Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.

Outcomes and Toxicities of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Real-World, Multicenter Retrospective Analysis.

BACKGROUND: Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies. RESULTS: The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses. CONCLUSION: To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting. IMPLICATIONS FOR PRACTICE: Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience.

B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.

Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis.

Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Evaluation of direct oral anticoagulants for the treatment of venous thromboembolism in the oncology population.

Direct oral anticoagulants (DOACs) have become an attractive option for the treatment of venous thromboembolism (VTE) in cancer patients. However, their use is currently not recommended as first-line treatment by national guidelines due to limited data in this patient population. The objective of this study was to evaluate the practice and safety patterns of DOACs when used for VTE treatment in the oncology population. This study was a retrospective chart review of adult cancer patients treated at Hackensack University Medical Center from January 2013 to October 2015 who received dabigatran, rivaroxaban, or apixaban for VTE treatment. Of 126 patients screened, 39 patients were included. Thirty-five patients received rivaroxaban and four patients received apixaban. Ten of 39 patients (26%) were not receiving a DOAC dosage consistent with the package insert. No patients experienced clinically significant bleeding, while four patients experienced a minor bleed. Four of 14 thrombocytopenic patients (29%) did not have their DOAC dose held for thrombocytopenia. All patients had their DOACs appropriately held for procedures. Increased education on dosing DOACs according to the package insert is warranted for oncology prescribers. Despite the increased risk for bleeding in cancer patients, no clinically significant bleeding events were identified in our patient cohort. This data suggests that the use of DOACs may be safe to use for VTE treatment in cancer patients and may provide foundation for larger, randomized controlled trials to determine whether DOACs should be used for VTE treatment in cancer patients.

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Use of naloxone for reversal of life-threatening opioid toxicity in cancer-related pain.

OBJECTIVE: To review the emergency-based approach to opioid toxicity reversal in cancer-related pain patients. DATA SOURCE: A MEDLINE and PubMed search was conducted (1966 to May 2014) using the terms opioids, cancer, naloxone, respiratory depression, morphine, morphine derivatives, emergency, and anaphylaxis. METHODS OF STUDY SELECTION: English articles in human subjects identified from the MEDLINE and PubMed search were evaluated. Citations were excluded if they addressed acute overdoses, non-cancer pain, and/or acute, non-chronic pain. DATA EXTRACTION AND SYNTHESIS: Pain is a common occurrence in the oncology population. Although toxicity from opioids is common, life-threatening toxicities are not. The use of naloxone in this particular patient population occurs frequently for any perceived opioid-related effect and can be detrimental to the oncology patient's care and quality of life. Difficulties exist when attempting to separate opioid toxicity from disease progression or metastases and, therefore, a thorough history is needed prior to complete opioid reversal in this population. Severity of the opioid intoxication should dictate reversal strategy. Dosing strategies that take into account both the treatment of the opioid-related effects as well as the negative effects reversal will have on the patient are offered. We also review the pre-hospital setting and identified the need for protocols that not only take the patient's symptoms into account, but also the patient's cancer history. CONCLUSION: Opioid reversal protocols should be developed by a multi-disciplinary team. Each protocol should differentiate those toxicities which are life-threatening and require complete opioid reversal with toxicities that require small aliquots of naloxone to mitigate the presenting symptoms.

Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis.

'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose-intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose-escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R-EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R-CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression-free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.

Reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR-Lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia.

Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced-dose FCR (FCR-Lite) plus lenalidomide (FCR(2) ) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR(2) . Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR(2) . Twenty patients were evaluable. After four cycles of FCR(2) , response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR(2) . After 17.4 months of median follow-up, one progression and one death occurred. Our findings suggest that FCR(2) combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission.

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

A Multidisciplinary Approach to Standardizing Processes for Blinatumomab Administration.

Blinatumomab (Blincyto®) has received accelerated approval for treatment of relapsed or refractory acute lymphoblastic leukemia. This article describes the authors' experience with a multidisciplinary collaboration among nursing, pharmacy, prescribers, and support staff, which has proven to be key for safe administration. The approach can be applied to other institutions planning to use blinatumomab.

Rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine overcomes risk features associated with inferior outcomes in treatment of newly diagnosed, high-risk diffuse large B-cell lymphoma.

Subtypes of diffuse large B-cell lymphoma (DLBCL) that have inferior outcomes after front-line therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) have been identified. While it is agreed that R-CHOP is probably not adequate in these patients, there is no standard treatment approach for patients with DLBCL with high-risk features. We present results of a retrospective cohort study of high-risk DLBCL (defined as having at least one unfavorable risk factor: non-germinal center [GC] subtype by immunohistochemistry [IHC], Ki-67 ≥ 80%, high International Prognostic Index [IPI], c-MYC rearrangement) treated with R-HCVAD/R-MTX-AraC (rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine; R-HCVAD) as front-line therapy. With a median follow-up of 25.3 months, the 3-year PFS and OS estimates are 79% (95% confidence interval [CI], 65-88%) and 76% (95% CI, 61-86%), respectively, which are higher than those for historical comparisons with R-CHOP data for high-risk patients. These data are in accord with other recent reports of dose-intense front-line therapy of high-risk DLBCL. This analysis represents the largest reported cohort of patients with DLBCL treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in patients with DLBCL treated with dose-intensive regimens.