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.

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.

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.

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.

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.

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.

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.

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.

Impact of PCR-based diagnosis of invasive pulmonary aspergillosis on clinical outcome.

The mortality rate of 60-90% in invasive pulmonary aspergillosis (IPA) is partly explained by diagnostic delay due to the limitation of current diagnostic tests. We assessed the influence of Aspergillus species (ASP) DNA detection by PCR from bronchoalveolar lavage (BAL) fluid, a new tool for diagnosing IPA, on the outcome of this disease in immune-compromised patients. The study population comprised 107 consecutive patients with hematological malignancies from a single medical center with IPA diagnosed between 1998 and 2005. Clinical variables and mortality rates were compared between two groups diagnosed according to traditional criteria without and with PCR-based ASP DNA detection in BAL fluid. The overall mortality rate during the study period was 38.3%. The addition of PCR to the diagnostic criteria shifted 31 patients from possible to probable IPA. Patients diagnosed with probable IPA according to traditional microbiological methods had significantly higher mortality rates compared to their counterparts who had in addition a PCR-based diagnosis (80 vs 35.6%, P=0.003). This study demonstrates that PCR-based ASP DNA detection for a diagnosis of IPA from BAL fluid has a significant effect on the outcome of patients with IPA, probably related to earlier diagnosis.

Oral integrity and salivary profile in myeloma patients undergoing high-dose therapy followed by autologous SCT.

The underlying mechanism of high-dose therapy (HDT)-related oral mucositis (OM) may be partly mediated by alterations in the normal salivary composition. This study evaluated salivary antioxidant and immunological capacities observed in myeloma patients suffering from HDT-related OM, and assessed potential contribution of these factors to OM development. Twenty-five consecutive myeloma patients treated with melphalan 200 mg/m(2) followed by autologous SCT were enrolled. Patients underwent a daily assessment for OM, and salivary samples were collected on days -3 and +7 of transplantation and analyzed for secretory IgA and antioxidant capacity. The degree of mucosal damage was assessed by measuring the salivary carbonyl and albumin (Alb) levels. OM, reported in 96% of patients, appeared to be most severe on 8 day after transplantation (range: +2 to +14). Clinical mucositis was associated with significant reduction in salivary secretory IgA (54%; P=0.05), and antioxidant activity, measured by total antioxidant status (40%; P=0.0004), antioxidant capacity (ImAnOx) (23%; P=0.002) and uric acid level (51%; P=0.006). The increase found in salivary Alb (119%; P=0.024) and carbonyl (28%; P=0.047) levels, indicates mucosal and oxidative damage, respectively. These salivary changes might enhance mucositis development and symptoms. Therapeutic interventions, enhancing antioxidative and immunological activities need to be investigated.

Granulocyte transfusions for neutropenic patients with life-threatening infections: a single centre experience in 47 patients, who received 348 granulocyte transfusions.

INTRODUCTION: The role of granulocyte transfusions (GT) in patients with neutropenia-related infections remains controversial. MATERIALS AND METHODS: A retrospective analysis of 47 neutropenic patients, treated with 348 consecutive GTs for life-threatening infections between 1999 and 2004, is presented. RESULTS: The only grade III-IV toxicity observed in GT recipients was respiratory deterioration (n = 6, 12.8%). The overall infection-related mortality (IRM) approached 38%. Achievement of a neutrophil count of > 700 cells per microl after at least 50% of days of GTs (n = 33, 70%) significantly correlated with reduced IRM (27.3% vs. 64.3%, P < 0.02). GT doses of > 2 x 10(10) neutrophils per bag appeared to increase both neutophil and platelet counts following transfusion. CONCLUSION: GTs are safe and should be considered for patients with life-threatening neutropenic infections. However, prospective randomized studies of GTs are the only way to establish the true role of GTs.

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.

Standard vs atraumatic Whitacre needle for diagnostic lumbar puncture: a randomized trial.

In order to define the impact of needle type on post-lumbar puncture headache (PLPH), we performed a prospective, randomized trial comparing the incidence of PLPH in patients undergoing lumbar punctures (LPs) with traumatic vs atraumatic 22-gauge needles. Fifty-eight patients underwent 85 LPs. The incidence of PLPH was 36% in the traumatic vs 3% in the atraumatic group (p = 0.002).

Use of 18F-FDG positron emission tomography following allogeneic transplantation to guide adoptive immunotherapy with donor lymphocyte infusions.

Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) provides valuable prognostic information in the management of lymphoma patients. However, the utility of (18)F-FDG PET following allografting is unclear. We analysed the use of (18)F-FDG PET after allogeneic reduced-intensity transplantation (RIT) performed in our institution. Between June 1998 and January 2002, 55 patients underwent RIT for either Hodgkin or non-Hodgkin lymphoma. At least one (18)F-FDG PET scan was performed during the post-transplant period (median five studies) in 15 (27.2%) of these 55 patients. PET scans were performed after re-staging computed tomography (CT) and were categorised depending on (18)F-FDG uptake. The first PET scan was informative in 11 of 15 patients (73%) and influenced the administration of donor lymphocyte infusions (DLI) in nine: leading to earlier DLI administration in two patients, earlier dose escalation in one, withholding of DLI administration in five and dose reduction in one. In addition, subsequent monitoring with (18)F-FDG PET scans documented a graft-versus-lymphoma effect in five patients (median post-DLI follow-up 33 months, range 13-36 months). These preliminary data suggest that (18)F-FDG PET has a role in guiding DLI administration and monitoring the immunotherapeutic effect in patients after allogeneic transplantation. This retrospective pilot study forms the basis for a prospective study to clarify the utility of (18)F-FDG PET/CT in these patients.

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.

Clinical use of rituximab in haematological malignancies.

Rituximab is a chimeric human/mouse monoclonal antibody that is approved for the treatment of relapsed and refractory non-Hodgkin's lymphoma (NHL) and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy as first-line therapy for diffuse large B-cell NHL, where it has shown the first survival advantage over CHOP alone in more than 20 years. Strategies to help define the optimal therapeutic usage of rituximab are being assessed, including first-line and maintenance or extended therapy, and the combination of rituximab with chemotherapy in indolent NHL. Emerging data suggest that earlier use may yield higher response rates, extended therapy can prolong remission, and the addition of rituximab to chemotherapy can increase clinical and molecular remission rates when compared with those achieved using chemotherapy alone. Studies in the peritransplant setting suggest a role for rituximab in vivo purging prior to transplant and/or maintenance rituximab as a means of clearing minimal residual disease. Rituximab has also shown activity in other B-cell disorders such as chronic lymphocytic leukaemia. The full potential of this immunotherapeutic agent remains to be defined in ongoing and future clinical trials.

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.

Fertility after treatment for Hodgkin's disease.

BACKGROUND: The investigational endeavors of ovarian cryopreservation await the clinical experience of auto- or xenotransplantation, in vitro maturation of thawed primordial follicles, their in vitro fertilization and embryo transfer. Although promising, this experience is not yet available. Moreover, the risk of possible reimplantation of malignant stem cells with the thawed cryoperserved ovary has been raised following experimental animal observations. Therefore, until these innovative endeavors prove successful, we have attempted to minimize the gonadotoxic effect of chemotherapy by the co-treatment with a gonadotropin-releasing hormone agonistic analog (GnRH-a) to induce a temporary prepubertal milieu. The immunoreactive inhibin-A and -B in these patients was measured before, during and following the gonadotoxic chemotherapy. METHODS: A prospective clinical protocol was undertaken in 60 women aged 15-40 years with lymphoma, 10 with leukemia and 10 undergoing chemotherapeutic treatments for non-malignant diseases such as systemic lupus erythematosus or other autoimmune diseases. A monthly injection of depot D-TRP(6)-GnRH-a was administered from before starting the chemotherapy until its conclusion, up to a maximum of 6 months. Hormonal profile [follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, T, P4, insulin-like growth factor (IGF)-1, IGF-BP3 and prolactin) was taken before starting the GnRH-a/chemotherapy co-treatment, and monthly thereafter until resumtion of spontaneous ovulation. This group was compared with a control group of 60 women who have been treated with similar chemotherapy. RESULTS: Whereas all but three (40, 36 and 34 year old) of the surviving patients within the GnRH-a/ chemotherapy co-treatment group resumed spontaneous ovulation and menses within 12 months, less than half of the patients in the 'control' group (chemotherapy without GnRH-a co-treatment) resumed ovarian function and regular cyclic activity (P <0.05). The remaining 55% experienced premature ovarian failure (POF). Temporarily increased FSH concentrations were experienced by about one-third of the patients resuming cyclic ovarian function, suggesting reversible ovarian damage in a larger proportion of women than those experiencing POF. Inhibin-A and -B decreased during the GnRH-a/ chemotherapy co-treatment but increased to normal levels in patients who resumed regular ovarian cyclicity, and/or spontaneously conceived, as compared with low levels in those who developed POF. CONCLUSIONS: If these preliminary data are consisent in a larger group of patients, GnRH-a co-treatment should be considered in every woman of reproductive age receiving chemotherapy, in addition to assisted reproductive technologies and the investigation into ovarian cryopreservation for future in vitro maturation, autotransplantation or xenotransplantation.