Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study.

Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.

Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe.

BACKGROUND: Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce. METHODS: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). RESULTS: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. CONCLUSIONS: In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population.

Health-Related Quality of Life in Multiple Myeloma Patients Treated with High- or Low-Dose Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation-Results from the LenaMain Trial (NCT00891384).

INTRODUCTION: The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. MATERIALS AND METHODS: Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. RESULTS: Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: -1.905 (range: -5.78-1.97); end of year 2: 16.071 (range: 5.72-26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. CONCLUSION: High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients' HR-QoL.

Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial.

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83-98). 2-year Kaplan-Meier estimates of time to progression and overall survival were 78% (95% CI 65-90) and 68% (95% CI 55-80) - similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2-17). In the low-risk group, 2-year EFS was 66% (95% CI 45-86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.

Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial.

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany.

BACKGROUND: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany. PATIENTS: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020. RESULTS: A total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue. CONCLUSION: This real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies.

Parallel evaluation of cell­based phage display panning strategies: Optimized selection and depletion steps result in AML blast­binding consensus antibodies.

Phage display technology (PD) is a powerful technique for the generation of tumor­targeting antibodies. However, there are a number of different selection methods established in different laboratories around the world. Cell­based PD panning methods using primary tumor cells are particularly heterogeneous between laboratories, which can lead to inconsistent results. Therefore, the present study evaluated different cell­based PD selection methods regarding their potential to generate acute myeloid leukemia (AML) blast­binding antibodies. In addition to this evaluation, the present study improved the PD procedure by optimizing selection as well as depletion strategies. To the best of our knowledge, the current study demonstrated for the first time that antigen diversity during the depletion step is of importance for the enrichment of tumor­targeting phage antibodies. It is demonstrated that medium levels of depletion antigen diversity led to the most promising antibody candidates. In addition, it was determined that purification of blast cells from patients with AML by immunomagnetic separation ameliorated the selection of AML­binding phages during panning. Furthermore, suggesting a common design­related mechanism using a 'single­pot' PD library, such as the well­known Tomlinson single­chain fragment variable (scFv) library, the present study identified specific binding consensus phage particles in independent panning procedures. By means of these optimized strategies, four promising AML blast­binding phage particles were isolated and soluble scFv­Fc (scFv cloned to a fragment crystallizable of an IgG2a mouse antibody) fusion proteins were produced. These scFv­Fc antibodies bound the surface of AML blasts and were successfully internalized into their cytoplasm, indicating that they are potential immunoconjugate candidates for AML immunotherapy.

A phase 3, randomized study of ofatumumab combined with bendamustine in rituximab-refractory iNHL (COMPLEMENT A + B study).

The standard of care for indolent non-Hodgkin lymphoma (iNHL) is rituximab, an anti-CD20 antibody, with/without chemotherapy. However, multiple relapses are common in these patients. This phase 3, randomized study compared outcomes of a combination of ofatumumab (a second-generation anti-CD20 antibody) and bendamustine, with bendamustine alone in patients unresponsive to prior rituximab-based treatment. Overall, 346 patients were randomized to receive either the combination or bendamustine alone. Bendamustine was given for ≤8 cycles and ofatumumab for ≤12 cycles. The primary end-point was progression-free survival (PFS) after 215 protocol-defined events assessed by independent review committee (IRC). Median IRC-assessed PFS was 16·7 and 13·8 months in the combination and monotherapy arms respectively [hazard ratio (HR) = 0·82; P = 0·1390]. Median overall survival (OS) was 58·2 and 51·8 months in the combination and monotherapy arms respectively (HR = 0·89, P = 0·4968). The safety profile was consistent with previous reports. Overall, 73% and 80% of patients in the combination and monotherapy arms, respectively, experienced a ≥grade 3 adverse event. The study did not meet its primary end-point. No significant improvement in PFS and OS was seen with the combination of ofatumumab and bendamustine as compared with bendamustine alone in rituximab-refractory iNHL (NCT01077518).

Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated ß2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

Efficacy and Tolerability of High- versus Low-dose Lenalidomide Maintenance Therapy of Multiple Myeloma after Autologous Blood Stem Cell Transplantation.

PURPOSE: For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10-15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated. PATIENTS AND METHODS: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS). RESULTS: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high- and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44-0.97; P = 0.032), 36% and 23% of patients had stringent CR as best response (P = 0.08), and 4-year OS was 79% and 67% (P = 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-of-life (QoL) scores in both arms were similar. CONCLUSIONS: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up- and down-titration for each patient to the current maximum tolerated dose is prudent.

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia.

Platelet autoantibody-induced platelet clearance represents a major pathomechanism in immune thrombocytopenia (ITP). There is growing evidence for clinical differences between anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib/IX mediated ITP. Glycoprotein V is a well characterized target antigen in Varicella-associated and drug-induced thrombocytopenia. We conducted a systematic study assessing the prevalence and functional capacity of autoantibodies against glycoprotein V. A total of 1140 patients were included. In one-third of patients, platelet-bound autoantibodies against glycoproteins Ib/IX, IIb/IIIa, or V were detected in a monoclonal antibody immobilization of platelet antigen assay; platelet-bound autoantiglycoprotein V was present in the majority of samples (222 out of 343, 64.7%). Investigation of patient sera revealed the presence of free autoantibodies against glycoprotein V in 13.5% of these patients by an indirect monoclonal antibody immobilization of platelet antigen assay, but in 39.6% by surface plasmon resonance technology. These antibodies showed significantly lower avidity (association/dissociation ratio 0.32±0.13 vs 0.73±0.14; P<0.001). High- and low-avidity antibodies induced comparable amounts of platelet uptake in a phagocytosis assay using CD14+ positively-selected human macrophages [mean phagocytic index, 6.81 (range, 4.75-9.86) vs 6.01 (range, 5.00-6.98); P=0.954]. In a NOD/SCID mouse model, IgG prepared from both types of anti-glycoprotein V autoantibodies eliminated human platelets with no detectable difference between the groups from the murine circulation [mean platelet survival at 300 minutes, 40% (range, 27-55) vs 35% (16-46); P=0.025]. Our data establish glycoprotein V as a relevant immune target in immune thrombocytopenia. We would suggest that further studies including glycoprotein V will be required before ITP treatment can be tailored according to platelet autoantibody specificity.

Outcome of non-mold effective anti-fungal prophylaxis in patients at high-risk for invasive fungal infections after allogenic stem cell transplantation.

Patients who develop severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (alloSCT) have a higher risk for invasive fungal infection (IFI). At our center, fluconazole prophylaxis is standard and upfront mold-effective prophylaxis performed only in patients with specific risk constellations. A total of 290 patients undergoing alloSCT between May 2002 and August 2011 were analyzed. Patients were regarded as high-risk if they suffered from acute GvHD II-IV° or extensive chronic GvHD. The 2-year incidence of an IFI after alloSCT was 8.97% (26/290) in the entire cohort and 7.78% (7/90) in the high-risk group. Mortality due to IFI was 3.85% (1/26) without including a high-risk patient. In the multivariate analysis a pre-transplant fungal infection was the only significant risk factor for developing an IFI after alloSCT (HR = 5.298; p = .001). A fluconazole prophylaxis in patients with GvHD after alloSCT is feasible in facilities with HEPA filtration and high awareness of clinical signs for IFI.

Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials.

BACKGROUND: Although intensified chemotherapy regimens have improved tumour control and survival in advanced-stage Hodgkin's lymphoma, data on the long-term sequelae are scarce. We did preplanned follow-up analyses of the German Hodgkin Study Group (GHSG) trials HD9 and HD12 to assess whether the primary results of these trials-which had shown that intensive initial therapy in advanced-stage Hodgkin's lymphoma has a beneficial effect on treatment outcomes-would continue with longer follow-up. METHODS: In HD9 (Feb 1, 1993, to March 10, 1998), 1282 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight alternating cycles of COPP and ABVD (COPP/ABVD), eight cycles of bBEACOPP, or eight cycles of eBEACOPP. In HD12 (Jan 4, 1999, to Jan 13, 2003; registered with ClinicalTrials.gov [NCT00265031]), 1670 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy, to analyse two non-inferiority objectives. In both trials, randomisation was done centrally in the GHSG trial coordination centre using the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease. Patients and investigators were not masked to treatment allocation. All analyses were done on the intention-to-treat principle. The primary endpoint of this follow-up analysis was progression-free survival (time from first diagnosis to progressive disease, relapse, or death from any cause or censoring at the date of last information on disease status). To assess whether long-term outcome might be impaired by long-term sequelae, we analysed overall survival and second primary malignant neoplasm incidence as key secondary endpoints. FINDINGS: Median observation time was 141 months (IQR 101-204) in HD9 and 97 months (69-143) in HD12. For HD9 trial patients, 15-year progression-free survival was 57·0% (95% CI 50·0-64·0) for COPP/ABVD, 66·8% (61·9-71·8) for bBEACOPP, and 74·0% (69·0-79·0) for eBEACOPP, 15-year overall survival was 72·3% (95% CI 66·5-78·1), 74·5% (70·1-78·9), and 80·9% (76·7-85·0), respectively. Progression-free survival and overall survival in the eBEACOPP group remained significantly better than in the COPP/ABVD group (hazard ratio [HR] 0·53, 95% CI 0·41-0·69, p<0·0001, and 0·68, 0·50-0·93, p=0·015, respectively). The 15-year cumulative incidence of second primary malignant neoplasms was 7·2% (95% CI 3·7-10·7) after COPP/ABVD, 13·0% (9·1-16·9) after bBEACOPP, and 11·4% (7·6-15·1) after eBEACOPP. For HD12 trial patients, non-inferiority of 4 + 4 was shown, with 10-year progression-free survival of 82·6% (95% CI 79·6-85·6) for eBEACOPP and 80·6% (77·4-83·7) for 4 + 4 (HR 1·13 [0·89-1·43], within non-inferiority margin of 1·50), and 10-year overall survival of 87·3% (95% CI 84·7-89·9) and 86·8% (84·2-89·4), respectively (HR 1·02 [95% CI 0·77-1·36]). Among 555 (37%) patients with residual disease after chemotherapy, omission of radiotherapy was associated with significantly worse 10-year progression-free survival (89·7% [95% CI 85·8-93·6] radiotherapy vs 83·4% [78·2-88·5] for no radiotherapy; p=0·027) and 10-year overall survival (94·4% [91·4-97·3] vs 88·4% [83·8-93·0]; p=0·025). 10-year cumulative second primary malignant neoplasms incidence was 6·4% (95% CI 3·3-9·5) for 4 + 4 and 8·8% (5·2-12·4) for eBEACOPP. INTERPRETATION: Long-term follow-up of HD9 and HD12 shows an ongoing benefit of intensive first-line treatment and consolidation radiotherapy to residual disease in terms of progression-free survival and overall survival. Our results support the use of eBEACOPP in advanced-stage Hodgkin's lymphoma. However, because late toxicities such as second primary malignant neoplasms contribute to mortality, less toxic but equally effective treatments need to be developed to further improve overall survival. FUNDING: Deutsche Krebshilfe e.V.

Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Targeted Next-Generation Sequencing Is a Sensitive Tool for Differential Diagnosis of Myelodysplastic Syndromes in Bone Marrow Trephines.

Myelodysplastic syndromes are hematological neoplasias in which immunohistologic examination of bone marrow trephines is important for a definite diagnosis. Unequivocal distinction from reactive bone marrow changes is, however, sometimes difficult. Because neoplastic clones in myelodysplastic syndrome carry mutations in recurrent genes, mutation detection by targeted next-generation sequencing may be a useful support for differential diagnosis. To elucidate the accuracy of this approach in the clinical diagnostic setting, we analyzed single and consecutive bone marrow trephines processed for immunohistologic examination from 145 patients by targeted next-generation sequencing of 12 genes recurrently mutated in myelodysplastic syndromes. Of 110 patients with immunohistologic unequivocal diagnosis, 41 of 47 with myelodysplastic syndrome carried mutations. In 14 consecutive samples available from these patients, remissions were accompanied by loss of mutations and ongoing disease with persisting mutations. Of 35 samples with indefinite immunohistologic appearance, 22 developed clinical unequivocal myelodysplastic syndrome in the further course, and 19 carried mutations already in the initial biopsy, which persisted in consecutive samples available from 13 patients. No mutation was detected in any initial and consecutive sample of 13 patients with indefinite immunohistologic appearance without clinical unequivocal myelodysplastic syndrome in the further course. We conclude that targeted next-generation sequencing is an accurate tool for differential diagnosis of myelodysplastic syndrome in the clinical diagnostic setting.

Maintenance Treatment for Patients With Mantle Cell Lymphoma: A Systematic Review and Meta-analysis of Randomized Trials.

Current treatment of patient with mantle cell lymphoma (MCL) is insufficient and does not result in cure. To assess the efficacy and safety of maintenance therapy for patients with MCL, we performed a systematic review and meta-analysis of randomized controlled trials. Six trials randomizing 858 patients were included in the meta-analysis. In 5 trials, maintenance therapy consisted of rituximab. The pooled hazard ratio (HR) of death with rituximab maintenance compared to observation was 0.79, 95% CI 0.58 to 1.06 (4 trials, 737 patients). Progression free survival was longer with rituximab maintenance in each of the trials and in the pooled analysis (HR 0.58, 95% CI 0.45-0.73). The risk of neutropenia was higher with maintenance compared to observation risk ratio (RR) 1.31, 95% CI 1.03 to 1.66. None of the trials reported on quality of life outcomes. The grade 3 to 4 infection rate was 7% in each of the treatment groups. The risk of grade 3 to 4 infection was not affected by allocation to maintenance. Rituximab maintenance is recommended after R-CHOP or R-cytarabine-containing induction in the frontline setting for transplant eligible and ineligible patients, and after R-CHOP in the relapse setting. It is unclear if maintenance is of benefit after different induction chemotherapy such as bendamustine or fludarabine. It is too early to conclude on other type of maintenance for MCL patients.