CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.

Norovirus and sapovirus infections after allogeneic hematopoietic stem cell transplantation: is it worth it to look for them?

Norovirus (NoV) and Sapovirus (SaV) are potential causative agents of diarrhea after allogeneic HSCT but little is known in this population. We performed a retrospective analysis by RT-PCR of calicivirus (NoV and SaV), Human adenovirus (HAdV), rotavirus (RV), Aichi virus (AiV), enterovirus (EV), human parechovirus (HPeV) and Human bocavirus (HBoV) in the diarrheal stools of patients after allogeneic HSCT. 49/162 patients had positive viral assays: HAdV (17%), EV (7%), NoV (4.3%), RV and HBoV (3.1% each), SaV (1.9%), AiV (1.2%), HPeV (0.6%). Seven patients were positive for NoV and 3 for SaV. Among viruses-positive samples, the frequency of caliciviruses cases was 7% in the 6 months post-HSCT compared to 40% after (p < 0.0001). The median duration of symptom was 0.7 months but 2 cases, occurring more than one year after HSCT, were chronic, undiagnosed and strongly contributed to morbidity. Systematic testing of caliciviruses appears especially useful in late chronic diarrhea.

Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia: a GRAALL-2005 study.

Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT.

Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO.

The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent (cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (cohort C). The main differences in patient characteristics in this study compared to the ADMIRAL trial were ECOG ≥ 2 (83.6% vs. 16.6%), FLT3-TKD mutation (21.0% vs. 8.5%), primary induction failure (15.0% vs. 40.0%) and line of treatment (beyond 2nd in 37.1% vs. 0.0%). The rates of composite complete remission, excluding those that occurred after hematopoietic stem cell transplantation (HSCT), were similar at respectively 25.4% and 27.5% in cohorts B and C. Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months. Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.

Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience.

PURPOSE: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). EXPERIMENTAL DESIGN: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. RESULTS: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. CONCLUSIONS: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

FLAMSA-Busulfan-Melphalan as a Sequential Conditioning Regimen in HLA-Matched or Haploidentical Hematopoietic Stem Cell Transplantation for High-Risk Myeloid Diseases.

Given the poor prognosis of relapsed/refractory myeloid malignancies, the concept of sequential conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven to be an effective approach. We sought to evaluate a sequential scheme combining fludarabine, amsacrine, and cytarabine (FLAMSA) for cytoreduction, followed by reduced-intensity conditioning with busulfan and melphalan (FLAMSA-BuMel), which was designed to be suitable for both HLA-matched and haploidentical HSCT. This single-center retrospective study included 36 adult patients with high-risk myeloid malignancies who underwent allo-HSCT from HLA-matched (n = 19) or haploidentical (n = 17) donors. Along with the standard prophylaxis for graft-versus-host disease (GVHD), patients with a haploidentical donor received post-transplantation high-dose cyclophosphamide. A post-transplantation consolidation treatment with low-dose 5-azacytidine and prophylactic donor lymphocyte infusions was provided whenever possible. Thirty patients (83%) achieved complete remission on day +30. With a median follow-up of 30.0 months, the 2-year overall survival was 89% in the HLA-matched group versus 34% in the haploidentical group (P = .0018). The 2-year disease-free survival in these 2 groups was 68% and 34%, respectively (P = .013). At 2 years, the probability of relapse was 32% and 20%, respectively, and nonrelapse mortality was 0% and 58%, respectively (P = .0003). The leading cause of death was relapse in the HLA-matched group (3 of 19) and hemorrhagic events (5 of 17) in the haploidentical group, favored by significantly delayed platelet reconstitution and a severe GVHD context. These data confirm the feasibility of FLAMSA-BuMel as a sequential conditioning in allo-HSCT for high-risk myeloid malignancies. The use of bone marrow as the preferred graft source might reduce the incidence of acute GVHD and nonrelapse mortality in the haploidentical transplantation setting.

Development and clinical validation of a simple and fast UPLC-ESI-MS/MS method for simultaneous quantification of nine kinase inhibitors and two antiandrogen drugs in human plasma: Interest for their therapeutic drug monitoring.

Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter- and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and vemurafenib; two active metabolites of them: N-desmethyl imatinib, N-oxide sorafenib; and two AAs: abiraterone and enzalutamide; with short pre-treatment and run time in order to be easily used in clinical practice for their therapeutic drug monitoring (TDM) and facilitating pharmacokinetics and pharmacokinetics/pharmacodynamics studies. Plasma samples were prepared by a single-step protein precipitation. Analytes were separated on a Waters Acquity UPLC® T3 HSS C18 column by non-linear gradient elution; with subsequent detection by Xevo® TQD triple quadrupole tandem mass spectrometer in a positive ionization mode. Analysis time was 2.8 min per run, and all analytes eluted within 1.46-1.97 minutes. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-500 ng/mL for abiraterone, dasatinib and ibrutinib; 5-500 ng/mL for cobimetinib and palbociclib; 10-5,000 ng/mL for imatinib, N-desmethyl imatinib, nilotinib, sorafenib, N-oxide sorafenib and ruxolitinib; 100-50,000 ng/mL for enzalutamide and 100-100,000 ng/mL for vemurafenib with coefficient of correlation above 0.995 for all analytes. This novel method was successfully applied to TDM in clinical practice.

Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: a new gold standard?

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML. METHODS AND RESULTS: We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21 months (14-33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML. CONCLUSIONS: Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.

Ponatinib-based therapy in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the real-life OPAL study.

The OPAL study is a French multicenter observational retrospective analysis of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia treated in a real-life setting by ponatinib. Twenty-nine patients were included since 2012. Median age was 55 years. The initial dose of ponatinib, combined to chemotherapy in half of the patients, was 45 mg/day in most instances. The remission rate was 90% and seven patients received allogeneic stem cell transplantation. Median disease-free and overall survival were only 3.5 and 9.9 months respectively. The outcome of patients with BCR-ABL mutation was similar to that of unmutated patients. With a median duration of exposure to ponatinib of 4 months, only 3 cardio-vascular events were recorded despite a high incidence of risk factors, and overall safety was acceptable. These results underline the place of ponatinib to induce early response in advanced disease and the need of new combinations to improve long-term outcome.

Gain of the short arm of chromosome 2 (2p gain) has a significant role in drug-resistant chronic lymphocytic leukemia.

The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy-chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late-stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first-line treatment in CLL) is not effective in removing the 2p+ clone - even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow-up is now required to evaluate bendamustine-rituximab, ibrutinib, and idelalisib-rituximab treatments.

Aspergillus PCR in Bronchoalveolar Lavage Fluid for the Diagnosis and Prognosis of Aspergillosis in Patients With Hematological and Non-hematological Conditions.

Objectives: We evaluated the usefulness of an Aspergillus fumigatus quantitative PCR assay performed in bronchoalveolar lavage fluid (BAL) for the diagnosis and prognosis of both invasive and non-invasive aspergillosis. Methods: This 4-year retrospective study involved 613 at-risk patients who had either hematological disorders or other immunosuppressive conditions, notably solid organ transplants. Thirty-five patients had proven/probable aspergillosis and thirteen had chronic non-invasive aspergillosis. We compared PCR, galactomannan index and mycological analysis of BAL. Results: For invasive aspergillosis (IA), PCR performed in BAL yielded 88.6% sensitivity and 95.5% specificity. Comparatively, galactomannan index and mycological examination yielded only 56.3 and 63.6% sensitivity and 97.6 and 94.5% specificity, respectively. Considering the 13 chronic aspergillosis cases, PCR, galactomannan index and mycological examination yielded 76.9, 15.4, and 84.6% sensitivity and 92.2, 94.9, and 93% specificity, respectively. Fungal load in BAL evaluated by PCR was able to discriminate between aspergillosis and contamination, but not between invasive and non-invasive forms. Finally, fungal load was predictive of 90-day mortality, with 23.1% mortality for patients with less than 500 copies/mL versus 68.4% for patients above that cut-off (p < 0.05). Conclusion: Our results indicate that Aspergillus PCR in BAL is of particular interest for both the diagnosis and the prognosis of IA. It is likewise an interesting tool for the diagnosis of non-invasive forms.

Prevention of Invasive Aspergillus Fungal Infections with the Suspension and Delayed-Release Tablet Formulations of Posaconazole in Patients with Haematologic Malignancies.

Posaconazole is a triazole antifungal used to prevent invasive fungal infections (IFIs) in patients receiving chemotherapy or haemotopoietic stem cell transplantation. Due to highly variable bioavailability of the oral suspension formulation, a delayed-release tablet was developed which showed improved bioavailability. A minimal target posaconazole plasma concentration of 0.7 mg/L is recommended for prophylaxis of IFIs. However, the relationship between plasma concentration of posaconazole and its efficacy against IFIs remains unclear. We analysed trough posaconazole concentrations and response against IFIs in 50 and 104 patients with haematologic malignancies receiving prophylactic posaconazole as the tablet or suspension formulation, respectively. Mean plasma concentration of posaconazole was 1.91 ± 1.06 mg/L and 0.82 ± 0.57 mg/L in the tablet and the oral suspension group, respectively (p < 0.0001). The percentage of patients reaching the minimal target concentration of 0.7 mg/L was 92.0% and 47.1% in the tablet and oral suspension groups, respectively (p < 0.0001). Emergent aspergillosis occurred in 9 (8.7%) patients in the suspension group and in none of the patients taking the tablet formulation (p = 0.032). Our results show a relationship between plasma concentrations of posaconazole and its prophylactic efficacy in patients with haematologic malignancies. Target posaconazole concentrations are reached more efficiently with the tablet than with the suspension formulation.