Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Molnupiravir is effective in patients with haematological malignancies.

Patients with hematologic malignancies are particularly vulnerable to severe infectious complications. SARS-CoV-2 infection is associated with a high risk of severe course and death in this patient population. In addition, immune deficits associated with both the blood cancer and the treatment used make vaccination against SARS-CoV-2 less effective than in immunocompetent individuals. Molnupiravir is one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death in COVID-19 in the general population. In this context, 175 haematology patients with diagnosed COVID-19, and treated with MOL between January and April 2022, came under our scrutiny with a view to defining their clinical characteristics and outcomes. The most common underlying conditions were lymphomas (45%), multiple myelomas (21%) and acute leukaemias or myelodysplastic syndrome (35%). Of all, 77% of the patients were vaccinated, and half of them received a booster. At 28 days after the breakthrough COVID-19 diagnosis, 35 (20%) subjects required hospital admission. Out of those patients, seven (4%) died during the follow-up due to the progression of COVID. Our results corroborate what has been established to date with regard to the positive clinical and safety outcomes of MOL in haematology patients with mild or moderate COVID-19.

Clinical efficacy and tolerability of venetoclax plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia-a real-world analysis of the Polish Adult Leukemia Study Group.

The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019-2023 outside clinical trials. Patients were treated with a median of 2 (range 1-9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27-39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients' exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

BACKGROUND: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. METHODS: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. FINDINGS: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. INTERPRETATION: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. FUNDING: Loxo Oncology.

Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study.

The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2-) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2- patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+ patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.gov as #NCT01712490 (EudraCT no. 2011-005450-60).

Rituximab and Chemotherapy for Newly Diagnosed Follicular Lymphoma: Real-World Report of Polish Lymphoma Research Group.

INTRODUCTION: Follicular lymphoma (FL) is the most common type of indolent B-cell lymphoma with a favorable prognosis in the majority of patients. The induction treatment is still based on rituximab and chemotherapy, though new anti-CD20 antibody and chemo-free regimen have been recently introduced. The aim of the study was to analyze the management, outcomes, and determinants of prognosis of newly diagnosed patients with FL in real-world experience. METHODS: Data of consecutive patients diagnosed with FL in 5 years period (2011-2015) in three oncohematological centers were reviewed. Variables were compared using Mann-Whitney or χ2 test as appropriate, survival outpoints were calculated using Kaplan-Meier method. RESULTS: One hundred eighty-one patients were included in the study. The median patients' age at diagnosis was 56.6 years. Low histological grade (G1-G2) was found in 62.1% of patients and advanced clinical stage in 77.0% of patients. ECOG 0 performance status was observed in 57.1% of patients. The median follow-up was 5.91 years. Initially, 31.5% of the patients were qualified to watch-and-wait (W&W) strategy, and 84.0% of the whole patients' group received systemic treatment during the observation period. As induction treatment, 53.9% and 41.4% of patients received RCVP and RCHOP regimens, respectively; 39.8% received rituximab maintenance (RM) after first-line therapy. During follow-up, transformation to aggressive lymphoma occurred in 7.2% of patients. Median overall survival (OS) was not achieved, and median progression-free survival (PFS) was 8.28 years (95% CI; 7.35, NA), 19.6% of patients relapsed during 24 months from the start of the treatment (POD24). Median PFS for POD24 group was 1.1 years (95% CI; 0.56, 1.45) with a median OS longer than 8 years. ECOG 0, low PRIMA PI, and no POD24 were found as determinants of longer PFS and OS. CONCLUSIONS: Our data from clinical practice showed that rituximab and chemotherapy is still an effective method of FL treatment resulting in survival more than 8 years from diagnosis in most patients. RCVP protocol followed with RM is a reasonable choice for the first-line therapy especially in low/intermediate group of patients. The prognosis was significantly worse in patients with POD24. Therefore, searching for precise initial clinical and biological markers is warranted and development therapies to improve prognosis of POD24 patients.

Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study.

BACKGROUND: Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. METHODS: PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990. FINDINGS: Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8-24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8-72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8-75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4-61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3-4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3-4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. INTERPRETATION: The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. FUNDING: Novartis Pharmaceuticals and Secura Bio.

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma.

BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

Hematological malignancies in Polish population: what are the predictors of outcome in patients admitted to Intensive Care Unit?

INTRODUCTION: Patients with hematological malignancies (HM) require intensive chemotherapy with curative intent, especially in case of AML that results in more frequent admissions to Intensive Care Units (ICU). Due to our knowledge, this study is the first multicenter retrospective analysis in Polish population. METHODS: A total of 200 patients with HM hospitalized in 4 Polish hematological centers. Data concerning clinical indices and outcomes during admission and ICU stay were collected retrospectively. RESULTS: The most common hematological malignancy was acute leukemia (55%). The main cause of ICU admission was respiratory failure (88.5%), often accompanied by sepsis (58.5%) and acute renal failure (51.5%). In patients with hematological malignancies, the following factors were associated with ICU mortality: prolonged ICU stay (odd ratio [OR] = 6.98, 95% confidence interval [CI]: 1.38-35.33, χ2 = 5.61, p = 0.02), the presence of acute respiratory failure (odd ratio [OR] = 5.35, 95% confidence interval [CI]: 1.01-28.46, χ2 = 3.93, p = 0.04), and the need for renal replacement therapy (odd ratio [OR] = 8.75, 95% confidence interval [CI]: 1.23-62.11, χ2 = 4.78, p = 0.03). There were following associations with in-hospital mortality in patients with hematological malignancies: prolonged ICU stay (odd ratio [OR] = 10.12, 95% confidence interval [CI]: 1.85-55.37, χ2 = 7.21, p = 0.008), the presence of acute respiratory failure (odd ratio [OR] =5.24, 95% confidence interval [CI]: 1.36-20.16, χ2 = 5.87, p = 0.02), the need for catecholamine support (odd ratio [OR] =3.43, 95% confidence interval [CI]: 1.06-11.05, χ2 = 4.32, p = 0.04), and renal replacement therapy (odd ratio [OR] =5.55, 95% confidence interval [CI]: 1.14-26.92, χ2 = 4.59, p = 0.03). CONCLUSIONS: We have demonstrated that ICU and in-hospital mortalities among patients with hematological malignancies are still poor, but easier access to the intensive care unit and close cooperation between hematologists and intensivists may improve outcomes. We have found that acute failure of key organs (acute respiratory failure, end-stage renal failure requires renal replacement therapy) and length of ICU stay (but probably no comorbidities and illness severity) may have impact on mortality (both ICU and in-hospital).

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia.

BACKGROUND: Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. METHODS: In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. RESULTS: Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. CONCLUSIONS: Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).

Outcomes of treatment with dose-adjusted EPOCH-R or R-CHOP in primary mediastinal large B-cell lymphoma.

BACKGROUND: The standard first-line treatment for primary mediastinal B-cell lymphoma (PMBCL) patients is rituximab-based immunochemotherapy; however, this is not due to the result of randomized clinical trials. AIMS: We retrospectively investigated 53 PMBCL patient outcomes treated either with R-CHOP-21 or DA-EPOCH-R-28. The primary endpoint was overall survival (OS). Secondary endpoints were complete remission (CR), overall response rate (ORR), progression-free survival (PFS), and treatment-related complications. RESULTS: Treatment with R-CHOP-21 resulted in a 92.0% ORR (60% CR), while DA-EPOCH-R yielded a 92.6% ORR (70.4% CR). There were no differences in the occurrence of grade 3-4 hematological adverse events, but grade 1-2 cardiologic complications (P = .003) were observed more frequently in the DA-EPOCH-R arm. Median PFS and OS were not achieved. The differences in estimated 12-month PFS in R-CHOP and DA-EPOCH-R group (87% vs 73.9%) and OS (100% vs 92%) were insignificant. Patients treated with R-CHOP-21 and autologous hematopoietic stem cell transplantation (auto-HSCT) had an improved OS (P = .03) but not PFS (P = .43) compared to those treated solely with R-CHOP-21. No differences in PFS or OS were observed between patients treated with R-CHOP-21/auto-HSCT and DA-EPOCH-R. CONCLUSION: The results of this study suggest that R-CHOP-21 may be an alternative to DA-EPOCH-R treatment for PMBCL patients.

HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies.

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.

Defective Sphingolipids Metabolism and Tumor Associated Macrophages as the Possible Links Between Gaucher Disease and Blood Cancer Development.

There is a rising number of evidence indicating the increased risk of cancer development in association with congenital metabolic errors. Although these diseases represent disorders of individual genes, they lead to the disruption of metabolic pathways resulting in metabolite accumulation or their deficiency. Gaucher disease (GD) is an autosomal recessive sphingolipidosis. It is a rare lysosomal storage disease. A strong correlation between GD and different types of cancers, such as multiple myeloma, leukemia, and hepatocellular carcinoma, has been reported. Common features for all types of GD include spleen and liver enlargement, cytopenia, and a variety of bone defects. Overall, the molecular bases leading to the association of GD and cancers are not clearly understood. Here, we describe the role of ceramides in GD, discuss the potential implications of immune cells activation and show how the disturbances in their metabolism might promote blood cancer development.

Decreased Activity of Blood Acid Sphingomyelinase in the Course of Multiple Myeloma.

Acid sphingomyelinase (aSMase) is involved in the generation of metabolites that function as part of the sphingolipid signaling pathway. It catalyzes the breakdown of sphingomyelin into ceramide, a bioactive lipid that, among other roles, is involved in regulation of apoptosis. Dry drop blood test (DBS) and colorimetric 2-step enzymatic assay were used to assess the activity of human blood aSMase, beta-galactosidase, and beta-glucosidase, these enzymes are lysosomal hydrolases that catalyze the degradation of related sphingolipids, of sphingolipid signaling molecules. Blood was collected from a group of healthy volunteers and patients that were diagnosed with multiple myeloma (MM) in various stages of the disease. Additionally, activity of those enzymes in patients diagnosed with other hematological cancers was also assessed. We found that aSMase activity in the blood of patients with MM (at the time of diagnosis) was 305.43 pmol/spot*20 h, and this value was significantly lower (p < 0.030) compared to the healthy group 441.88 pmol/spot*20 h. Our collected data suggest a possible role of aSMase in pathogenesis of MM development.

Microenvironment-induced PIM kinases promote CXCR4-triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration.

Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment-dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first-line treatment. In primary CLL cells, inhibition of PIM kinases with a pan-PIM inhibitor, SEL24-B489, decreased PIM-specific substrate phosphorylation and induced dose-dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24-B489 was similar in TP53-mutant and TP53 wild-type cells. Finally, inhibition of PIM kinases decreased CXCR4-mediated cell chemotaxis in two related mechanisms-by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4-triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12-triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment-modulated PIM expression, their pro-survival function and a role of PIMs in CXCR4-induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.

FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas.

Inhibition of spleen tyrosine kinase (SYK) in tonic B-cell receptor (BCR) signal-dependent diffuse large B-cell lymphomas (DLBCLs) inhibits cellular proliferation, decreases cholesterol biosynthesis, and triggers apoptosis, at least in part via a mechanism involving decreased activity of phosphatidylinositol 3-kinase/AKT axis. Because forkhead box O1 (FOXO1) is a major effector of this pathway, we investigated the role of FOXO1 in toxicity of BCR pathway inhibition. Inhibition of SYK in DLBCL cells with tonic BCR signaling decreased phospho-AKT and phospho-FOXO1 levels and triggered FOXO1-driven gene expression. Introduction of constitutively active FOXO1 mutant triggered cell cycle arrest and apoptosis, indicating that increased FOXO1 activity is toxic to these DLBCL cells. Depletion of FOXO1 with short hairpin RNA led to almost complete resistance to chemical SYK inhibitor R406, demonstrating that FOXO1 is also required for R406-induced cell death. FOXO1 in these cells is also involved in regulation of expression of the critical master regulator of cholesterol biosynthesis, SREBP1. Because HRK is the key effector of SYK inhibition, we characterized a mechanism linking FOXO1 activation and HRK induction that involves caspase-dependent cleavage of HRK's transcriptional repressor DREAM. Because AKT in lymphoma cells can be regulated by other signals than BCR, we assessed the combined effects of the AKT inhibitor MK-2206 with R406 and found markedly synergistic FOXO1-dependent toxicity. In primary DLBCLs, FOXO1 expression was present in 80% of tumors, correlated with SYK activity, and was associated with longer overall survival. These results demonstrate that FOXO1 is required for SYK and AKT inhibitor-induced toxicity.

The efficacy and safety of pomalidomide in relapsed/refractory multiple myeloma in a "real-world" study: Polish Myeloma Group experience.

BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) have poor prognosis. Pomalidomide is an immunomodulatory compound that has demonstrated activity in MM patients with disease refractory to lenalidomide and bortezomib. OBJECTIVES: Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. PATIENTS AND METHODS: We analyzed retrospectively 50 patients treated with pomalidomide in 12 Polish sites between 2014 and 2017. Median age was 63 years, median time since diagnosis 4.5 years and median number of prior regimens 4. RESULTS: The overall response rate was 39.1%. Median progression-free survival (PFS) and overall survival (OS) were 10.0 and 14.0 months, respectively. Previous treatment with immunomodulatory drugs, bortezomib or stem cell transplant had no impact on PFS and OS. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia 24.0%, thrombocytopenia 10.0%, anemia 8.0%). Most common grade 3/4 non-hematologic toxicities were respiratory tract infection (14.0%) and neuropathy (4.0%). CONCLUSIONS: This real-world data have confirmed that pomalidomide is an active drug in RRMM and support results of published clinical trials and other real-world studies.