Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.

Haploidentical hematopoietic stem cell transplantation with busulfan, cyclophosphamide, and fludarabine conditioning for X-linked adrenal cerebral leukodystrophy.

OBJECTIVE: We investigated the safety and efficacy of haploidentical stem cell transplantation (SCT) in pediatric patients with X-linked adrenoleukodystrophy (ALD). METHODS: A retrospective analysis of transplantation data from 29 cases of ALD, treated between December 2014 and April 2022, was conducted. Neurologic function scores (NFS) were assessed. The conditioning regimen was busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg, and fludarabine 90 mg/m2 (BFC). Graft-versus-host disease prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil, and short course of methotrexate. RESULTS: Among the 29 cases, 14 cases (NFS = 0) were asymptomatic, and 15 (NFS ≥ 1) were symptomatic. The median age at SCT was 8 years (range: 4-16 years); the median follow-up time was 1058 days (range: 398-3092 days); 28 cases were father donors and 1 case was a grandfather donor. Hematopoietic reconstitution was successful in all patients, and all of them achieved complete donor chimerism at the time of engraftment. The leading cause of death was still primary disease progression (n = 4). Survival free of major functional disabilities was 100% in asymptomatic patients versus 66.67% in the symptomatic group (p = .018). CONCLUSION: BFC regimen used in haploidentical SCT was administered safely without major transplant-related complications even in symptomatic patients, and neurological symptoms were stabilized after SCT.

ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.

Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients - A clinical trial to registry data comparison.

A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.

Comparison of Melphalan Dose in Patients with Myelodysplastic Syndrome Undergoing Allogeneic Transplantation with Reduced-Intensity Conditioning.

The present study compared lower-dose melphalan (80 mg/m2, FM80) and higher-dose melphalan (140 mg/m2, FM140) when administering reduced-intensity conditioning with fludarabine in adult patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data (2006 to 2019) and compared transplant outcomes between the 2 groups. Ninety-two patients (median age, 61 [interquartile range, 56 to 65] years) were assigned to the FM80 and FM140 groups by propensity score matching. The 3-year overall survival (OS) rate in the FM140 group (63.9%; 95% confidence interval [CI], 52.9% to 73.0%) was significantly higher than that in the FM80 group (54.2%; 95% CI, 37.1% to 52.1%) (P = .038). The FM140 group had a nonsignificantly (P = .095) lower 3-year cumulative incidence of relapse (15.5%; 95% CI, 8.9% to 23.8% versus 26.0%; 95% CI, 17.3% to 35.5%). The 3-year cumulative incidences of nonrelapse mortality were 22.3% (95% CI, 14.1% to 31.8%) and 23.7% (95% CI, 15.4% to 33.2%) in the FM80 and FM140 groups, respectively (P = .49). The beneficial effect of FM140 was more evident in patients with a poor cytogenetic risk. Our findings suggest the superiority of FM140 in patients with MDS undergoing allo-HSCT, especially in high-risk patients.

Impact of Different Fludarabine Doses in the Fludarabine-Based Conditioning Regimen for Unrelated Bone Marrow Transplantation.

The purine analog fludarabine (Flu) plays a central role in reduced-intensity conditioning and myeloablative reduced-toxicity conditioning regimens because of limited nonhematologic toxicities. Few reports assess the impact of different dose of Flu on the clinical outcomes and the Flu doses vary across reports. To compare the effect of Flu dose, the clinical outcomes of patients who received Flu and busulfan (FB; n = 1647) or melphalan (Flu with melphalan (FM); n = 1162) conditioning for unrelated bone marrow transplantation were retrospectively analyzed using Japanese nationwide registry data. In the FB group, high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were given to 1334 and 313 patients, respectively. The 3-year overall survival (OS) rates were significantly higher in the HFB group than in the LFB group (49.5% versus 39.2%, P < .001). In the HFB and LFB groups, the cumulative incidences were 30.4% and 36.6% (P = .058) for 3-year relapse and 25.1% and 28.1% (P = .24) for 3-year nonrelapse mortality (NRM), respectively. In the multivariate analysis for OS and relapse, Flu dose was identified as an independent prognostic factor (hazard ratio: 0.83, P = .03; hazard ratio: 0.80, P = .043). In the FM group, high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were given to 118 and 1044 patients, respectively. The OS, relapse, and NRM after 3 years did not differ significantly between the HFM and LFM groups (48.3% versus 48.8%, P = .92; 23.7% versus 27.2%, P = .55; 31.9% versus 30.8%, P = .67). These findings suggest that high-dose Flu was associated with favorable outcomes in the FB group but not in the FM group.

Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma.

BACKGROUND AIMS: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. METHODS: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. RESULTS: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). CONCLUSIONS: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.

Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance.

Leukemic stem cells (LSCs) possess similar characteristics to normal hematopoietic stem cells, including self-renewal capacity, quiescence, ability to initiate leukemia, and drug resistance. These cells play a significant role in leukemia relapse, persisting even after apparent remission. LSCs were first described in 1994 by Lapidot et al. Although they have been extensively studied in acute leukemia, more LSC research is still needed in chronic lymphocytic leukemia (CLL) to understand if reduced apoptosis in mature cells should still be considered as the major cause of this disease. Here, we provide new evidence suggesting the existence of stem-like cell populations in CLL, which may help to understand the disease as well as to develop effective treatments. In this study, we identified a potential leukemic stem cell subpopulation using the tetraploid CLL cell line I83. This subpopulation is characterized by diploid cells that were capable of generating the I83 tetraploid population. Furthermore, we adapted a novel flow cytometry analysis protocol to detect CLL subpopulations with stem cell properties in peripheral blood samples and primary cultures from CLL patients. These cells were identified by their co-expression of CD19 and CD5, characteristic markers of CLL cells. As previously described, increased alkaline phosphatase (ALP) activity is indicative of stemness and pluripotency. Moreover, we used this method to investigate the potential synergistic effect of curcumin in combination with fludarabine and ibrutinib to deplete this subpopulation. Our results confirmed the effectiveness of this ALP-based analysis protocol in detecting and monitoring leukemic stem-like cells in CLL. This analysis also identified limitations in eradicating these populations using in vitro testing. Furthermore, our findings demonstrated that curcumin significantly enhanced the effects of fludarabine and ibrutinib on the leukemic fraction, exhibiting synergistic effects (combination drug index, CDI 0.97 and 0.37, respectively). Our results lend support to the existence of potential stem-like populations in CLL cell lines, and to the idea that curcumin could serve as an effective adjuvant in therapies aimed at eliminating these populations and improving treatment efficacy.

Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With NPM1 and FLT3 Mutations.

PURPOSE: To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. PATIENTS AND METHODS: One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). RESULTS: There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. CONCLUSION: Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.

Fludarabine Enhances Radiosensitivity by Promoting Ferroptosis in B-Cell Lymphoma.

The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity of B-cell lymphoma (BCL) and to explore the underlying mechanisms. Radiotherapy is one of the primary treatments for BCL, and STAT1 plays a critical role in the transcription of cell proliferation-related genes, which are associated with radiotherapy and ferroptosis. This study aims to determine whether fludarabine can enhance the radiosensitivity of BCL and to elucidate the molecular pathways involved. Various in vitro methodologies, including CCK-8 assays, clonogenic formation assays, immunohistochemistry, immunofluorescence, flow cytometry, qRT-PCR, and Western blot analyses, were employed in B-cell lymphoma cell models to thoroughly investigate the effects of fludarabine on radiosensitivity. Subsequently, the obtained results were further validated through in vivo animal models and by examining human diffuse large B-cell lymphoma (DLBCL) cancer samples. Our findings demonstrate that the combination of fludarabine and irradiation synergistically inhibits cell viability and colony formation, while inducing apoptosis and ferroptosis in B-cell lymphoma cell lines Raji and Su-DHL-10. Moreover, fludarabine was found to enhance the ferroptosis induced by radiation, thereby synergistically impeding the growth of BCL. In vivo experiments confirmed these findings, revealing that the intraperitoneal injection of fludarabine significantly enhanced the inhibitory effects of radiation on Raji cell xenograft models, leading to an increased percentage of ferroptosis compared to models without fludarabine. Additionally, the administration of liproxstatin-1, a ferroptosis inhibitor, attenuated the inhibition of xenograft growth caused by the combination of fludarabine and irradiation. Furthermore, our analysis of clinical data revealed that increased co-expression of STAT1 and GPX4 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. These results highlight the potential of fludarabine to enhance radiosensitivity and ferroptosis induction as a promising therapeutic strategy for BCL. Our results demonstrated that fludarabine promoted radiation-induced BCL death through the ferroptosis pathway. We have identified a previously unrecognized mechanism in the fludarabine and radiation combination, indicating that it is necessary to conduct prospective clinical trials to verify this new treatment regimen in BCL.

Busulfan with 400 centigray of total body irradiation and higher dose fludarabine: An alternative regimen for hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia.

BACKGROUND: Hematopoietic stem cell transplantation can be curative for children with difficult-to-treat leukemia. The conditioning regimen utilized is known to influence outcomes. We report outcomes of the conditioning regimen used at the Alberta Children's Hospital, consisting of busulfan (with pharmacokinetic target of 3750 µmol*min/L/day ±10%) for 4 days, higher dose (250 mg/m2 ) fludarabine and 400 centigray (cGy) of total body irradiation. PROCEDURE: This retrospective study involved children receiving transplant for acute lymphoblastic leukemia (ALL). It compared children who fell within the target range for busulfan with those who were either not measured or were measured and fell outside this range. All other treatment factors were identical. RESULTS: Twenty-nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14 days [8-30 days]. The cumulative incidence of acute graft-versus-host disease was 44.8% [95% confidence interval, CI: 35.6%-54.0%], while chronic graft-versus-host disease was noted in 16.0% [95% CI: 8.7%-23.3%]. At 2 years, the overall survival was 78.1% [95% CI: 70.8%-86.4%] and event-free survival was 74.7% [95% CI: 66.4%-83.0%]. Cumulative incidence of relapse was 11.3% [95% CI: 5.1%-17.5%]. There were no statistically significant differences in between the group that received targeted busulfan compared with the untargeted group. CONCLUSION: Our conditioning regiment for children with ALL resulted in outcomes comparable to standard treatment with acceptable toxicities and significant reduction in radiation dose. Targeting busulfan dose in this cohort did not result in improved outcomes.

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.

ABSTRACT: We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.

BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Evaluation of palonosetron, fosaprepitant, and olanzapine as antiemetic prophylaxis for fludarabine and melphalan-based conditioning regimens prior to allogeneic hematopoietic stem cell transplants.

BACKGROUND: Limited data are available regarding efficacious antiemetic regimens to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). In patients aged 60 years or older, allogeneic HSCT is associated with improved survival, but tolerability of the transplant is a significant barrier. Fludarabine and melphalan (Flu-Mel) is a frequently utilized multi-day reduced intensity conditioning regimen for allogeneic HSCT. However, the optimal CINV prevention regimen is unknown. OBJECTIVE: The purpose of this study was to evaluate the efficacy of a novel CINV prophylaxis regimen prior to allogeneic HSCT with Flu-Mel compared to a historical control group. STUDY DESIGN: This was a retrospective, single-center, cohort review of 123 patients who received a Flu-Mel preparative regimen prior to allogeneic HSCT from January 1, 2019, to September 30, 2022. Fifty-nine patients received high dose ondansetron (HDO) for CINV prevention, while sixty-four patients received a combination of palonosetron, fosaprepitant, and olanzapine (PFO). The primary outcome was average number of rescue antiemetic doses administered per day. A key secondary outcome was time to first rescue antiemetic. RESULTS: The median number of antiemetic doses used per day was significantly lower in patients who received PFO compared to HDO (1.94 doses [0.31-3.60] vs 3.31 doses [1.61-4.92]; p = 0.002). In addition, use of PFO significantly prolonged the median time to first rescue antiemetic compared to HDO (41.3 h [24.3-122.7] vs 26.2 h [14.7-48.1]; p = 0.016). CONCLUSION: The combination of palonosetron, fosaprepitant, and olanzapine is an effective antiemetic regimen for patients receiving a Flu-Mel-based preparative regimen.

Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.

Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.

Feasibility of pevonedistat combined with azacitidine, fludarabine, cytarabine in pediatric relapsed/refractory AML: Results from COG ADVL1712.

BACKGROUND: Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival. PROCEDURE: We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m2 days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza-FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1-21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy-related AML (n = 1). RESULTS: Overall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) Cmax , VSS , T1/2 , and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m2 , 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m2 , respectively. T1/2 , VSS , and Cmax , but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi). CONCLUSIONS: Pevonedistat 20 mg/m2 combined with Aza-FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza-FLA combination demonstrated significant anti-leukemic activity.

Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.

Methods: Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data, and the relation of results was predicted via the GeneMANIA website. The information of 7 samples covered three stages: observation stage, pretreatment by CIT with rituximab, fludarabine, and cyclophosphamide (pre-CIT), and post-CIT. The differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. B cell subpopulations and pseudotime trajectories analysis was conducted. Results: A total of 70,659 DEGs were identified. Each patient's DEGs presented their own characteristics, with low similarity. Therefore, it is difficult to identify potential hub genes. Similarly, pathway enrichment analysis showed significant tumor heterogeneity among CLL patients. Analysis of relapsed post-CIT compared to the observation stage suggested that the TP53 pathway should be taken seriously as it is closely related to treatment strategy and patient prognosis. Conclusions: Tumor heterogeneity may be a more common manifestation of CLL. Individualized treatment should be considered for CLL. TP53 abnormality and its regulatory factors should still be the focus of CLL diagnosis and treatment.

Retrospective comparison of survival and responses to Fludarabine, Cytarabine, GCSF (FLAG) in combination with gemtuzumab ozogamicin (GO) or Idarubicin (IDA) in patients with newly diagnosed core binding factor (CBF) acute myelogenous leukemia: MD Anderson experience in 174 patients.

Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG-based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO; N = 65) or in combination with idarubicin (FLAG-IDA; N = 109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59%, respectively (p-value = .02). In multivariate analysis for RFS, age (p = .0001), FLAG-GO regimen (p = .04), 4 log reduction in CBF-related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p = .03), and additional cytogenetic abnormalities (p = .03) were significant variables. Lower age (p = .0001) and 3 log or more transcript reduction at end of induction (p = .04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p = .06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p = .002), mid-consolidation (p < .01), and end of consolidation (p < .001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts.