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The coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in increased morbidity and mortality in patients with impaired immunity, hematologic malignancies, and immunosuppressive regimens. COVID-19 can cause a cytokine storm with some patients benefiting from blockade of the pro-inflammatory cytokine, interleukin 6 (IL6). As Castleman disease (CD) is an atypical lymphoproliferative disorder that can involve a cytokine storm and often requires immunosuppressive therapies, including IL6 inhibition, we sought to evaluate outcomes following COVID-19 and SARS-CoV-2 vaccination in CD patients. We administered a survey in April 2021 to characterize experiences with COVID-19 and SARS-CoV-2 vaccination among 300 CD patients enrolled in ACCELERATE, a natural history registry of CD patients. Among 128 respondents, the prevalence of SARS-CoV-2 infection (16/95, 17%), severe disease (1/16, 6%), vaccination rates (112/128, 88%), and vaccine adverse effects after dose one (62/112, 55%) were comparable to the general U.S. population. While there were two cases of CD flares occurring shortly after SARS-CoV-2 infection (N=1) and vaccination (N=1), over 100 patients in this study that were infected and/or vaccinated did not experience CD flares. The median anti-spike titer six months after the second dose among CD patients was comparable to individuals with other immune-related diseases and healthy populations. Data from this small cohort suggest that, despite being on immunosuppressive therapies, CD patients do not appear to be at increased risk of poor COVID-19 outcomes and can mount a humoral response to SARS-CoV-2 vaccination. This study was registered on clinicaltrials.gov (#NCT02817997).
ABSTRACT
PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .
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Not available.
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ABSTRACT: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score-matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score-matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Cyclophosphamide , Doxorubicin , Ifosfamide , Lymphoma, Large B-Cell, Diffuse , Prednisone , Rituximab , Vincristine , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Ifosfamide/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Prednisone/therapeutic use , Prognosis , Rituximab/therapeutic use , Treatment Outcome , Vincristine/therapeutic use , Case-Control StudiesABSTRACT
PURPOSE: To evaluate factors affecting the diagnostic yield (percent of biopsy samples leading to a pathologic diagnosis) of lesional bone biopsies in patients with hematologic malignancies. MATERIALS AND METHODS: This retrospective study included 206 lesional bone biopsies in 182 patients with a hematologic malignancy between January 2017 and December 2022. The parameters that were reviewed to evaluate diagnostic yield included biopsy device type (manual vs. electric-powered drill), number of biopsy cores acquired, core biopsy needle gauge, preliminary intra-procedural sample adequacy (touch preparation cytology determining if samples are adequate for final pathologic examination), lesion morphology on Computed Tomography (CT), and presence of crush artifact. RESULTS: Review of 206 lesional biopsies showed overall diagnostic yield to be 89.8% (185/206). The two statistically significant factors affecting diagnostic yield were biopsy device type and in-room adequacy. 41/42 samples obtained with the electric-powered drill and 144/164 samples obtained using a variety of manual needles were diagnostic (97.6% vs 87.8%, p = 0.03). Of the 192 samples that were assessed for sample adequacy intra-procedurally, 97/102 of the samples that were deemed adequate were diagnostic, and 77/90 of the samples where intra-procedural adequacy was not confirmed were diagnostic (95.1% vs 85.6%, p = 0.018). The remaining factors did not affect diagnostic yield. CONCLUSION: The use of an electric-powered drill bone biopsy device and intra-procedural confirmation of sample adequacy are associated with a higher diagnostic yield of lesional bone biopsies in patients with hematologic malignancies. The presence or absence of crush artifact did not significantly affect the diagnostic yield in these patients.
Subject(s)
Bone Diseases , Hematologic Neoplasms , Humans , Retrospective Studies , Bone and Bones/pathology , Biopsy, Fine-Needle , Image-Guided Biopsy/methodsABSTRACT
Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Positron Emission Tomography Computed Tomography , Humans , Positron Emission Tomography Computed Tomography/methods , Prognosis , Fluorodeoxyglucose F18/therapeutic use , Positron-Emission Tomography , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/therapy , Retrospective StudiesABSTRACT
BACKGROUND: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. METHODS: We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per µL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. FINDINGS: Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. INTERPRETATION: Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. FUNDING: National Institutes of Health and National Cancer Institute.
Subject(s)
HIV Infections , Hodgkin Disease , Humans , Hodgkin Disease/pathology , Brentuximab Vedotin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Doxorubicin/therapeutic use , HIV Infections/complications , HIV Infections/drug therapyABSTRACT
AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for pre-exposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or realworld experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 high-risk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher firsttime dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.
Subject(s)
COVID-19 , Hematologic Neoplasms , Pre-Exposure Prophylaxis , Humans , COVID-19/prevention & control , SARS-CoV-2 , Breakthrough Infections , Retrospective Studies , Antibodies, Monoclonal , Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapySubject(s)
Hematologic Neoplasms , Leukemia , Lymphoma , Humans , Hematologic Neoplasms/drug therapyABSTRACT
Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin B-cell lymphoma that has historically been difficult to define, though is now formally recognized by the World Health Organization Classification. To better characterize the clinical outcomes of patients with NMZL, we reviewed a sequential cohort of 187 patients with NMZL to describe baseline characteristics, survival outcomes, and time-to-event data. Initial management strategies were classified into five categories: observation, radiation, anti-CD20 monoclonal antibody therapy, chemoimmunotherapy, or other. Baseline Follicular Lymphoma International Prognostic Index scores were calculated to evaluate prognosis. A total of 187 patients were analyzed. The five-year overall survival was 91% (95% confidence interval [CI], 87-95), with a median follow-up time of 71 months (range, 8-253) among survivors. A total of 139 patients received active treatment at any point, with a median follow-up time of 56 months (range, 13-253) among survivors who were never treated. The probability of remaining untreated at five years was 25% (95% CI, 19-33). For those initially observed, the median time to active treatment was 72 months (95% CI, 49-not reached). For those who received at least one active treatment, the cumulative incidence of receiving a second active treatment at 60 months was 37%. Transformation to large B-cell lymphoma was rare, with a cumulative incidence of 15% at 10 years. In summary, our series is a large cohort of uniformly diagnosed NMZL with detailed analyses of survival and time to event analyses. We showed that NMZL commonly presents as an indolent lymphoma for which initial observation is often a reasonable strategy.
Subject(s)
Antineoplastic Agents , Lymphoma, B-Cell, Marginal Zone , Humans , Retrospective Studies , Lymphoma, B-Cell, Marginal Zone/therapy , Lymphoma, B-Cell, Marginal Zone/drug therapy , Prognosis , Antineoplastic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic useABSTRACT
Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months for PTCL with a TP53 mutation (n = 21) vs 10.5 months for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.
Subject(s)
Lymphoma, T-Cell, Peripheral , Humans , Lymphoma, T-Cell, Peripheral/drug therapy , Lymphoma, T-Cell, Peripheral/genetics , Prognosis , Retrospective Studies , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/adverse effects , MutationABSTRACT
Recent prospective clinical trial data suggest that patients with Hodgkin's lymphoma who continue treatment with ABVD, despite failing to attain a complete metabolic response on interim PET (PET2+), may fare better than previously published. We describe the outcomes of PET2+ patients who continued ABVD and compare the performance of a quantitative measure based on the lesion-to-liver SUV ratio (LLS qPET2+) to that of the subjective Deauville criteria (dvPET2+). We analyzed all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at the Memorial Sloan Kettering Cancer Center between 2008 and 2017. Eligibility was set to correspond with the RATHL inclusion criteria. Images were reviewed by two nuclear medicine physicians and discordant cases were resolved with a third expert in consensus. qPET2+ was defined as LLS ≥ 1.3. We identified 227 patients of whom 25% (57) were qPET2+, but only 14% (31) were dvPET2+. Forty-eight patients (84%) continued ABVD with a 3-year PFS of 70% for qPET2+ and 64% for dvPET2+. In conclusion, interim PET interpretation in clinical practice may be associated with a higher rate of scans deemed positive. Irrespective of the criteria for PET2 positivity, a subset of patients may continue ABVD without a dismal outcome.
Subject(s)
Lymphoma, Non-Hodgkin , Neoplasm Recurrence, Local , Humans , CREB-Binding Protein/genetics , E1A-Associated p300 Protein/genetics , Epigenesis, Genetic , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/genetics , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/geneticsABSTRACT
Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.
Subject(s)
Burkitt Lymphoma , Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Child , Humans , Adult , Burkitt Lymphoma/pathology , Herpesvirus 4, Human , Lymphoma, Large B-Cell, Diffuse/pathology , MutationABSTRACT
There is limited understanding of the extent to which mucosa-associated lymphoid tissue (MALT) lymphoma affects a patient's risk of death and how classically considered prognostic factors affect lymphoma-specific vs other noncancer mortality. This study analyzed major long-term outcomes of patients with MALT lymphoma and the prognostic significance of baseline clinical features. We reviewed the clinical features, treatments, disease course, and survival of 593 patients with MALT lymphoma diagnosed at Memorial Sloan Kettering between 2000 to 2012. Outcomes were analyzed using crude overall survival (OS) and relative survival (RS) by standardized mortality ratio. The median age was 60 years, 72% were at stage I/II. With a median follow-up of 9.2 years, the 10-year OS, lymphoma-specific mortality, and competing nonlymphoma mortality was 75%, 4%, and 21%, respectively; the overall standardized mortality ratio was 1.41 (95% confidence interval, 1.19-1.67; P < .001). Using multivariate analysis, older age, advanced stage, and poor performance status were independently associated with inferior OS. Several subgroups had similar RS to the normal matched population, including those with an age of ≥70 years, stage I, and skin or gastric origin. Increased lymphoma-specific death was associated with spread disease, whereas death from nonlymphoma causes was correlated with older age. Overall, a diagnosis of MALT lymphoma was associated with moderately compromised survival. Age and advanced-stage disease emerged as the most important prognostic factors. Younger patients had better OS but worse RS. Disease dissemination was the lymphoma-specific risk factor.
Subject(s)
Lymphoma, B-Cell, Marginal Zone , Humans , Middle Aged , Aged , Retrospective Studies , Lymphoma, B-Cell, Marginal Zone/pathology , Case-Control Studies , Prognosis , Disease ProgressionABSTRACT
In this retrospective study, 232 spleen biopsies from 218 patients with cancer were assessed. Biopsies resulting in hemorrhage requiring hospitalization, transfusion, or other interventions were compared with those that did not. The maximization of the Youden index helped determine the optimal systolic blood pressure (SBP) and platelet count thresholds. There were 15 (7%) major hemorrhages among 211 core biopsies. A multivariate logistic regression model showed that higher SBP, lower platelet count, and the lack of ultrasound guidance were independently associated with major hemorrhage (P < .05). The optimal SBP cutoff was 140 mm Hg, and the platelet count cutoff was 120,000 platelets/µL. In conclusion, the high major hemorrhage rate of 7% among percutaneous core spleen biopsies in patients with cancer may be mitigated by controlling SBP to <140 mm Hg and avoiding biopsy in patients with thrombocytopenia.