High CD34-positive cell dose in matched unrelated donor allogeneic hematopoietic stem cell transplant is not associated with graft-versus-host disease or mortality.

BACKGROUND: CD34+ stem cells serve as the primary graft source for allogeneic transplants, with a minimum of 2-4 × 106 cells/kg needed for engraftment. There are conflicting data on outcomes at high stem cell doses, with studies limited by few patients receiving doses far above the minimum target. STUDY DESIGN AND METHODS: In this retrospective, single-center study of patients with hematologic malignancies who underwent matched unrelated donor transplants, we assessed outcomes for engraftment, survival, relapse, and graft-versus-host disease (GVHD) for the highest CD34+ dose quintile (>13 × 106 cells/kg, n = 36) compared to the remaining patients (n = 139). Similar analysis was performed correlating T cell dose and outcomes. RESULTS: There was no difference between the groups in neutrophil engraftment, with a trend toward faster platelet engraftment. There was no significant difference in mortality (adjusted risk ratio [aRR] = 1.02, 95% confidence interval [CI] = 0.85-1.22), relapse (aRR = 1.10, 95% CI = 0.85-1.42), or overall survival by Kaplan-Meier analysis (p = .44). High CD34+ dose was not associated with higher incidence of acute GVHD (aRR = 0.99 grades II-IV, aRR = 1.18 grades III-IV) or chronic GVHD (aRR = 0.87 overall, RR = 1.21 severe). There was limited correlation between CD34+ and T cell dose (R2 = .073), and there was no significant difference in survival, relapse, or GVHD in the highest T cell dose quintile (n = 33) compared to the remaining quintiles (n = 132). DISCUSSION: We found no difference in survival, relapse, or GVHD incidence or severity in patients receiving CD34+ doses above prior cutoffs reported in the literature. These data do not support the routine use of graft CD34+ dose reduction.

PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Yttrium-90 ibritumomab tiuxetan followed by rituximab maintenance as treatment for patients with diffuse large B-cell lymphoma are not candidates for autologous stem cell transplant.

BACKGROUND: Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. (90)Y ibritumomab tiuxetan ((90)Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. METHODS: This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with (90)Y-IT (0.4 or 0.3 mCi (90)Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. RESULTS: 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. CONCLUSION: The ORR of 36% with (90)Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.

Interleukin-2 and regulatory T cells in graft-versus-host disease.

BACKGROUND: Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. METHODS: In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. RESULTS: A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). CONCLUSIONS: Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).

Successful treatment of refractory Guillain-Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.

This is the case of a 79-year-old man with chronic lymphocytic leukemia who presented with Guillain-Barré syndrome with features overlapping with the Miller Fisher syndrome and Bickerstaff brainstem encephalitis and positive antiganglioside GQ1b antibody about 6 months after treatment with bendamustine and rituximab. His clinical and neurologic condition continued to deteriorate despite sequential treatment with corticosteroids, intravenous immunoglobulin and plasmapheresis, but in the end, he had a complete and durable response to treatment with alemtuzumab.

Lenalidomide enhances anti-myeloma cellular immunity.

Lenalidomide is an effective therapeutic agent for multiple myeloma that exhibits immunomodulatory properties including the activation of T and NK cells. The use of lenalidomide to reverse tumor-mediated immune suppression and amplify myeloma-specific immunity is currently being explored. In the present study, we examined the effect of lenalidomide on T-cell activation and its ability to amplify responses to a dendritic cell-based myeloma vaccine. We demonstrate that exposure to lenalidomide in the context of T-cell expansion with direct ligation of CD3/CD28 complex results in polarization toward a Th1 phenotype characterized by increased IFN-γ, but not IL-10 expression. In vitro exposure to lenalidomide resulted in decreased levels of regulatory T cells and a decrease in T-cell expression of the inhibitory marker, PD-1. Lenalidomide also enhanced T-cell proliferative responses to allogeneic DCs. Most significantly, lenalidomide treatment potentiated responses to the dendritic cell/myeloma fusion vaccine, which were characterized by increased production of inflammatory cytokines and increased cytotoxic lymphocyte-mediated lysis of autologous myeloma targets. These findings indicate that lenalidomide enhances the immunologic milieu in patients with myeloma by promoting T-cell proliferation and suppressing inhibitory factors, and thereby augmenting responses to a myeloma-specific tumor vaccine.

Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P < .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P < .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.

Prognostic value of minimal residual disease among patients with classical Hodgkin lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated.

Immune Reconstitution following High-Dose Chemotherapy and Autologous Stem Cell Transplantation with or without Pembrolizumab Maintenance Therapy in Patients with Lymphoma.

Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Whereas the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects that may contribute to its antitumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (ClinicalTrials.gov identifier NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. This study was conducted to characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Peripheral blood (PB) mononuclear cell samples were prospectively collected at 1 to 18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. A median of 5 (range, 1 to 8) post-ASCT PB samples were collected from 144 patients (59 in the pembrolizumab group and 85 in the control group). Clinical characteristics of the 2 cohorts were similar. Compared with cHL patients, DLBCL patients (all of whom received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution that persisted for at least 18 months after ASCT. No other differences in immune reconstitution based on lymphoma subtype were observed. Post-ASCT pembrolizumab maintenance therapy was associated with an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) that persisted for the duration of pembrolizumab treatment, along with a significant reduction in PD-1+ T cells that persisted for 6 to 12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ terminal effector memory cell count (defined as CD3+CD4+CD45RA+CD62L-) was associated with inferior progression-free survival (PFS), but only among patients who received pembrolizumab maintenance (P = .003). As continuous variables, lower absolute levels of NK cells (P = .009), PD-1+ CD4+ T cells (P = .005), and PD-1+ CD8+ T cells (P = .005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Our findings indicate that post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation of circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and the risk of irAE and warrant additional investigation. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Open notes sounds great, but will a provider's documentation change? An exploratory study of the effect of open notes on oncology documentation.

OBJECTIVE: The effects of shared clinical notes on patients, care partners, and clinicians ("open notes") were first studied as a demonstration project in 2010. Since then, multiple studies have shown clinicians agree shared progress notes are beneficial to patients, and patients and care partners report benefits from reading notes. To determine if implementing open notes at a hematology/oncology practice changed providers' documentation style, we assessed the length and readability of clinicians' notes before and after open notes implementation at an academic medical center in Boston, MA, USA. MATERIALS AND METHODS: We analyzed 143 888 notes from 60 hematology/oncology clinicians before and after the open notes debut at Beth Israel Deaconess Medical Center, from January 1, 2012 to September 1, 2016. We measured the providers' (medical doctor/nurse practitioner) documentation styles by analyzing character length, the number of addenda, note entry mode (dictated vs typed), and note readability. Measurements used 5 different readability formulas and were assessed on notes written before and after the introduction of open notes on November 25, 2013. RESULTS: After the introduction of open notes, the mean length of progress notes increased from 6174 characters to 6648 characters (P < .001), and the mean character length of the "assessment and plan" (A&P) increased from 1435 characters to 1597 characters (P < .001). The Average Grade Level Readability of progress notes decreased from 11.50 to 11.33, and overall readability improved by 0.17 (P = .01). There were no statistically significant changes in the length or readability of "Initial Notes" or Letters, inter-doctor communication, nor in the modality of the recording of any kind of note. CONCLUSIONS: After the implementation of open notes, progress notes and A&P sections became both longer and easier to read. This suggests clinician documenters may be responding to the perceived pressures of a transparent medical records environment.

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation.

Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Peripheral blood progenitor cell product contains Th1-biased noninvariant CD1d-reactive natural killer T cells: implications for posttransplant survival.

OBJECTIVE: Bone marrow (BM) Th1 populations can contribute to graft-vs-leukemia responses. Granulocyte/granulocyte macrophage colony-stimulating factor (CSF)-mobilized peripheral blood progenitor cells (PBPC) have become widely accepted alternatives to BM transplantation. T cells coexpressing natural killer cell proteins (NKT) include a CD1d-reactive subset that influences immunity by rapidly producing large amounts of Th1 and/or Th2 cytokines dependent upon microenvironment and disease. There are two types of CD1d-reactive NKT. iNKT express a semi-invariant T-cell receptor-alpha. Other noninvariant CD1d-reactive NKT from BM and liver produce large amounts of interleukin-4 or interferon-gamma, respectively, and within the intestine can be biased in either direction. Recent data suggests that NKT might contribute to clinical benefits of PBPC. MATERIALS AND METHODS: To address these issues, we phenotypically and functionally studied PBPC NKT. RESULTS: Similarly to BM, NKT-like cells were common in allogeneic and autologous PBPC, there were relatively few classical iNKT, but high CD1d-reactivity concentrated in NKT fractions. Significantly, PBPC CD1d-reactive cells were relatively Th1-biased and their presence was associated with better prognosis. Granulocyte CSF treatment of BM to yield PBPC in vivo as well as in vitro Th2-polarizes conventional T cells and iNKT. However, granulocyte CSF treatment of BM in vitro produced Th1-biased NKT, providing a mechanism for opposite polarization of NKT from BM vs PBPC. CONCLUSIONS: These results suggest distinct Th1 CD1d-reactive NKT cells could stimulate anti-tumor responses from those previously described, which can suppress graft-vs-host disease.

Significant and Distinctive n-Grams in Oncology Notes: A Text-Mining Method to Analyze the Effect of OpenNotes on Clinical Documentation.

PURPOSE: OpenNotes is a national movement established in 2010 that gives patients access to their visit notes through online patient portals, and its goal is to improve transparency and communication. To determine whether granting patients access to their medical notes will have a measurable effect on provider behavior, we developed novel methods to quantify changes in the length and frequency of use of n-grams (sets of words used in exact sequence) in the notes. METHODS: We analyzed 102,135 notes of 36 hematology/oncology clinicians before and after the OpenNotes debut at Beth Israel Deaconess Medical Center. We applied methods to quantify changes in the length and frequency of use of sequential co-occurrence of words (n-grams) in the unstructured content of the notes by unsupervised hierarchical clustering and proportional analysis of n-grams. RESULTS: The number of significant n-grams averaged over all providers did not change, but for individual providers, there were significant changes. That is, all significant observed changes were provider specific. We identified eight providers who were late note signers. This group significantly reduced its late signing behavior after OpenNotes implementation. CONCLUSION: Although the number of significant n-grams averaged over all providers did not change, our text-mining method detected major content changes in specific providers' documentation at the n-gram level. The method successfully identified a group of providers who decreased their late note signing behavior.

Reduced-Intensity Conditioning Regimens, Prior Chronic Lymphocytic Leukemia, and Graft-Versus-Host Disease Are Associated with Higher Rates of Skin Cancer after Allogeneic Hematopoietic Stem Cell Transplantation.

To assess incidence and risk factors for skin cancer associated with allogeneic hematopoietic stem cell transplantation, we evaluated 1,974 adult allogeneic hematopoietic stem cell transplantation patients from Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute who received transplants between January 1995 and July 2013 for hematologic malignancy and survived at least 100 days. Median age was 51.1 years, and median follow-up time was 3 years. Overall, 119 patients had 221 skin cancers. The incidences of squamous cell carcinomas (incidence rate ratio = 9.8; 95% confidence interval = 7.7-12.3), basal cell carcinomas (incidence rate ratio = 2.5; 95% confidence interval = 1.9-3.2), and melanoma (standardized incidence ratio = 3.3; 95% confidence interval = 1.7-5.9) were elevated in our cohort. In multivariable models, risk factors for squamous cell carcinomas were increased age (P < 0.0001), chronic lymphocytic leukemia (P = 0.02), and chronic graft-versus-host disease (P = 0.0002). Risk factors for basal cell carcinomas were chronic lymphocytic leukemia (P = 0.003), reduced-intensity conditioning (P = 0.02), acute graft-versus-host disease (P = 0.03), and chronic graft-versus-host disease (P = 0.003). To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma. This study also supports chronic graft-versus-host disease as a risk factor for nonmelanoma skin cancer, particularly squamous cell carcinoma.

Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia.

PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02135133.

A case of HIV-negative primary effusion lymphoma treated with bortezomib, pegylated liposomal doxorubicin, and rituximab.

Primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma that usually occurs in HIV-positive patients and has a very poor prognosis with limited treatment options. Prospective studies are lacking to define the standard of care for this disease, and various case series report median survival at 6 months with anthracycline-based chemotherapy. Reports of antiviral agents, immune modulators, and some targeted therapies are present in the literature with variable results. Herein, we report a case of an elderly HIV-negative man of Mediterranean origin who was diagnosed with primary effusion lymphoma and responded dramatically to 6 cycles of a combination of bortezomib, pegylated liposomal doxorubicin, and rituximab. He has since been maintained on rituximab and remains in complete remission 2 years after diagnosis. In this report, we discuss the rationale for using these agents in this patient and advocate the further study of bortezomib-based therapy in PEL.

Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom's macroglobulinemia: results of WMCTG Trial 03-248.

PURPOSE: Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM. EXPERIMENTAL DESIGN: In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m(2) on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease. RESULTS: Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P < 0.0001). The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of 1.4 months. The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months. The most common grade III/IV toxicities occurring in > or =5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy. CONCLUSIONS: The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.

False-positive axillary lymph node on FDG-PET/CT scan resulting from immunization.

An initial CT of a 59-year-old man with increasing back pain and weight loss showed lymphadenopathy in multiple nodal beds. A biopsy showed diffuse, large B-cell lymphoma (DLBCL). After initial chemotherapy, residual disease prompted an autologous stem cell transplant. After a follow-up FDG-PET/CT scan showed no FDG-avid disease, a subsequent study showed FDG uptake in a nonenlarged left axillary lymph node. Questioning elicited a recent immunization history. A follow-up PET/CT scan showed no uptake in this lymph node and no disease recurrence. Without this history, an unnecessary biopsy or treatment may have ensued. Methods to avoid such occurrences are discussed.