Interim PET-CT-guided therapy in elderly patients with Hodgkin lymphoma-a retrospective national multi-center study.

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1-3 while 17% had scores of 4-5. Patients with iPET scores of 1-3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4-5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome.

Outcome and prognostic factors in patients with mantle-cell lymphoma relapsing after autologous stem-cell transplantation: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT).

BACKGROUND: Autologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting. PATIENTS AND METHODS: Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients. RESULTS: Median overall survival (OS) after relapse of the whole study group was 19 months. A long (>12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis. Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation. CONCLUSIONS: MCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.

Novel agents for the treatment of lymphomas during pregnancy: A comprehensive literature review.

Lymphoproliferative diseases occurring during pregnancy present unique diagnostic and therapeutic challenges aiming to achieve maternal cure without impairing fetal health, growth, and survival. These goals are further complicated by the fast-paced emergence of novel therapies and their introduction as standard of care, even in newly diagnosed patients. Due to the rarity of hematological malignancies in pregnancy and the exclusion of pregnancy in almost all clinical trials, available data on the fetal effects of novel drugs are limited to animal models and case reports. The current review addresses the entire multidisciplinary team involved in treating pregnant patients with lymphoproliferative diseases. We describe novel agents according to their mechanism of action, and summarize our knowledge of their effects during the gestational period, particularly those associated with fetotoxicity. Therapeutic dilemmas associated with the employment of these new agents are also discussed.

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma.

Patients diagnosed with B-cell non-Hodgkin lymphoma (B-NHL), particularly if recently treated with anti-CD20 antibodies, are at risk of severe COVID-19 disease. Because studies evaluating humoral response to COVID-19 vaccine in these patients are lacking, recommendations regarding vaccination strategy remain unclear. The humoral immune response to BNT162b2 messenger RNA (mRNA) COVID-19 vaccine was evaluated in patients with B-NHL who received 2 vaccine doses 21 days apart and compared with the response in healthy controls. Antibody titer, measured by the Elecsys Anti-SARS-CoV-2S assay, was evaluated 2 to 3 weeks after the second vaccine dose. Patients with B-NHL (n = 149), aggressive B-NHL (a-B-NHL; 47%), or indolent B-NHL (i-B-NHL; 53%) were evaluated. Twenty-eight (19%) were treatment naïve, 37% were actively treated with a rituximab/obinutuzumab (R/Obi)-based induction regimen or R/Obi maintenance, and 44% had last been treated with R/Obi >6 months before vaccination. A seropositive response was achieved in 89%, 7.3%, and 66.7%, respectively, with response rates of 49% in patients with B-NHL vs 98.5% in 65 healthy controls (P < .001). Multivariate analysis revealed that longer time since exposure to R/Obi and absolute lymphocyte count ≥0.9 × 103/µL predicted a positive serological response. Median time to achieve positive serology among anti-CD20 antibody-treated patients was longer in i-B-NHL vs a-B-NHL. The humoral response to BNT162b2 mRNA COVID-19 vaccine is impaired in patients with B-NHL who are undergoing R/Obi treatment. Longer time since exposure to R/Obi is associated with improved response rates to the COVID-19 vaccine. This study is registered at www.clinicaltrials.gov as #NCT04746092.

Traumatic vs. atraumatic 22 G needle for therapeutic and diagnostic lumbar puncture in the hematologic patient: a prospective clinical trial.

We investigated the impact of needle type on post lumbar puncture headache (PLPH) in hematologic patients undergoing LP. We prospectively compared traumatic (TN) vs. atraumatic 22G needles. Twenty-seven patients underwent 48 LPs, 22 with chemotherapy injection. PLPH occurred almost exclusively with TN (4% vs. 30% p=0.02), irrespective of chemotherapy injection.

Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis.

We aimed to evaluate the efficacy and toxicity profile of busulfan-fludarabine (Bu-Flu) compared with busulfan-cyclophosphamide (Bu-Cy) as a preparative regimen for patients undergoing allogeneic hematopoietic cell transplantation. We performed a systematic review and meta-analysis of all comparative trials, both randomized controlled trials (RCTs) and non-randomized. Our search yielded 15 trials recruiting 1830 patients. Four trials were RCTs and 11 were either one-arm intervention trials compared with historical controls or retrospective studies. There was a lower risk for non-relapse mortality (NRM) at 100 days in patients given Bu-Flu regimen compared with those given Bu-Cy regimen (relative risk (RR) 0.56; 95% confidence interval (CI) 0.34-0.92, 8 trials); however, there were no differences in all-cause mortality at 100 days (RR 0.85; 95% CI 0.56-1.30, 9 trials) and at the end of study (RR 0.81; 95% CI 0.64-1.02, 13 trials). The risks of sinusoidal obstruction syndrome (SOS) and microbiologically documented infections were lower in patients given Bu-Flu regimen (RR 0.34; 95% CI 0.19-0.62, 8 trials and RR 0.79; 95% CI 0.64-0.97, 2 trials, respectively); however, risk for SOS was no longer lower when performing sensitivity analysis according to RCTs. Engraftment kinetics, risk of grade 3-4 mucositis, GvHD, relapse and NRM at the end of the study were all similar between the two groups. We conclude that both regimens have similar efficacy profiles, whereas toxicity is lower with the Bu-Flu regimen.

PO-45 - The role of microvesicles in multiple myeloma progression.

INTRODUCTION: Multiple myeloma (MM) is an incurable, genetically heterogeneous malignancy of plasma cells that secrete non-functioning immunoglobulins and present high proteasome activity. MM is characterized by bone marrow infiltration leading to multiple lytic bone lesions, cytopenia and increased rate of thrombotic events. Microvesicles (MVs) include exosomes (30-100 nm) and microparticles (0.1-1 micron) shed from various cells and expressing antigens reflecting their cellular origin. MVs are involved in thrombosis, inflammation and cancer.However, the effect of MM-MVs on disease progression and their mechanism of action are unclear. We assume that MVs play a role in the interaction between malignant plasma cells and mesenchymal and endothelial cells (EC). AIM: To characterize MM-MVs and investigate their effects on microenvironment cells. MATERIALS AND METHODS: MVs were isolated from MM cell line RPMI 8226 untreated or treated with bortezomib and from peripheral blood (PB) and bone marrow (BM) of MM patients (n=13) and healthy controls (n=14). MM-MV size, concentration and cell origin were measured by Nanosite and FACS. Protein content was evaluated by protein arrays and ELISA. Coagulation and proteasome activity were assessed using chromogenic assays. Migratory capacity (migration assay), proliferative rate (XTT assay) and cell-signaling effects (Western blot analysis) of MVs on BM-mesenchymal and ECs were analyzed. RESULTS: MM cells exhibited high MV shedding rate, which further increased with the exposure to bortezomib. Significant elevation in MV production was found in MM patients compared to controls. MM-MVs expressed membrane MM markers (syndecan-1/ CD138, CD38), coagulation factor (TF, TFPI, EPCR, TM) and angiogenic factors (VEGFR1, VEGFR2, and CD31). MM-MVs contained high levels of growth factors (Angiogenin, PDGF-BB and VEGF) and displayed procoagulant and proteasome activity. MM-MVs penetrated cells and affected their function. MVs of untreated cells and patient MVs increased EC and mesenchymal cell migration and EC proliferation, while MVs obtained from bortezomib-treated cells decreased these effects. MVs of untreated cells increased ERK1/2 and c-Jun phosphorylation in ECs (by 6.15 and 1.84 fold) but did not affect MAPKAPK-2. MVs of bortezomib-treated cells reduced c-Jun phosphorylation in ECs. CONCLUSIONS: MM cells are characterized by high shedding rate of MVs. They are pro-coagulants and increase EC thrombogenicity, suggesting their involvement in MM-related thrombosis. MVs contain high levels of angiogenic factors that affect mesenchymal and EC, induce cell migration and proliferation via specific signal transductions. MVs exposed to bortezomib display lower levels of angiogenic factors, which limits proliferation and migration of MVs, reflecting the efficacy of therapy and MM dynamics.

JC polyomavirus reactivation is common following allogeneic stem cell transplantation and its preemptive detection may prevent lethal complications.

Extended application of allogeneic stem cell transplantation (alloSCT) is expected to increase the frequency of JC polyomavirus (JCPyV)-related progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess frequency, risk factors and course of JCPyV reactivation in allografted hematology patients. This retrospective study included consecutive adult patients, treated with alloSCT between January 2008 and December 2011. Quantitative JCPyV-PCR analysis was performed on whole blood DNA samples, originally drawn for cytomegalovirus detection since transplant date. The study included 164 patients diagnosed with hematological malignancies. Patients received reduced-intensity conditioning (n=74) or myeloablative conditioning (n=90), followed by alloSCT. Twenty patients developed transient and 20 had persistent JCPyV reactivation. Two of the patients with persistent reactivation showed a gradual increase in JCPyV levels, preceding PML development by 96 and 127 days. Cessation of immunosuppression resulted in complete resolution of neurological symptoms in one patient, while the other died of PML. Seventy percent of the 'persistently reactivating' patients died. Multivariate analysis confirmed age to be the only significant predictive factor for JCPyV reactivation. In conclusion, JCPyV reactivation occurs in a quarter of allografted patients. Preemptive detection of JCPyV reactivation in high-risk subjects and early discontinuation of immunosuppressive therapy may prevent development of lethal PML.

Stem cell transplantation in adult ALL patients.

Less than 40% of adult acute lymphocytic leukaemia (ALL) patients will still be alive at 5 years post-diagnosis. Ways to improve patients' outcome, using high-dose therapy followed by autologous/allogeneic stem cell transplantation (SCT) in first complete remission (CR1) rather than consolidation/maintenance chemotherapy, have been investigated. However, prospective studies are small and results are inconclusive. The largest prospective trial ever being performed in adult ALL patients, the ongoing UKALL 12/ECOG 2993 trial, is assigning all patients who have a sibling donor to receive allogeneic SCT (alloSCT) in CR1, whereas all other patients are randomized to continue chemotherapy versus autologous SCT. An interim analysis of this trial seems to support an alloSCT in first CR in adult ALL patients (reflected by a significantly reduced relapse rate with an improved disease-free survival). However, less than 30% of the patients have a matched sibling donor, the majority of the patients are over 40 years old, which makes them less suitable for conventional allograft, and even in those who have a matched sibling donor and are young and fit enough to receive it the treatment-related mortality (TRM) is about 20%. Strategies for expanding donor availability, meanwhile, to reduce the TRM, remain challenges. Data regarding the efficacy of reduced-intensity regimens in ALL patients are still scanty. Another way of improving patient outcome is to select patients for allograft more carefully. There are enough data to suggest now that children who achieved a clinical remission but failed to obtain a molecular/immunological remission are more prone to relapse. Similar data have recently been published for adult ALL. However, data are still limited, and the significance of minimal residual disease (MRD) has never been studied prospectively in adult ALL patients. A reasonable approach is to assign all patients with a matched related donor who has failed to achieve a molecular/immunological remission to receive a conventional alloSCT, whereas all others might be randomized to receive alloSCT versus chemotherapy/autologousSCT. However, patients with Ph(+) ALL who have a donor should receive an alloSCT in CR1, regardless of their MRD results. It appears that alloSCT provides the best chance for cure. However, by improving our ability to select those who have the highest risk for relapse, unnecessary toxicity/mortality might be prevented and the general outcome might improve.

Myelodysplastic syndrome and associated skin lesions: a review of the literature.

The skin involvement of the myelodysplastic syndrome (MDS) can take the form of either a neoplastic infiltration or various non specific lesions. The occurrence of these lesions may be the presenting feature of the disease (MDS) or may herald its progression to acute leukemia. Recognition and early diagnosis have therapeutic and prognostic significance.

Bone marrow transplant in Ph+ ALL patients.

Although the outcome for Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) with conventional chemotherapy is poor, the outcome after a sibling-matched allogeneic bone marrow transplantation (BMT) seems to be significantly better. The surprising success of allogeneic BMT may be because of disease response to high-dose chemotherapy combined with a graft-versus-leukemia effect. However, less than 30% of patients have a matched related donor available, and some of them will be too old/not fit for conventional BMT. While young patients who do not have a matched related donor should be considered for matched unrelated donor (MUD) transplant, older patients may be treated with autologous stem cell transplantation (ASCT) or rarely considered for a low-intensity MUD transplant. The efficacy of autologous BMT compared with chemotherapy is still debatable, although the new tyrosine kinase inhibitor Imatinib may be used for pretransplant purging/post-transplant therapy, aiming to improve autologous and allogeneic BMT results. The advantage of low-intensity sib/MUD allograft compared with chemotherapy is not proven either and is currently under investigation. However, if shown to be curative, low-intensity allograft may significantly improve the outcome of older Ph+ ALL patients, who are not eligible for conventional allograft.

Nosocomial outbreak of Legionella pneumophila serogroup 3 pneumonia in a new bone marrow transplant unit: evaluation, treatment and control.

A nosocomial outbreak of pneumonia caused by Legionella pneumophila serogroup 3 occurred in four patients following hematopoietic stem cell transplantation (HSCT) in a new bone marrow transplantation (BMT) unit during a 2 week period. The causative organism was recovered from the water supply system to the same unit just before the outbreak. Nineteen other BMT patients were hospitalized in the same unit at the same time, giving a frequency of proven infection of 4/23 = 17%. Immediately after recognition of the outbreak, use of tap water was forbidden, humidifiers were disconnected, and ciprofloxacin prophylaxis was started for all patients in the unit, until decontamination of the water was achieved. No other cases were detected. In conclusion, contamination of the hospital water supply system with legionella carries a high risk for legionella pneumonia among BMT patients. Early recognition of the outbreak, immediate restrictions of water use, antibiotic prophylaxis for all non-infected patients, and water decontamination, successfully terminated the outbreak.

Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation.

We report the incidence, characteristics and outcome of neurological complications occurring following reduced-intensity conditioning (RIC) in 85 patients who received a related/unrelated donor stem cell transplantation following therapy with alemtuzumab, fludarabine and melphalan. Six patients (probability 8.9%) developed severe neurological complications at a median of 151 days (24-334 days). Five of them presented with progressive peripheral sensori-motor radiculo-neuropathy and/or myelitis, preceded by one or more viral reactivation/infection. Despite treatment with immunoglobulins/plasmapheresis/steroids, four died of respiratory failure due to progressive peripheral neurophathy. Viral infection was identified as the only risk factor for the development of neurological complications. Patients who are treated with alemtuzumab-based RIC may have a lower risk of developing regimen-related neurological complications, but are more susceptible to develop peripheral radiculo-neuropathy or myelitis. This phenomenon may be possibly related to viral infection associated with delayed immunological recovery or immunological dysregulation caused by alemtuzumab-induced T-cell depletion.

Overdiagnosis of 21-hydroxylase late onset congenital adrenal hyperplasia: correlation of corticotropin test and human leukocyte antigen typing.

OBJECTIVE: To evaluate the reliability of the ACTH test as a means for detection of late onset congenital adrenal hyperplasia (CAH) and discriminating it from polycystic ovary syndrome (PCOS), by repeating the test after 6 months of cyproterone acetate and ethinyl E2 treatment. DESIGN: Follow-up comparison study. SETTING: Reproductive Endocrinology in an university tertiary center. PATIENTS: Thirty-one young women with hirsutism, oligoamenorrhea, and acne, 21 of them detected as late onset CAH, and 10 as non-late onset CAH (PCOS). INTERVENTION: Cyproterone acetate and ethinyl E2 treatment for > or = 6 months. The ACTH test, before and after 6 months of cyproterone acetate + ethinyl E2 treatment, and human leukocyte antigen (HLA) typing. MAIN OUTCOME MEASURE: The ACTH test interpretation correlated to HLA typing. RESULTS: By repeating the ACTH stimulation test in the 31 women (after cyproterone acetate + ethinyl E2 administration), we found a diminution in the rate of accumulation of 17 alpha-hydroxyprogesterone (delta 17-OHP) + P, in all 21-hydroxylase late onset CAH cases. As a result of treatment with cyproterone acetate + ethinyl E2, a decrease in the accumulation rate of 17-OHP + P, below the discriminative value for late onset CAH (6.5 ng/dL per minute), was noted among 12 of 21 women defined primarily as late onset CAH. Among the nine other women, a decrease in the accumulation rate of 17-OHP + P was noted, however not < 6.5 ng/dL per minute. CONCLUSIONS: The interpretation of delta 17-OHP + P for the diagnosis of late onset CAH may be too sensitive as to the correct clinical diagnosis of late onset CAH. By repeating the ACTH test after 6 months of treatment with cyproterone acetate-ethinyl E2, specificity and accuracy may be improved.

Preservation of fertility and ovarian function and minimizing chemotherapy-induced gonadotoxicity in young women.

BACKGROUND: After the improved long-term survival in young women with lymphoma and leukemia undergoing chemotherapy, the preservation of future fertility has been the focus of recent interest. AREAS OF REVIEW: Three major topics are reviewed. They include the following: (1) the role of chemotherapy in the treatment of malignant and nonmalignant disease in young women, the types of chemotherapy and their gonadal effects (differing between ovaries and testes) in both human and other species, and the reasons for differences in the outcomes of various studies; (2) the human experience with GnRH-agonist therapy for minimizing chemotherapy-associated gonadotoxicity; and (3) inhibin measurements in young women treated by chemotherapy and in perimenopausal patients and those with impending premature ovarian failure (POF). Whereas egg retrieval for in vitro fertilization (IVF) and embryo cryopreservation is a valid assisted reproductive technology (ART) for married couples, it may be unacceptable for the young single woman. The investigational endeavors of ovarian cryopreservation awaits the clinical experience of in vitro maturation of thawed primordial follicles, their IVF, and embryo transfer. Although promising, this experience is not yet available. Moreover, the risk of possible reimplantation of malignant stem cells with the thawed cryopreserved ovary has been raised after animal observations. Therefore, until these innovative endeavors prove successful, and in parallel with them, an attempt was made to minimize the gonadotoxic effect of chemotherapy by the cotreatment with a GnRH agonistic analogue (GnRH-a) to induce a temporary prepubertal milieu, because prepubertal ovaries were found more resistant to alkylating agents' effect than the ovaries of older women. To characterize the correlation with ovarian function after gonadotoxic chemotherapy for Hodgkin or non-Hodgkin lymphoma in young women, the immunoreactive inhibin-A concentrations in the sera of these patients were measured before, during, and after the gonadotoxic chemotherapy. CONCLUSIONS: The GnRH-a cotreatment should be considered in every woman in the reproductive age receiving chemotherapy, in addition to ART and the investigational attempts of ovarian cryopreservation for future in vitro maturation or reimplantation. If these preliminary data are confirmed in a larger group of patients, inhibin-A concentrations may serve as a prognostic factor for predicting the resumption of ovarian function in addition to the levels of FSH, LH, and estradiol.

Hyperhomocysteinemia is common in patients with antiphospholipid syndrome and may contribute to expression of major thrombotic events.

Homocysteine plasma levels were measured by high-performance liquid chromatography in 52 patients with primary antiphospholipid syndrome (APS). Elevated homocysteine concentrations (>or= 15 micromol/l) were found in 16/52 (30.8%) APS patients. Elevated homocysteine levels were found to be associated with an increased risk for a major thromboembolic event (50 versus 16.7%, P = 0.014). Hyperhomocysteinemia is a common finding in APS patients, and may contribute to severity of thrombotic tendency observed in this syndrome.

Matched unrelated donor allogeneic transplantation provides comparable long-term outcome to HLA-identical sibling transplantation in relapsed diffuse large B-cell lymphoma.

The objective of this retrospective analysis was to compare outcomes of patients with diffuse large B-cell lymphoma (DLBCL) who received either a matched sibling (sib) or an unrelated donor (URD) allogeneic hematopoietic cell transplantation (allo-HCT). Long-term outcome of 172 DLBCL patients receiving URD-HCT between 2000 and 2007 and reported to the European Group for Blood and Marrow Transplantation, was compared with that of 301 subjects, allografted from sib-HCT. With a median follow-up of 45 months, 3-year PFS approached 35% for both groups; overall survival (OS) was 42% for sib-HCT versus 37% for URD (NS). Multivariate analyses confirmed that donor type was not associated with differences in non-relapse mortality (NRM), relapse rate (RR), PFS or OS. Poor performance status (PS) and refractory disease adversely affected PFS and OS. Prior auto-SCT and multiple previous therapies predicted for shorter PFS. NRM was adversely affected by older age (⩾50 years), poor PS and refractory disease, and RR by time from diagnosis to allo-HCT of <36 months, prior auto-SCT, refractory disease, poor PS and in vivo T-cell depletion with alemtuzumab. This large study shows for the first time that URD-HCT is not inferior to sib-HCT, providing a reasonable therapeutic approach for DLBCL patients, having no HLA-identical sibling available.