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Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor–induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating idelalisib-induced Grade ≥3 irAEs with improved efficacy. [ABSTRACT FROM AUTHOR]

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m2/day for 2 days followed 14 days later by SCT. Sixteen subjects in partial remission (PR) with maximal FDG-PET SUVs ≤8 prior to bendamustine received autologous SCT, while 13 with suboptimal responses were allografted. Five subjects did not proceed to transplant. No bendamustine toxicities precluded transplantation and no detrimental effect on engraftment or early treatment-related mortality (TRM) was attributable to bendamustine. At 1 year, 75% of auto-recipients and 31% of allo-recipients were alive with CR. Two subjects in the autologous arm developed therapy-related myeloid neoplasia (t-MN). In conclusion, a bendamustine bridge to SCT can be administered without early toxicity to patients with suboptimal responses to salvage chemotherapy. However this approach may increase the risk of t-MN. (NCT02059239). Supplemental data for this article is available online at . [ABSTRACT FROM AUTHOR]

In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1–12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m2 (dose levels 1, 2, 3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1–12 plus bortezomib 1.0 mg/m2 on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents. [ABSTRACT FROM AUTHOR]

The article describes the case of a 78-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL) four years prior presentation when she was found to have lymphadenopathy on positron-emission tomography (PET) scan obtained for follow-up of her breast and bladder cancer. Topics discussed include treatment she received for CLL, finding on a full body computed tomography (CT) scan, and efficacy of ibrutinib on disease outside of a lymph node.

A letter to the editor is presented regarding the extended follow-up with ibrutinib, an inhibitor of Bruton's tyrosine kinase, in previously treated patients with the non-Hodgkin lymphoma Waldenström's macroglobulinemia.

Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical non-Hodgkin lymphoma (NHL) models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included four planned dose levels (1.5, 4, 6 and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday–Friday) for 10 days. Twenty-two patients were treated. The most common possibly related toxicities were infusion reaction, anemia, lymphopenia, neutropenia and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2 and 4, respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ∼2 h. In seven patients, In-111 imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug. [ABSTRACT FROM AUTHOR]

Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy. [ABSTRACT FROM AUTHOR]

Existing data suggest that myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) peak in incidence 5–10 years following exposure to ionizing radiation, while most publications report less than 5 years of follow-up after radioimmunotherapy (RIT). We report the rate of secondary MDS/AML among 60 patients treated with two front-line sequential chemotherapy-RIT trials with over 11 years of follow-up. Among 35 patients evaluated after fludarabine-RIT and 25 patients evaluated after CVP (cyclophosphamide, vincristine, prednisone)-RIT treatment, the crude, cumulative and Kaplan–Meier rates of MDS/AML at 11 years of follow-up from the combined trials were 0.12/person, 0.010/person-year and 14% (95% confidence interval [CI] 5–24%), respectively. Additionally, we found that patients treated with RIT consolidation appear to have durable remissions but that relapses after 10 years do occur. Studies of efficacy and secondary MDS/AML that report fewer than 10 years of follow-up likely underestimate risk. [ABSTRACT FROM AUTHOR]

Radioimmunotherapy (RIT) is effective treatment for indolent non-Hodgkin lymphomas (NHLs), but response durations are usually limited, especially in aggressive NHL. We hypothesized that administration of bortezomib as a radiosensitizer with RIT would be tolerable and improve efficacy in NHL. This phase 1 dose-escalation study evaluated escalating doses of bortezomib combined with 131I-tositumomab in patients with relapsed/refractory NHL. Twenty-five patients were treated. Treatment was well tolerated, with primarily hematologic toxicity. The maximum tolerated dose (MTD) was determined to be 0.9 mg/m2 bortezomib, in combination with a standard dose of 75 cGy 131I-tositumomab. Sixteen patients responded (64%), including 44% complete responses (CRs), with 82% CR in patients with follicular lymphoma (FL). At a median follow-up of 7 months, median progression-free survival was 7 months, and seven of 11 patients with FL remained in remission at a median of 22 months. In conclusion, bortezomib can be safely administered in combination with 131I-tositumomab with promising response rates. [ABSTRACT FROM AUTHOR]

Understanding the biology of Waldenström macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secretes human immunoglobulin M (h-lgM) with K-light chain restriction identical to the primary tumor.The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2), with a consistent amplification of 14q32 (immunoglobulin heavy chain; IgH) identical to its founding tumor sample. The clonal relationship is confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in the MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Overall, RPCI-WM1 represents a valuable model to study Waldenstr0m macroglobulinemia. [ABSTRACT FROM AUTHOR]

Patients with relapsed or refractory diffuse large B-cell lymphoma may experience extended survival with second-line chemotherapy and autologous stem cell transplant (ASCT). Since a major determinant of outcome after ASCT is responsiveness to second-line therapy, the development of more effective second-line treatments is desirable. We investigated the addition of bortezomib to rituximab, dexamethasone, ifosfamide, cisplatin and etoposide (VIPER). Fifteen patients were enrolled, of whom seven were refractory to first-line chemotherapy and only three had maintained first response for 1 year. Nine (60%) patients achieved objective responses, of which three (20%) were IWC-PET (International Workshop Criteria positron emission tomography) complete responses. Median progression-free survival was 3 months, and median overall survival was 10 months. At a median follow-up of 26 months, five patients (33%) remained alive. Treatment was well tolerated with no unexpected toxicity. Although response rates did not meet predefined criteria, activity was at least comparable to other second-line approaches despite a poor-prognosis patient population. [ABSTRACT FROM AUTHOR]

Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL. [ABSTRACT FROM AUTHOR]

Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively ( p == 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively ( p == 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Despite advances in therapy, chronic lymphocytic leukemia remains an incurable disease and novel, effective therapies are needed. In this open-label, dose-escalation, phase I study, dacetuzumab (IgG1 humanized monoclonal antibody) was administered to 12 adults, all of whom had received several prior systemic therapies (median, 4; range, 2–11). Intrapatient dose escalation (maximum weekly doses of 3–8 mg/kg) was used to diminish first-dose-related inflammatory symptoms. No dose-limiting toxicities or dose-dependent trends in adverse events (AEs) were observed. The most common AEs (in ≥2 patients) were fatigue, headache, anorexia, conjunctivitis, hyperhidrosis, and night sweats, all of which were mild or moderate. No deaths, serious AEs, or discontinuations due to AEs occurred. Although no patient achieved an objective response, five patients demonstrated stable disease after 1 cycle of therapy, with no discernable correlation between dacetuzumab dose and outcome. This modest single-agent activity may warrant further testing of dacetuzumab in combination with other chronic lymphocytic leukemia therapies. [ABSTRACT FROM AUTHOR]

Research Findings: This in-depth single case study explores the experiences of a single father with finding and maintaining child care for his son. This American middle-income, Caucasian father lives and works in Minnesota. Findings include difficulty locating and maintaining child care, dissatisfaction with child care quality, concerns about paying for care, and using grandparents as a secondary form of care. Practice or Policy: This article contributes to the literature because it is the only case study available about a father's involvement in child care and how single fathers engage with nonparental care. [ABSTRACT FROM AUTHOR]

Diagnostic splenectomy is frequently performed in patients with suspected or known lymphoma. We evaluated whether preoperative 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results may correlate with splenic pathology. Of 165 patients undergoing splenectomy at the Weill Cornell Medical Centre/New York Presbyterian Hospital from 2004 to 2006, 10 were identified as being performed to evaluate known or suspected lymphoma and included a pre-splenectomy FDG-PET scan. The scans were assigned to low, intermediate or high splenic metabolic activity based on standardized uptake values (SUV). Low activity was associated with benign findings or mantle cell lymphoma at splenectomy, intermediate activity with marginal zone lymphoma and high activity with DLBCL. This comprises the largest pathologically confirmed series of cases to evaluate splenic FDG-PET uptake in suspected or known lymphoma. Low splenic SUV appears less likely to be associated with splenic involvement of lymphoma; intermediate and high values suggest presence of lymphoma. Our findings support a potential role for preoperative FDG-PET in consideration of the need for splenectomy in these settings. [ABSTRACT FROM AUTHOR]

The prednisone, etoposide, procarbazine and cyclophosphamide (PEP-C) oral combination chemotherapy regimen (prednisone 20 mg, cyclophosphamide 50 mg, etoposide 50 mg, and procarbazine 50 mg with an oral anti-emetic) was employed at our center to treat 22 patients with heavily pretreated, recurrent mantle cell lymphoma (MCL). All medications were administered daily until leukocytes fell to <3.0 × 109/L whereupon treatment was withheld until recovery from the nadir. Therapy was then reinstituted on a daily, alternate day, or fractionated basis (e.g. 5 of 7 days) depending on patient tolerance. Doses given per day were held constant. Eighty-two percent achieved an objective response with 46% complete responses and 36% partial responses. Median time on therapy was 17 months. The regimen was well tolerated. Our findings demonstrate that low-dose oral agents administered in combination for continuous, prolonged periods with minimal drug-free intervals (metronomic therapy) may represent a novel, effective, easily tolerated approach to MCL and that this treatment approach warrants further exploration. [ABSTRACT FROM AUTHOR]

Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor >25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of >25% and platelet count of ≥150 000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count <500 cells/mm3 or platelets <25 000/mm3 for >17 days, or absolute neutrophil count <750/mm3 or platelets <50 000/mm3 for >24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 – 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with >25% BMI has acceptable toxicity and can result in lymphoma responses. [ABSTRACT FROM AUTHOR]

In this article the authors discuss the role of allogeneic transplantation in the treatment of chronic lymphocytic leukemia (CLL) and the article "Low Tumor Burden Is Associated With Early B-Cell Reconstitution and Is a Predictor of Favorable Outcome After Non-Myeloablative Stem Cell Transplant for Chronic Lymphocytic Leukemia" by K. Hebenstreit, S. Iacobelli, S. Leiblein et al. within the issue. They are supportive of using the drugs idelalisib and ibrutinib to treat CLL and of only using allogenic transplantation in patients who do not respond to the drugs.

A correction to the article "I Want Child Care He's Gonna Be Happy In: A Case Study of a Father's Child Care Experiences" is presented.