Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.

Cutaneous Presentation of Angioimmunoblastic T-Cell Lymphoma: A Harbinger of Poor Prognosis?

A 62-year-old woman presented with a 2-year history of extensive, pruritic dermatosis over her face, trunk, and limbs. She was initially treated for psoriasis with methotrexate 5 mg twice weekly and topical clobetasol cream; however, her condition worsened, and she was admitted for generalized exfoliative dermatitis. Examination showed generalized erythema and scaling affecting her face (Figure 1A), chest (Figure 1B), back, and limbs. There were also cervical, axillary, and inguinal lymphadenopathy. Laboratory studies revealed a high white blood cell count of 125×109/L (reference range: 4-10×109/L), hemoglobin level of 11.9 g/dL (reference range: 12-16 g/dL), and normal platelet level of 396×109/L (reference range: 140-440×109/L). Results from direct Coombs test were negative and lactate dehydrogenase levels were normal.

Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial.

BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations. METHODS: In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov, number NCT01500733, and is fully enrolled. FINDINGS: Between Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12.9-27.0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient. INTERPRETATION: The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings. FUNDING: Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc.

Treatment outcomes of T and natural-killer/T-cell lymphoma with ifosfamide, carboplatin and etoposide chemotherapy.

BACKGROUND: Contemporary data of peripheral T-cell lymphoma (PTCL) and natural-killer/T-cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited. AIMS: We performed a retrospective analysis to estimate outcomes of ICE-treated PTCL and NKTL patients at three tertiary cancer centres in Singapore. METHODS AND RESULTS: Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first-line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow-up duration of 71.0 months, the median progression-free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7-6.0) and 16 months (95%CI, 8.3-45.4) respectively. CONCLUSION: In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real-world CHOP data and warrants further study.

High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma.

The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004-0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m2 by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes.

Real world experience of R-CHOP with or without consolidative radiotherapy vs DA-EPOCH-R in the first-line treatment of primary mediastinal B-cell lymphoma.

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct clinico-pathological subtype of diffuse large B-cell lymphoma with unclear prognostic factors and limited clinical data. Optimal treatment and role for radiotherapy is not fully defined. We performed a multicenter retrospective review of 124 patients with newly diagnosed PMBCL between 2001 and 2016. Treatment regimens were R-CHOP (n = 41), R-CHOP + RT (n = 37), and DA-EPOCH-R (n = 46). 6% (n = 3) in the DA-EPOCH-R group received RT. With a median follow up of 45 months, the overall 5-year OS and PFS was 89.4% and 82.4%, respectively. The type of chemo-radiotherapy regimen, B symptoms and Ann-Arbor staging showed a significant association with OS on univariate analysis but only B symptoms remained prognostic (P = 0.012) after multivariate analysis. The chemo-radiotherapy regimen, Japanese IPI and Ann-Arbor stage was significantly associated with PFS in univariate analysis, but only chemo-radiotherapy regimen remained significant (P = 0.02) after multivariate analysis. Patients who received R-CHOP + RT or DA-EPOCH-R had better PFS than those receiving R-CHOP alone, with 5-year PFS of 90% vs 88.5% vs 56%, respectively (P = 0.02). In the subgroup analysis of patients with bulk (n = 71), R-CHOP alone (n = 21) had inferior 5-year PFS 56.6% compared to those who received R-CHOP + RT (n = 23) 91.3% or DA-EPOCH-R (n = 27) 92.6% (P = 0.007). In contrast, in patients without bulk (n = 42), there was no impact of treatment regimen on PFS (P = 0.25). In conclusion, R-CHOP + RT and DA-EPOCH-R provide excellent outcomes in patients with PMBCL. In patients with bulky disease, the use of DA-EPOCH-R may be preferable as it allows omission of RT without reduction in efficacy.

The impact of time from diagnosis to treatment in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a high-grade lymphoma that requires treatment. We retrospectively analyzed the impact of time from diagnosis-to-treatment (TDT) on progression-free survival (PFS) and overall survival (OS) in 581 R-CHOP-treated patients. TDT was defined as the interval between diagnostic biopsy date and day 1 R-CHOP. Cox regression showed stage 3-4 disease (p = .01) and longer TDT (HR 1.13, p =.031) were associated with shorter OS. Eastern Cooperative Oncology Group ≥2 (p = .02), stage 3-4 disease (p < .001), and longer TDT (HR 1.12, p = .028) predicted shorter PFS. The significant interactions between TDT with lactate dehydrogenase (LDH) and with disease stage prompted separate analyses in high versus normal LDH, and stage 3-4 versus 1-2 disease. Longer TDT was associated with shortened PFS and OS only with advanced stage, and, if high LDH was present. Treatment should be started as early as possible for high-tumor burden disease. Delaying treatment in patients with early stage or low LDH does not seem harmful.

Clinicopathological features and outcome of chronic lymphocytic leukaemia in Chinese patients.

Chronic lymphocytic leukaemia (CLL) is uncommon in Chinese population and its biology, genetics and treatment outcome in Chinese patients have not been comprehensively investigated. In this study, we studied the clinicopathological features and outcome of 212 Chinese patients with newly diagnosed CLL in Hong Kong and Singapore. The median age at diagnosis was 64 years. The majority of patients presented with early-stage disease (Binet stage A, 56.1%). Del(13)(q14) was the most frequent abnormality (41.7%) detected by fluorescence in situ hybridization (FISH) analysis. Del(17p) and TP53 gene mutations were detected in 7.8% and 8.2% of patients, respectively. MYD88 mutations were found at a higher frequency (11.5%) than expected. CLL with unmutated variable region of the immunoglobulin heavy chain genes (IGHV) occurred in only 31.2% of cases, and was associated with advanced-stage disease (p <0.01) and adverse FISH abnormalities (p<0.01). With a median follow-up of 39 months, the median overall survival (OS) was 108 months. The presence of del(17p) or TP53 mutations was associated with a significantly shorter time to first treatment and an inferior OS (p <0.01). Unmutated IGHV was also associated with a significantly shorter time to treatment (p <0.01). Among patients who required treatment, the median OS and progression-free survival (PFS) were 107 and 23 months, respectively. The presence of del(17p) was associated with a significantly inferior OS and PFS (p <0.01). In summary, Chinese CLL patients had similar genetic aberrations at diagnosis compared with those of Western populations. FISH abnormalities are major factors affecting outcome.

Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy.

PURPOSE: Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAb) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in preclinical studies, in vitro ibrutinib was reported to decrease CD20 expression and inhibit cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox. EXPERIMENTAL DESIGN: Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs. RESULTS: We demonstrate that CD20 expression on ibrutinib was rapidly and persistently downregulated (median reduction 74%, day 28, P < 0.001) compared with baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and downregulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pretreatment cells (median reduction 75%, P < 0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay-accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. In addition, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. CONCLUSIONS: Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal antitumor effects of such combinations requires further investigation.

Role of Surveillance Imaging in Patients With Peripheral T-Cell Lymphoma.

INTRODUCTION: The role of surveillance imaging (SI) in patients with peripheral T-cell lymphoma (PTCL) in first complete remission (CR1) is unclear. MATERIALS AND METHODS: Patients with PTCL were identified through prospectively maintained T-cell lymphoma databases from the National Cancer Centre Singapore/Singapore General Hospital and Weill-Cornell Medical College after institutional review board approval. Patients with leukemia or indolent, composite, and cutaneous lymphomas were excluded. The patients' medical records were retrospectively reviewed to determine the frequency and type of SI used. Of those with relapse, the method of relapse detection and data on symptoms, signs, and elevated lactate dehydrogenase LDH were extracted. RESULTS: A total of 338 patients were included in the present study. In the first year after achieving CR1, patients had an average of 1.2 and a median of 1 SI performed (range, 0-4). In the second year after achieving CR1, they had an average of 0.78 and a median of 1 SI performed (range, 0-4). Of the 135 patients who achieved CR1, 61 (45%) developed a relapse. Relapses were detected before SI in 48 (84%), and 9 patients had relapses detected during routine SI. Of the 9 patients whose relapses were detected during planned SI, only 3 did not have any symptoms or signs suggestive of relapsed disease. Of these 3 patients, 2 had angioimmunoblastic T-cell lymphoma and 1 had natural killer/T-cell lymphoma. CONCLUSION: Most PTCL relapses were detected before planned SI, and most patients had symptoms with relapse. Only 3 patients (5.2%) were completely asymptomatic at relapse, suggesting a limited utility of routine imaging for detecting PTCL relapses.

Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study.

PURPOSE: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. EXPERIMENTAL DESIGN: Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed. RESULTS: Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4(+)T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+)T cells in vitro Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells. CONCLUSIONS: In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. See related commentary by Bachireddy and Wu, p. 1547.

Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial.

BACKGROUND: Patients with relapsed or refractory peripheral T-cell lymphoma have a poor prognosis after conventional chemotherapy. Approved novel agents have only modest single-agent activity in most subtypes of peripheral T-cell lymphoma. Panobinostat is a potent oral pan-deacetylase inhibitor. Findings of many preclinical studies have shown synergistic antilymphoma activity when panobinostat is combined with the proteasome inhibitor bortezomib. We aimed to study the effect of panobinostat and bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma. METHODS: In this open-label, multicentre phase 2 trial, we recruited patients aged 21 years or older with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy from five tertiary hospitals in Singapore, Malaysia, and South Korea. Patients received 20 mg oral panobinostat three times a week and 1·3 mg/m(2) intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The primary endpoint was the proportion of patients who achieved an objective response in accordance with the International Working Group revised response criteria; analyses were by intention to treat. The study is completed and is registered with ClinicalTrials.gov, number NCT00901147. FINDINGS: Between Nov 9, 2009, and Nov 26, 2013, we enrolled 25 patients with various histological subtypes of peripheral T-cell lymphoma. Of 23 patients assessable for responses, ten (43%, 95% CI 23-63) patients had an objective response, of which five were complete responses. Serious adverse events were reported in ten (40%) of 25 patients. Common treatment-related grade 3-4 adverse events included thrombocytopenia (17 [68%]), neutropenia (ten [40%]), diarrhoea (five [20%]), and asthenia or fatigue (two [8%]). We recorded peripheral neuropathy of any grade in ten (40%) patients. INTERPRETATION: Combined proteasome and histone deacetylase inhibition is safe and feasible and shows encouraging activity for patients with peripheral T-cell lymphoma. Our findings validate those of preclinical studies showing synergism in the combination and represent a rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma. FUNDING: Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Singhealth Foundation.

Use of sonography in assessing elbow medial collateral ligament injury after arm wrestling.

Medial collateral ligament injury is an infrequent occurrence in arm wrestlers. We report here a male patient who injured his left elbow while arm wrestling. Ultrasonography showed a medial collateral ligament tear. We assessed both elbows using ultrasonography at his 3-year follow-up visit. Dynamic ultrasonography showed a decreased gap at the ulnotrochlear joint space in his left elbow. A medial collateral ligament tear in his right elbow was also evident using ultrasonography. This case report shows the advantages of ultrasonography, especially dynamic ultrasonography, in the evaluation of elbow injury. Ultrasonography provides more information than valgus stress radiography, arthrography, and magnetic resonance imaging in the assessment of medial collateral ligament injury. In addition, the contralateral side can readily be assessed for comparison during ultrasonography.