Summary Background Therapy-related myeloid neoplasms are secondary malignancies that are often fatal, but their risk factors are not well understood. Evidence suggests that individuals with clonal ...haemopoiesis have increased risk of developing haematological malignancies. We aimed to identify whether patients with cancer who have clonal haemopoiesis are at an increased risk of developing therapy-related myeloid neoplasms. Methods We did this retrospective case-control study to compare the prevalence of clonal haemopoiesis between patients treated for cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). All patients in both case and control groups were treated at MD Anderson Cancer Center (Houston, TX, USA) from 1997 to 2015. We used the institutional medical database to locate these patients. Patients were included as cases if they were treated for a primary cancer, subsequently developed therapy-related myeloid neoplasms, and had available paired samples of bone marrow from the time of therapy-related myeloid neoplasm diagnosis and peripheral blood from the time of primary cancer diagnosis. Patients were eligible for inclusion as age-matched controls if they were treated for lymphoma, received combination chemotherapy, and did not develop therapy-related myeloid neoplasms after at least 5 years of follow-up. We used molecular barcode sequencing of 32 genes on the pretreatment peripheral blood samples to detect clonal haemopoiesis. For cases, we also used targeted gene sequencing on bone marrow samples and investigated clonal evolution from clonal haemopoiesis to the development of therapy-related myeloid neoplasms. To further clarify the association between clonal haemopoiesis and therapy-related myeloid neoplasm development, we also analysed the prevalence of clonal haemopoiesis in an external cohort of patients with lymphoma who were treated in a randomised trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin. This trial was done at MD Anderson Cancer Center between 1999 and 2001 (protocol number 98-009). Findings We identified 14 cases and 54 controls. Of the 14 cases, we detected clonal haemopoiesis in the peripheral blood samples of ten (71%) patients. We detected clonal haemopoiesis in 17 (31%) of the 54 controls. The cumulative incidence of therapy-related myeloid neoplasms in both cases and controls at 5 years was significantly higher in patients with clonal haemopoiesis (30%, 95% CI 16–51) than in those without (7%, 2–21; p=0·016). In the external cohort, five (7%) of 74 patients developed therapy-related myeloid neoplasms, of whom four (80%) had clonal haemopoiesis; 11 (16%) of 69 patients who did not develop therapy-related myeloid neoplasms had clonal haemopoiesis. In the external cohort, the cumulative incidence of therapy-related myeloid neoplasms at 10 years was significantly higher in patients with clonal haemopoiesis (29%, 95% CI 8–53) than in those without (0%, 0–0; p=0·0009). In a multivariate Fine and Gray model based on the external cohort, the presence of clonal haemopoiesis significantly increased the risk of therapy-related myeloid neoplasm development (hazard ratio 13·7, 95% CI 1·7–108·7; p=0·013). Interpretation Preleukaemic clonal haemopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal haemopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms. A prospective trial to validate this concept is warranted. Funding Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, NIH through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program.
Summary Background The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this ...patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov , number NCT00358982. Findings 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients 17% in the 110 mg group, three 11% in the 85 mg group); fatigue (five patients 22% in the 110 mg group, three 11% in the 85 mg group); and pneumonia (four patients 17% in the 110 mg group, two 7% in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
Summary Background The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated ...dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. Methods Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1–21 of each 28-day cycle. 375 mg/m2 intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00294632. Findings 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3–4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached NR). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. Interpretation Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. Funding Celgene.
Abstract Purpose The population of patients aged 80 years or older who are diagnosed with diffuse large B-cell lymphoma (DLBCL) continues to increase, but an optimal treatment strategy has not been ...established. We sought to examine the influence of consolidative radiation therapy (RT) on outcome and toxicity among the very elderly diagnosed with stage I-IV DLBCL. Methods and materials We evaluated 131 patients treated at a single institution between 2002 and 2014 who were eligible for RT after successful treatment with chemotherapy. Results The median age was 83 years (range, 80-96). Advanced-stage disease was present in 61.8% of patients. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was administered to 80% of patients (n = 108), and 23.7% of patients received consolidative RT. Among early-stage (ES) patients treated with 3 to 4 cycles of chemotherapy and RT (n = 12) versus 6 to 8 cycles of chemotherapy alone (n = 17), there were no statistically significant differences in 3-year disease-free, progression-free, or overall survival rates. The 3 year disease-free survival was 91.7% versus 88.2% among patients treated with combined modality therapy versus chemotherapy alone ( P = .78). The 3-year overall survival was 82.5% versus 87.5% among patients treated with combined modality therapy compared with chemotherapy alone ( P = .852). Anemia and neuropathy occurred more frequently among ES patients who received 6 to 8 cycles of chemotherapy alone. Among advanced-stage patients with bulky disease (n = 35), consolidative RT to sites of bulky disease may have improved local control (3-year local control, 100% vs 60.3%, P = .160). Conclusions Among patients aged 80 years or older who have with ES DLBCL, 3 to 4 cycles of chemotherapy followed by RT is at least equivalent in efficacy to chemotherapy alone and is associated with lower levels of toxicity, which suggests that it may be a better choice for therapy when trying to balance treatment efficacy and tolerability.
Abstract Background For patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL), whole-brain radiation therapy (WBRT) to doses of ≥45 Gy are often given after a ...partial response (PR) to methotrexate-based induction chemotherapy. We conducted an exploratory analysis to determine whether lower-dose WBRT, given with a boost to sites of persistent disease, might be a reasonable alternative. Methods and materials We retrospectively reviewed the records of 22 patients with PCNSL who received WBRT, with or without a boost, after methotrexate-based induction chemotherapy. Outcomes were compared among patients according to response to chemotherapy using the Kaplan-Meier method. Results Median follow-up was 52 months. All patients with a complete response (CR) (n = 5) received WBRT to 23.4 Gy. One CR patient died after an in-field relapse. Patients with partial response (PR) (n = 10) received a median whole-brain dose of 23.4 Gy with (n = 8) or without (n = 2) a boost; there were 2 relapses within the central nervous system (CNS). All PR patients were alive at the time of analysis. The overall survival ( P = .127) and freedom from relapse within the CNS ( P = .967) were not different for patients with CR versus PR. Baseline and follow-up neurocognitive evaluations were available for 4 PR patients, and there were no significant differences between pre- and post-treatment evaluations ( P > .05 for language, memory, visual-spatial, attention, or motor functions). All patients who progressed or did not respond to chemotherapy and then received WBRT had died at a median time of 3.4 months. Patients who progressed or did not respond to chemotherapy had worse overall survival ( P = .001) and freedom from CNS relapse ( P = .005) compared with CR patients. Conclusions Among patients with a PR to induction chemotherapy, reduced-dose WBRT with a boost to residual PCNSL may be a viable treatment approach that merits further investigation.
Summary Background Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. ...These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. Methods We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00904722. Findings We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). Interpretation The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. Funding National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
•Hemophagocytic lymphohistiocytosis (HLH)-like toxicities occur after CAR T-cells•This is now termed immune effector cell (IEC) associated HLH-like syndrome (IEC-HS)•Independent of cytokine release ...syndrome (CRS) and neurotoxicity, IEC-HS can be fatal•Consensus for identification and grading of IEC-HS has been developed by experts•Treatment, supportive care, and future research are imperative to improving outcomes of IEC-HS
T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term “immune effector cell-associated HLH-like syndrome (IEC-HS)” to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.
To identify predictors of hypothyroidism after chemoradiation therapy for Hodgkin lymphoma (HL) and to compare outcomes after intensity modulated radiation therapy (IMRT) with those after ...3-dimensional (3D) conformal radiation therapy (CRT).
Ninety patients who underwent involved-site IMRT in 2009 through 2014 were evaluated for treatment-induced hypothyroidism, defined as elevated thyroid-stimulating hormone or decreased free thyroxine levels (or both). Receiver operating characteristic curve analysis identified individuals at low versus high risk based on dosimetric variables. Dosimetric cutoff points were verified with an external data set of 50 patients who underwent 3D-CRT.
In the IMRT group, most patients (75 83%) had stage II HL, and the median prescribed dose was 30.6 Gy; in the 3D-CRT group, 32 patients (64%) had stage II HL, and the median prescribed dose was 32.0 Gy. No differences were found in the proportions of patients with bilateral (P = .982) or unilateral (P = .074) neck involvement between the 2 groups. Hypothyroidism rates were marginally higher in the IMRT group, with estimated 3-year rates of freedom from hypothyroidism of 56.1% in the 3D-CRT group and 40% in the IMRT group (P = .057). Univariate analysis showed that smaller thyroid volume and higher thyroid dose were associated with hypothyroidism in both groups (P < .05). In the IMRT group, the percentage of the thyroid gland volume receiving ≥25 Gy (V25) and the absolute volume of the thyroid gland spared from 25 Gy (VS25Gy) were the strongest predictors of hypothyroidism (P = .001 and P < .001, respectively). Cutoff points of 63.5% (V25) and 2.2 mL (VS25Gy) classified patients as high risk (80%-82%) or low risk (37%-44%) (P < .001). Use of a thyroid avoidance structure reduced the incidence of hypothyroidism (P < .05) in the IMRT group.
The percentage of the thyroid receiving 25 Gy and the volume of the thyroid spared from 25 Gy predicted the risk of hypothyroidism after either IMRT or 3D-CRT for HL. IMRT may confer a higher risk than 3D-CRT unless a treatment avoidance structure is used during planning.
We assessed the efficacy of radiation therapy (RT) in the management of secondary central nervous system (CNS) lymphoma.
The cohort comprised 44 patients with systemic diffuse large B-cell lymphoma ...(DLBCL) secondarily involving the brain and/or leptomeninges at initial diagnosis or relapse that was treated with RT.
Of these patients, 29 (66%) were in systemic remission when CNS disease was diagnosed. The overall response rate to RT by magnetic resonance imaging was 88% (42% complete, 46% partial). The median overall survival (OS) after RT initiation was 7 months (95% confidence interval 4-10 months). The OS curve plateaued at 31% from 2 to 8 years. OS was superior in patients who achieved a complete or partial response to RT, underwent stem cell transplantation after RT, and had brain parenchymal (vs leptomeningeal) disease. Eight cases of CNS disease progression occurred after RT: 1 involved the brain parenchyma, and 7 involved the spine and/or cerebrospinal fluid and/or meninges.
We conclude that RT is associated with high response rates and may contribute to long-term OS. In addition, RT may provide CNS disease control that facilitates successful salvage with stem cell transplantation in patients with chemotherapy-refractory disease.
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