobilization cutoff of 50 × 106 CD34+ cells/ L and tested somatic variables, blood counts, and granulocyte-colony-stimulating factor ( G- CSF) dose and molecular form. Results A total of 360 donors were analyzed (male, 201; female, 159; sibling, 348; unrelated, 12; median [range] age, 44.8 [13-80] years). Median peak CD34+ in PB was 54.4 × 106/ L (range, 5 × 106-299 × 106). By multivariate analysis, we identified the following variables to correlate with good mobilization: 1) male sex (p < 0.0005); 2) younger age (p = 0.007); 3) higher baseline (premobilization) white blood cell ( WBC) count (p < 0.0005); 4) higher G- CSF dosage (p < 0.0005); and 5) use of lenograstim rather than filgrastim (p < 0.002). Conclusion In healthy donors it is possible to predict successful HPC mobilization by donor sex, age, WBC count, and G- CSF form and dose. Furthermore, based on these data, it may be possible, at least in parental setting, to modulate G- CSF dosage on the basis of donor characteristics. [ABSTRACT FROM AUTHOR]

Background Although the efficacy of plerixafor in peripheral blood stem cell ( PBSC) mobilization has been explored in several studies, factors associated with successful plerixafor mobilization after administration of granulocyte-colony-stimulating factor ( G- CSF), with or without chemotherapy, have not been investigated. We analyzed data on PBSC mobilization from a large Italian database of lymphoma and myeloma plerixafor-treated patients. Study Design and Methods Two endpoints were established to define successful mobilization: patients with at least 2 × 106 CD34+ cells/kg collected by three leukapheresis procedures and patients achieving a peak count of at least 20 × 106 CD34+ cells/ L during mobilization. Results Plerixafor achieved successful mobilization in both predicted (n = 64) and proven poor mobilizers ( PMs; n = 143), classified according to the Gruppo Italiano Trapianto di Midollo Osseo ( GITMO) criteria. Successful mobilization was independent of type of mobilization (steady state or chemotherapy); age; sex; disease; number or type of chemotherapy regimens preceding plerixafor; radiation therapy; prior treatment with melphalan, carmustine, lenalidomide, and radioimmune conjugates; and laboratory variables. Multivariate analysis identified previous fludarabine treatment and premobilization platelet count as predictors of successful mobilization. Conclusion This large, prospective, nationwide study confirmed plerixafor efficacy for mobilizing PBSCs when added to G- CSF with or without chemotherapy. Plerixafor can overcome negative effects of most predictors of poor mobilization to achieve satisfactory harvest both in predicted and proven PM. [ABSTRACT FROM AUTHOR]

To date, no prospective study on Plerixafor 'on-demand' in combination with chemotherapy and granulocyte colony-stimulating factor ( G- CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on-demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G- CSF to mobilize peripheral blood stem cells ( PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34+ cells in peripheral blood was reduced by 'on-demand' strategy compared to conventional mobilization; from 13·0 to 3·0% ( P = 0·004). Failure to harvest CD34+ cells 2 × 106/kg decreased from 20·9 to 4·0% ( P = 0·0001). The on-demand Plerixafor strategy also resulted in a lower rate of mobilization failure ( P = 0·03) and harvest failure ( P = 0·0008) when compared to a 'bias-adjusted set of controls'. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G- CSF, the 'on-demand' use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost. [ABSTRACT FROM AUTHOR]

Aim: To investigate the clinical role of the bone turnover markers type I collagen C telopeptide (CTX), osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) in the assessment of bone status in women with postmenopausal osteoporosis. Methods: Serum CTX (s-CTX), OC and BAP were measured in 200 healthy menopausal women at their initial visit and were correlated with spine and femur bone mineral density (BMD), determined on dual-energy X-ray absorptiometry. The relationship between biochemical markers of bone turnover and age, age at menopause, body mass index (BMI) and BMD was analyzed using linear correlation. A receiver operating characteristic (ROC) curve was constructed for each serum marker versus both femur and vertebral BMD. Results: No correlation was found between serum levels of OC and BAP and vertebral or femur BMD. A statistically significant inverse correlation was found between s-CTX and BMD at spine and femur. S-CTX levels were higher in women with osteoporosis than in women with normal or moderately low (osteopenic) values of BMD. The sensitivity and specificity versus spine BMD were 73.9% and 41.6% for s-CTX, 40.4% and 80.6% for BAP, and 68.3% and 39% for OC, respectively. The sensitivity and specificity versus femur BMD were 76.9% and 40.4% for s-CTX, 23.8% and 88.3% for BAP, and 80.4% and 53.3% for OC, respectively. Conclusions: Determination of s-CTX, BAP and OC is of limited clinical value in the initial evaluation of bone status in menopausal women. [ABSTRACT FROM AUTHOR]

Although a double autologous peripheral blood stem cell transplant (APBSCT) is an effective therapy for patients (pts) with multiple myeloma and extends progression-free survival and overall survival, pts show a continued pattern of recurrent disease. The feasibility and tolerability of thalidomide (Thal) administered in the post-transplantation period as maintenance therapy was tested in 17 pts at a dose of 100 mg/d starting between 3 and 5 months after the second transplantation and continuing either until toxicity precluded further therapy or until pts had disease progression. After a median administration of 13 months (range: 3–26), 76.5% (13 pts) failed to tolerate Thal because of: transiet ischemic attack (three pts), severe fatigue (two), neutropenia (one), piastrinopenia (one), severe opportunistic infectious (two), erectile impotence (one), gastointestinal toxicity (anorexia with weight loss one), peripheral neuropathy (two). After a median follow-up of 36 months (range: 10–59) from the second transplant, 13 patients attained a CR + near CR (with a conversion rate from 47.1% to 76.5%). In conclusion, Thal as maintenance therapy after double ASCT is associated with low feasibility and high toxicity and could prevent a lengthy use of this antineoplastic agent. [ABSTRACT FROM AUTHOR]

We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high-dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty-seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post-transplant ( n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 μg/kg ( n = 19 patients) starting on day 5 post-transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively ( P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes × 109 L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients. [ABSTRACT FROM AUTHOR]

No specific characteristics have been identified as predictors of peripheral blood stem cells (PBSC) mobilization in healthy donors. In this study, clinical characteristics and laboratory data for 122 healthy donors who underwent apheresis on day 5 of treatment with recombinant granulocyte colony-stimulating factor (G-CSF) were retrospectively analyzed for correlations with CD34+ cell mobilization. The variables that were analyzed included age, sex, body weight, basal complete blood count, and maximum white blood count (WBC) before apheresis, G-CSF type, and dosage. Median age and body weight were 42.5 years (range 16-65) and 72.5 kg (range 47-121), respectively. By univariate analysis, male sex ( P = 0.007), body weight (≤ 70 vs. >70 kg, P = 0.04), and donor's age (≤ 50 vs. > 50 years; P = 0.015) were correlated with the number of CD34+ cells mobilized. By multivariate analysis, donor's age and male sex were the only two variables that significantly predicted a high CD34+ cell level. In conclusion, our data suggest that male sex and younger age are the only factors that significantly affect CD34+ mobilization in healthy donors. J Clin Apheresis. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Mobilization of CD34+ into peripheral blood is attained by either glycosylated (lenograstim) or non-glycosylated recombinant G-CSF (filgrastim). 101 donors, 57 males, median age 42 years (range 16-63) entered this retrospective study. Group I (55 cases) received filgrastim and group II lenograstim subcutaneously for 5-6 days. The peak number of CD34+ cells/μl blood observed on day 4 and 5 was not significantly different in the two groups. No differences were shown in terms of both circulating CFU-GM at the time of harvesting and CD34+ target of collection. The most frequent side effects were bone pain (18.2% grade I; 36.4% grade II, 7.3% grade III), headache (18.2%), nausea (9.1%), fever (5.5%) and a mild splenomegaly (>2cm) (5.5%) in filgrastim group, and bone pain (37.0% grade I, 26.1% grade II, 2.2% grade III), headache (17.4%), nausea (15.2%), fever (4.4%) and a mild splenomegaly (4.3%) in lenograstim group, respectively. CD34+ collection was associated with thrombocytopenia, which was not significantly different between the two groups. No donor in either group developed long-term adverse effects. We conclude that both G-CSFs are comparable in terms of CD34+ cell collection, safety and tolerability. J. Clin. Apheresis © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

L-Carnitine (3-hydroxy-4-N,N,N-trimethylaminobutyrate) is a conditionally essential nutrient with a major role in cellular energy metabolism. It is available in the United States as both a prescription drug and an over-the-counter nutritional supplement. Accumulating evidence from both animal and human studies indicates that pharmacologic doses of L-carnitine (LCAR) have immunomodulatory effects resembling those of glucocorticoids (GC). On the other hand, in contrast to GC, which cause bone loss, LCAR seems to have positive effects on bone metabolism. To explore the molecular bases of this GC-like activity of LCAR, we investigated its effects on glucocorticoid receptor (GR)-modulated cytokine release ex vivo, and on the transcriptional activity, intracellular trafficking, and binding of GR in vitro. At high noncytotoxic doses, LCAR (a) suppressed the lipopolysaccharide-stimulated release of tumor necrosis factor α and interleukin-12 from primary human monocytes in a GC-like fashion, (b) stimulated the transcriptional activity of GR on the GC-responsive promoters, (c) triggered nuclear translocation of green fluorescent protein (GFP)-fused GR, and (d) reduced the whole cell binding of [³H]-dexamethasone to GR. These results suggest that LCAR is a "nutritional modulator" of the GR, by acting as an agonist-like compound. Since LCAR appears to have positive effects on bone metabolism, in contrast to GC, LCAR may share some of the therapeutic properties of GC, particularly on the immune system, but not their deleterious side effects on some of other organs/tissues. Thus, LCAR is potentially a useful alternative compound of GC in particular therapeutic situations. The clinical and therapeutic implications of these findings, as well as a better understanding of their mechanisms, warrant further research. [ABSTRACT FROM AUTHOR]

Glucocorticoids exert their extremely diverse effects on numerous biologic activities of humans via only one protein module, the glucocorticoid receptor (GR). The GR binds to the glucocorticoid response elements located in the promoter region of target genes and regulates their transcriptional activity. In addition, GR associates with other transcription factors through direct protein-protein interactions and mutually represses or stimulates each other's transcriptional activities. The latter activity of GR may be more important than the former one, granted that mice harboring a mutant GR, which is active in terms of protein-protein interactions but inactive in terms of transactivation via DNA, survive and procreate, in contrast to mice with a deletion of the entire GR gene that die immediately after birth. We recently found that GR physically interacts with the chicken ovalbumin upstream promoter- transcription factor II (COUP-TFII), which plays a critical role in the metabolism of glucose, cholesterol, and xenobiotics, as well as in the development of the central nervous system in fetus. GR stimulates COUP-TFII-induced transactivation by attracting cofactors via its activation function-1, while COUPTFII represses the GR-governed transcriptional activity by tethering corepressors, such as the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressors (NCoRs) via its C-terminal domain. Their mutual interaction may play an important role in gluconeogenesis, lipoprotein metabolism, and enzymatic clearance of clinically important compounds and bioactive chemicals, by regulating their rate-limiting enzymes and molecules, including the phosphoenolpyruvate carboxykinase (PEPCK), the cytochrome P450 CYP3A and CYP7A, and several apolipoproteins. It appears that glucocorticoids exert their intermediary effects partly via physical interaction with COUP-TFII. [ABSTRACT FROM AUTHOR]

Summary. To evaluate the clinical impact of minimal residual disease in multiple myeloma, apheretic products from 51 autotransplanted patients were tested by fluorescent (GeneScan) polymerase chain reaction (PCR). Sixty-nine per cent of harvests were contaminated when evaluated for IgH rearrangement. Forty-six patients responded to transplant, with 52·9% achieving complete response (CR). The clinical response of patients was significantly influenced by the number of re-infused CD34+ cells. Positive PCR results of re-infused harvests were not significantly related to patient outcome. Median overall survival (OS) was 33 months, and a significant advantage for patients transplanted by 12 months from diagnosis was observed. Moreover, OS was longer for patients receiving PCR-negative stem cells, with 72% of patients surviving to 70 months in the group receiving PCR-negative harvests vs 48% in the group transplanted with contaminated precursors (not statistically significant). Ex vivo purging caused a reduction of contamination of up to 3 logs; nevertheless, 80% of purged harvests remained PCR-positive and the purging procedure did not alter response or survival rates. Thus, the failure of a predictive role for this highly sensitive molecular method could be explained by the assumption that in vivo persisting malignant cells are the true source of relapse in MM. [ABSTRACT FROM AUTHOR]

Investigates the influence of L-Carnitine (LCAR) on the various properties of the glucocorticoid receptor (GR), including binding capacity and affinity, intracellular trafficking and transcriptional and biologic activities. Examination on the ability of LCAR to influence cell trafficking of GRα; Discussion on the stimulation of the transcriptional activity of GRα by LCAR; Conclusions.

The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups., (© 2022 John Wiley & Sons Ltd.)

The recent development of reduced intensity conditioning and allotransplantation (RICT) has opened a new way to assure engraftment of donor cells while reducing early transplant-related mortality. We evaluated the combination of high-dose therapy and autologous peripheral blood stem cells transplantation (APBSCT) followed by RICT to extend the benefit of allografting procedures in de novo multiple myeloma (MM) patients. Fifteen subjects with stage III MM (median age 51 years, range 40-57) received high dose melphalan (200 mg/m(2)) followed by APBSCT previously collected after cyclophosphamide (4 g/m(2)) and granulocyte colony-stimulating factor (G-CSF). After 3-4 months from APBSCT, the patients underwent RICT, consisting of fludarabine 30 mg/m(2) + cyclophosphamide 300 mg/m(2) on days -4, -3, and -2. Acute graft-versus-host disease (GVHD) occurred in 2 patients; 6 patients developed chronic GVHD; 4 patients developed CMV antigenemia and were treated pre-emptively with ganciclovir. No transplant related mortality was shown. Response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF); when IF was negative, patients were classified in complete remission (CR) and when it remained positive, near CR (nCR). After a median follow up of 44 months post APBSCT, 100 and 43% of patients are still alive and progression-free, respectively. Overall, the CR + nCR rate after dose-reduced allograft was enhanced from 26.7 to 73.3%. A correlation not statistically significant between GVHD and remission was found. In conclusion, an up-front tandem strategy with a very low reduced intensity-conditioning regimen for allografting following autografting is feasible and induces high CR/nCR rate in MM.