Impaired humoral and cellular response to primary COVID-19 vaccination in patients less than 2 years after allogeneic bone marrow transplant.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.

Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome.

Despite the development of highly effective, targeted inhibitors of B-cell proliferation and anti-apoptotic pathways in chronic lymphocytic leukemia (CLL), these treatments are not curative, and many patients will develop either intolerance or resistance to these treatments. Transformation of CLL to high-grade lymphoma-the so-called Richter syndrome (RS)-remains a highly chemoimmunotherapy-resistant disease, with the transformation occurring following targeted inhibitors for CLL treatment being particularly adverse. In light of this, cellular therapy in the form of allogenic stem cell transplantation and chimeric antigen receptor T-cell therapy continues to be explored in these entities. We reviewed the current literature assessing these treatment modalities in both high-risk CLL and RS. We also discussed their current limitations and place in treatment algorithms.

Myeloid Toxicity of Radionuclide Cancer Therapy.

Emergent genomic analytic techniques in patients with cancer offer the potential to define the risk of myelo dysplastic syndrome (MDS) and acute leukemia (AL) manifesting following targeted radionuclide therapy of metastatic lymphoma, neuroendocrine tumors (NETs), and prostate cancer. Characterization of the genetic profile will allow risk stratification of patients before theranostic radionuclide management of advanced cancers and offers the opportunity to minimize toxicity while preserving optimal individualized efficacy in the practice of personalized precision nuclear oncology. Our review of a single-center experience of prospective radionuclide theranostic management of metastatic non-Hodgkin lymphoma (NHL), NETs, and castration-resistant prostate cancer (metastatic castrate-resistant prostate cancer [mCRPC]) over the past decade, and comparison with published studies, shows that while the risk of significant myelotoxicity is generally low, at <3%, the consequences in the small minority of patients who develop MDS or AL are substantial, and survival is poor. Timely identification of patients at heightened risk of hematologic toxic complication, using novel genomic technology before institution of radionuclide therapy, will facilitate amelioration of myelotoxicity. In current clinical practice, the minimal hematological toxicity of chemo-free theranostic management of advanced cancer is significantly less compared with newly adopted chemotherapy -immunotherapy regimens, and the financial toxicity associated with these novel agents is avoided.

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

BACKGROUND: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. METHODS: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. RESULTS: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response. CONCLUSIONS: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

Long-term hematologic toxicity of 177Lu-octreotate-capecitabine-temozolomide therapy of GEPNET.

Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with four cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥ 3 hematologic toxicity was analyzed. At a median follow-up of 7-years (range 1-10), six (16%) patients developed persistent hematologic toxicity (PHT) (defined as sustained grade ≥ 3 hematologic toxicity beyond 36-months follow-up) and three (8%) developed MDS/AL with a median time-to-event of 46 and 34 months, respectively. The estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45-24.01). Development of PHT was the only significant risk factor for secondary MDS/AL (RR, 16; 95% CI: 2.53 to 99.55; P < 0.001). The median PFS was 48 months (95% CI: 40.80-55.20), and the median OS was 86 months (95% CI: 56.90-115.13). Twenty-one deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL > 10% mandates the long-term monitoring of treated patients. However, time to onset is unpredictable, and incidence does not correlate with conventional baseline risk factors. Novel methods are required for the stratification of prospective patients based on genetic risk.

Efficacy and Haematologic Toxicity of Palliative Radioligand Therapy of Metastatic Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen in Heavily Pre-Treated Patients.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant contributor to the global cancer burden. lutetium-177-prostate-specific membrane antigen radioligand therapy (177Lu-PSMA RLT) is an effective salvage treatment. However, studies have highlighted haematologic toxicity as an adverse event of concern. We report our single-centre experience of compassionate access palliative 177Lu-DOTAGA-(I-y)fk(Sub-KuE) (177Lu-PSMA I&T) with respect to efficacy and haematologic safety. METHODS: Patients with mCRPC and adequate bone marrow/liver function were included. All patients included underwent baseline and response assessment by Gallium-68-PSMA-11 positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT). Prescribed activity of therapy was a median 6.24 GBq per patient per cycle (IQR1.29 GBq), administered in 8-week intervals, up to four cycles. Response was assessed by prostate specific antigen (PSA) and a week-12 PET/CT. Incidence of grade ≥ 3 haematologic toxicity, including association with risk factors (age ≥ 70 years, prior/concurrent therapy, presence of metastases, and number of cycles completed), was analysed. RESULTS: One hundred patients completed one cycle of 177Lu PSMA I&T and underwent response assessment by both PSA and PET/CT. Two patients had an uninterpretable week-12 PET/CT. Median age was 70 (50-89), median number of prior therapies was three (1-6), and median follow up was 12-months. Fifty-four percent achieved a PSA response. Disease control rate (DCR) by PET/CT was 64% (29% SD, 34% PR, and 1% CR). Disease control by PET/CT was associated with an improved one-year overall survival (OS) compared to non-responders, median OS not-reached vs 10-months (p < 0.0001; 95% CI: 0.08-0.44). Regarding haematologic toxicity, 11% experienced a grade ≥ 3 cytopenia (self-limiting). No cases of myelodysplasia/acute leukaemia (MDS/AL) have been recorded. No association with risk factors was demonstrated. CONCLUSION: 177Lu-PSMA I&T is a safe and effective palliative outpatient treatment for mCRPC. 68Ga-PSMA-11 PET/CT response is associated with an improved one-year OS and may be used to adapt therapy.

Front-Line Treatment of High Grade B Cell Non-Hodgkin Lymphoma.

PURPOSE OF REVIEW: Rituximab-based chemoimmunotherapy has resulted in a marked improvement in the survival of diffuse large B cell lymphoma (DLBCL). We reflect upon the history front-line (1L) therapy and highlight advances in management. RECENT FINDINGS: Since the introduction of R-CHOP, the majority of randomized studies in the front-line treatment of DLBCL have failed to show a benefit. Such studies have involved treatment intensification, adding novel agents to the R-CHOP backbone and targeting such novel agents to biologically defined subgroups. R-CHOP therefore remains standard-of-care for most but new insights into the molecular biology of these diseases, and the development of active targeted molecules offers promise for the future. Accumulating evidence in the very elderly suggests dose attenuation does not compromise survival. Intensification in primary mediastinal B cell lymphoma may avoid the need for radiotherapy, but must be balanced against the risks. PET-CT- and ctDNA-based response assessment may now enable response adapted therapy and early prognostication, improving patient selection and potentially outcomes. Novel technologies and therapies in combination with novel molecular diagnostics will likely become the standard-of-care approach for the personalized therapy of DLBCL but need to be proven in well-designed and conducted randomized trials.

Salvage Radiopeptide Therapy of Advanced Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen: Efficacy and Safety in Routine Practice.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-based radiopeptide/radioligand therapy represents a rapidly expanding field in the management of metastatic castrate-resistant prostate cancer (mCRPC). However, there remains concern for the development of significant toxicities in heavily pretreated patients. In this study, the authors present their local experience, with respect to efficacy and toxicity, of 22 consecutive patients treated with lutetium-177-DOTAGA-(I-y)fk(Sub-KuE) or 177Lu-PSMA I&T radioimmunotherapy for progressive mCRPC, followed up over 1 year. MATERIALS AND METHODS: All patients had progressive mCRPC, an European Cooperative Oncology Group (ECOG) ≤2 with adequate bone marrow and liver function. 177Lu-PSMA I&T therapy was administered at 8-week intervals with a mean prescribed activity of 5.5 GBq (gigabecquerel) per patient. RESULTS: Twenty patients had evaluable results, median age of 71 years, and median duration of follow-up of 17 months. Three patients (15%) experienced a G1/2 myelotoxicity and four (20%) G3/4. No incidences of myelodysplasia/acute leukemia have been identified. All toxicities were self-limiting. Baseline cytopenia was predictive of the development of subsequent G3/4 myelotoxicity (p = 0.0035). Eight patients (40%) experienced an objective PSA response, with a median time to response of 15 weeks. The median time to PSA progression was not reached. Patients receiving three cycles of therapy were statistically more likely to experience a disease response when compared to those treated with one, two, or four cycles (p < 0.0001). CONCLUSIONS: 177Lu-PSMA I&T radioimmunotherapy of progressive mCRPC is safe and effective with three cycles being the potential optimal number for determining long-term disease response.

Imaging of Early Response to Predict Prognosis in the First-Line Management of Follicular Non-Hodgkin Lymphoma with Iodine-131-Rituximab Radioimmunotherapy.

The purpose of this study was to evaluate prediction of prognosis after first-line radioimmunotherapy (RIT) of advanced follicular non-Hodgkin lymphoma (FL), by imaging with fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG-PET/CT) three months after induction treatment by Iodine-131-rituximab (131I-rituximab). Objective response was determined using the Deauville 5-point scale in 68 prospective clinical trial patients. Baseline 18F-FDG-PET/CT studies were used to calculate total-metabolic-tumor-volume (TMTV). Non-imaging studies included the Follicular lymphoma international prognostic index (FLIPI) and absolute baseline monocyte and lymphocyte counts. Patients were monitored for over ten years (median follow-up 59 months), and no patient was lost to follow-up. Complete response (CR) of 88% predicted excellent prognosis with median time-to-next-treatment (TTNT) not yet reached. Those patients (12%) who failed to achieve CR (Deauville ≤ 3) on 18F-FDG-PET/CT at three months had significantly poorer outcomes (p < 0.0001) with a median TTNT of 41 months. Requirement for re-treatment was predicted by FLIPI and absolute baseline monocyte count but not lymphocyte count. The TTNT was accurately predicted by 18F-FDG-PET/CT Deauville response at three months following first-line therapy of FL with RIT. Early response demonstrated by imaging does, therefore, foretell prognosis in the individual FL patients.

Myelotoxicity of Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Decade of Experience.

AIM: This review of the literature, and the authors' own decade of experience with lutetium-177-octreotate-capecitabine±temozolomide peptide receptor radionuclide therapy (PRRT)-chemotherapy of GEPNETs, analyses the risk of both short- and long-term hematotoxicity. BACKGROUND: Myelodysplastic syndrome (MDS) and acute leukemia (AL) have been associated with PRRT in heavily pretreated patients with a history of exposure to alkylating agents. Commenced 15 years ago, PRRT is now becoming established as first- and second-line therapy for gastroentero pancreatic neuroendocrine tumors (GEPNETs), and early treatment minimizes myelotoxicity, which is the most significant potential adverse event following PRRT. RESULTS: Sixteen key articles involving primary research were identified. A total of 2225 patients were treated (2104 treated with PRRT monotherapy and 121 with PRRT combined with chemotherapy). The average age of patients in these studies ranged from 53 to 64 years with median duration of follow-up ranging from 6 to 62 months. Short-term myelotoxicity was observed in 221 patients (10%), occurring in 213 of 2104 patients treated with PRRT monotherapy and 8 of 121 patients treated with PRRT combined with chemotherapy. Acute toxicity manifested as modest self-limited grade 3/4 toxicity (CTCAE or WHO), most often affecting platelets during the first cycle of treatment. Toxicity manifesting early was easily managed with dose modification or therapy cessation and was ameliorated by appropriate patient selection. MDS/AL was a rare stochastic event occurring in 32 (1.4%) patients. Where bone marrow biopsy was performed, cases of MDS displayed cytogenetic abnormalities, consistent with secondary MDS. Factors associated with myelotoxicity included age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior chemotherapy (alkylating agents), and prior radiotherapy. CONCLUSION: Early therapy with PRRT-containing regimens improves outcomes, minimizes myelotoxicity, and renders the risk of MDS and AL negligible.

Hematological toxicity of combined 177Lu-octreotate radiopeptide chemotherapy of gastroenteropancreatic neuroendocrine tumors in long-term follow-up.

BACKGROUND: The combination of radiopeptide therapy [peptide receptor radionuclide therapy (PRRT)] with radiosensitizing chemotherapy of gastroenteropancreatic neuroendocrine tumors (GEP NETs) may improve efficacy, but has the potential to increase myelotoxicity. In a prospective clinical study of GEP NET patients treated with (177)Lu-octreotate PRRT in combination with capecitabine and temozolomide, as a prelude to a planned Australasian Gastro-Intestinal Trials Group (AGITG) international randomized controlled trial, we characterized the incidence and degree of hematological toxicity. MATERIALS AND METHODS: Well-differentiated progressive metastatic GEP NETs in 65 patients were treated with 4 cycles of 7.8 GBq (177)Lu-octreotate, 1,650 mg/m(2) capecitabine (n = 28) and 1,500 mg/m(2) capecitabine with 200 mg/m(2) temozolomide (n = 37), and monitored for hematological toxicity over a 5-year period. RESULTS: Short-term, self-limited hematological toxicity grade 3/4 comprised anemia in 1 patient (3.5%) in the 28 patient-cohort of patients treated with (177)Lu-octreotate and capecitabine. One of these patients (3.5%) later developed significant anemia and one developed thrombocytopenia (3.5%) over a median follow-up of 60 months (SD 20). The incidence of short-term grade 3/4 reversible myelosuppression in 37 patients after (177)Lu-octreotate/capecitabine/temozolomide was zero. Long- term follow-up for a median of 36 months (SD 11) showed significant thrombocytopenia in 2.7% and neutropenia in 2.7% of the patients and anemia in 10.8% of the patients (n = 4). The 3-year median hemoglobin and platelet and neutrophil counts trended downwards, but remained within normal ranges. Two patients in this cohort developed myelodysplastic syndrome. CONCLUSION: The modest reversible hematological toxicity of PRRT of GEP NETs is not significantly increased by the addition of radiosensitizing chemotherapy with capecitabine and temozolomide in combination with (177)Lu-octreotate, which has the potential to enhance the efficacy of radiopeptide therapy.