Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study.

BACKGROUND: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. PATIENTS AND METHODS: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. RESULTS: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: -3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (-7.4 and -8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. CONCLUSION: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact HRQoL over time. WBRT did not result in deterioration of HRQoL in the first 2 years.

Monoclonal gammopathy of renal significance (MGRS) histopathologic classification, diagnostic workup, and therapeutic options.

Monoclonal gammopathy of renal significance (MGRS) includes all kidney disorders caused by a monoclonal protein (M-protein) secreted by a small plasma cell clone or other B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. The underlying disorder in patients with MGRS is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). MGRS-associated kidney disorders are various and the list is still expanding. The kidney disorders can manifest as glomerular diseases, tubulopathies, and vascular involvement with varying clinical presentations. Diagnosis is often challenging because of the wide spectrum of MGRS, and it is difficult to establish a pathogenic link between the presence of the M-protein or serum free light chains and kidney diseases; further complicating accurate diagnosis is the high incidence of MGUS and/or kidney disorders, independent of MGRS, in elderly patients. However, MGRS can significantly impair kidney function. Because treatment can stop and also reverse kidney disease, early recognition is of great importance. A combined haematologic and nephrologic approach is crucial to establish the causative role of the M-protein in the pathogenesis of kidney disease. Clone-directed therapy, which may include autologous stem cell transplantation in eligible patients, often results in improved outcomes. In this review, we discuss the histopathologic classification of MGRS lesions, provide a renal and haematologic diagnostic workup, discuss treatment options for MGRS, and introduce a Benelux MGRS Working Group.

Cardiac amyloidosis: the need for early diagnosis.

Amyloidosis is a collection of systemic diseases characterised by misfolding of previously soluble precursor proteins that become infiltrative depositions, thereby disrupting normal organ structure and function. In the heart, accumulating amyloid fibrils lead to progressive ventricular wall thickening and stiffness, resulting in diastolic dysfunction gradually progressing to a restrictive cardiomyopathy. The main types of cardiac amyloidosis are amyloid light chain (AL) amyloidosis caused by an underlying plasma cell dyscrasia, amyloid transthyretin (TTR) amyloidosis of wild-type (normal) TTR at older age (ATTRwt) and hereditary or mutant amyloid TTR (ATTRm) in which a genetic mutation leads to an unstable TTR protein. Overall survival is poor once heart failure develops, underlining the need for early referral and diagnosis. Treatment for AL amyloidosis has improved markedly over the last decades, and TTR amyloidosis gene silencers and orally available transthyretin stabilisers are ready to enter the clinical arena after recent positive outcome trials. Novel therapies aiming at fibril degradation with monoclonal antibodies are under investigation. In this review, we focus on 'red flag' signs and symptoms, diagnosis and management of cardiac amyloidosis which differs considerably from the general management of heart failure. Only by increasing awareness, prognosis for patients with this devastating disease can be improved.

'Transformation' from amyloid light chain amyloidosis to symptomatic multiple myeloma.

Amyloid light chain (AL) amyloidosis and multiple myeloma (MM) are both clonal plasma cell disorders, and may be concurrently present in patients. However, symptomatic MM seldom develops in patients with AL amyloidosis, while the other way around is common. With this case report, we discuss the difficulties in the differential diagnosis between AL amyloidosis and MM, and extend on the possible mechanisms involved in the development of these overlapping disorders. In addition, we provide clinicians with tools that may help improve their management and monitoring of such patients.

[Unexpected symptoms of monoclonal gammopathy]. / Onverwachte gevolgen van monoklonale gammopathie.

Monoclonal gammopathy of undetermined significance (MGUS) is a common haematological disorder characterized by the presence of a monoclonal protein (M-protein). MGUS is considered an asymptomatic 'innocent' pre-malignant precursor condition of - mostly - multiple myeloma, without indication for treatment. We present three cases illustrating that MGUS can lead to serious problems. The first patient, a 51-year-old female, presented with polyneuropathy due to anti-MAG antibodies related to IgM MGUS. The second patient, a 37-year-old female, presented with proteinuria due to immunotactoid glomerulopathy caused by renal monoclonal IgG deposition associated with MGUS. The third patient, a 55-year-old female, presented with severe bleeding caused by an aspecific inhibitor of the coagulation cascade as part of IgG MGUS. In conclusion, in addition to the risk of progression to an overt haematological malignancy, MGUS can lead to severe symptoms and significant organ damage by auto-antibody activity or pathological accumulation in tissues of its toxic M-protein.

In search of the optimal platform for Post-Allogeneic SCT immunotherapy in relapsed multiple myeloma: a systematic review.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce sustained remissions in patients with multiple myeloma (MM). Currently, allo-SCT is primarily performed in high-risk MM patients, most often in the setting of early relapse after first-line therapy with autologous SCT. However, the implementation of allo-SCT for MM is jeopardized by high treatment-related mortality (TRM) rates as well as high relapse rates. In this systematic review, we aimed to identify a safe allo-SCT strategy that has optimal 1-year results regarding mortality, relapse and severe GvHD, creating opportunities for post-transplantation strategies to maintain remissions in the high-risk group of relapsed MM patients. Eleven studies were included. Median PFS ranged from 5.2 to 36.8 months and OS was 13.0 to 63.0 months. The relapse related mortality at 1 year varied between 0 and 50% and TRM between 8 and 40%. Lowest GvHD incidences were reported for conditioning regimens with T-cell depletion using ATG or graft CD34+ selection. Similar strategies could lay the foundation for a post-transplant immune platform, this should be further evaluated in prospective clinical trials.

Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography.

We performed a prospective study in patients with chemotherapy induced febrile neutropenia to investigate the diagnostic value of low-dose computed tomography compared to standard chest radiography. The aim was to compare both modalities for detection of pulmonary infections and to explore performance of low-dose computed tomography for early detection of invasive fungal disease. The low-dose computed tomography remained blinded during the study. A consensus diagnosis of the fever episode made by an expert panel was used as reference standard. We included 67 consecutive patients on the first day of febrile neutropenia. According to the consensus diagnosis 11 patients (16.4%) had pulmonary infections. Sensitivity, specificity, positive predictive value and negative predictive value were 36%, 93%, 50% and 88% for radiography, and 73%, 91%, 62% and 94% for low-dose computed tomography, respectively. An uncorrected McNemar showed no statistical difference (p = 0.197). Mean radiation dose for low-dose computed tomography was 0.24 mSv. Four out of 5 included patients diagnosed with invasive fungal disease had radiographic abnormalities suspect for invasive fungal disease on the low-dose computed tomography scan made on day 1 of fever, compared to none of the chest radiographs. We conclude that chest radiography has little value in the initial assessment of febrile neutropenia on day 1 for detection of pulmonary abnormalities. Low-dose computed tomography improves detection of pulmonary infiltrates and seems capable of detecting invasive fungal disease at a very early stage with a low radiation dose.

Efficacy of host-dendritic cell vaccinations with or without minor histocompatibility antigen loading, combined with donor lymphocyte infusion in multiple myeloma patients.

Donor lymphocyte infusions (DLI) can induce durable remissions in multiple myeloma (MM) patients, but this occurs rather infrequently. As the graft-versus-tumor (GvT) effect of DLI depends on the presence of host-dendritic cells (DCs), we tested in a phase I/II trial whether the efficacy of DLI could be improved by simultaneous vaccination with host-DCs. We also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mismatched hematopoietic cell-specific minor histocompatibility antigens (mHags). Fifteen MM patients not responding to a first DLI were included. Eleven patients could be treated with a second equivalent dose DLI combined with DC vaccinations, generated from host monocytes (moDC). For four patients, the DC products did not meet the quality criteria. In four of the treated patients the DCs were loaded with host mHag peptides. Toxicity was limited and no acute GvHD occurred. Most patients developed objective anti-host T-cell responses and in one patient a distinct mHag-specific T-cell response accompanied a temporary clinical response. These findings confirm that DLI combined with host-DC vaccination, either unloaded or loaded with mHag peptides, is feasible, safe and capable of inducing host-specific T-cell responses. The limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors.

Chemotherapy-induced neuropathy in multiple myeloma: influence on quality of life and development of a questionnaire to compose common toxicity criteria grading for use in daily clinical practice.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) may negatively influence multiple myeloma (MM) patients' health-related quality of life (HRQOL). Dose modification is the only way to minimize CIPN. To measure CIPN in daily practice, the Indication for Common Toxicity Criteria (CTC) Grading of Peripheral Neuropathy Questionnaire (ICPNQ) was developed which can be completed within five minutes by the patient. The aims of this study were to (1) perform a psychometric evaluation of the ICPNQ and (2) examine the prevalence of CIPN and its influence on HRQOL in population-based MM patients. METHODS: One hundred fifty-six MM patients, diagnosed between 2000 and 2014, completed the ICPNQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20), and EORTC QLQ-C30 (65 % response). RESULTS: The psychometric analyses showed a Cronbach's alpha of 0.84, 0.74, and 0.61 for, respectively, the sensory, motoric, and autonomic subscales of the ICPNQ. Test-retest reliability and construct validity were good for all subscales. Overall, 65 % of patients reported grade 2-3 neuropathy according to the ICPNQ. Patients with the highest CTC grades (grade 2 with neuropathic pain and grade 3 (38 %)) according to the ICPNQ reported significantly worse scores on all EORTC QLQ-CIPN20 subscales compared to patients with lower CTC grades (p ≤ 0.002). In addition, they reported statistically significant and clinically relevant worse HRQOL scores on almost all EORTC QLQ-C30 subscales. CONCLUSIONS: CIPN is a common side effect in MM patients, which has a negative impact on HRQOL. The ICPNQ is a valid instrument to distinguish the highest CIPN CTC grades from the lower CTC grades necessary to decide on dose modifications of chemotherapy in daily clinical practice.

Human herpes virus 6 reactivation: important predictor for poor outcome after myeloablative, but not non-myeloablative allo-SCT.

Hematopoietic SCT (HSCT) is often complicated by viral reactivations. In this retrospective cohort study (January 2004-August 2008), predictors for human herpes virus 6 (HHV6)-reactivation and associations between HHV6-reactivation and clinical outcomes after allogeneic HSCT were studied. HHV6 DNA load in plasma was monitored weekly by quantitative real-time PCR. Associations between the main end point HHV6-reactivation and other end points, that is, acute GVHD (aGVHD) and NRM were analyzed using Cox proportional hazard models. In total, 108 patients receiving either a myeloablative (MA; n=60) or non-myeloablative (NMA; n=48) conditioning regimen were included. Median age was 40 years (range 17-65); median follow-up was 20 months (range 3-36). In 16/60 (27%) patients with MA conditioning regimen, a HHV6 reactivation was observed (mean viral load 50 323 cp/mL) compared with 2/48 (4%) patients with a NMA conditioning regimen with low viral load (mean 1100 cp/mL). In multivariate analysis, MA conditioning was the only predictor for HHV6 reactivation (P=0.02). In addition, HHV6 reactivation was associated with grades 2-4 aGVHD (P<0.001) and NRM (P=0.03). Regular monitoring of HHV6 reactivation after HSCT might be important in MA HSCT patients to enable early initiation of antiviral treatment or to anticipate aGVHD, all of which may improve clinical outcome.

Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia.

On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.

A survey on diagnostic methods and treatment strategies used in patients with Waldenström's macroglobulinaemia in The Netherlands.

BACKGROUND: Waldenström's macroglobulinaemia (WM) is defined as a lymphoplasmacytic lymphoma primarily located in the bone marrow, accompanied by an immunoglobulin M (IgM) monoclonal protein in the serum. The symptoms are highly variable, which can sometimes lead to a diagnostic delay. Currently, there is a wide range of therapeutic options used for the management of WM but no approved therapeutic agents are available specifically for this disease. METHODS: An online survey was prepared and sent out to haematologists and haemato-oncologists in The Netherlands, together with an invitational letter to participate. Information was gathered about the preferred methods of diagnosing and treating patients with WM in general, and about the last WM patient diagnosed in their department. RESULTS: 83 (31.8%) responses were obtained, out of which 68 (81.9%) contained responses to all three parts of the survey. The respondents most commonly used either rituximab-CVP or chlorambucil as first-line treatment, whereas rituximab in combination with purine analogues was the most frequently applied second-line treatment. The prevention of an IgM 'flare' was managed by the respondents in various ways, and rituximab maintenance treatment was not commonly used. CONCLUSION: This survey indicates that in general the diagnostic methods and treatment options for WM are well known to a representative number of Dutch haematologists. The areas of uncertainty are knowledge about asymptomatic vs symptomatic disease, risk of hyperviscosity in relation to IgM level, and the occurrence and prevention of an IgM 'flare'. These issues should be addressed in clinical research and guidelines to improve care for WM patients in The Netherlands.

Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1.

Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy.

Prognostic factors and outcome in relapsed multiple myeloma after nonmyeloablative allo-SCT: a single center experience.

For relapsed multiple myeloma (MM) patients, allo-SCT is a possible treatment option, but recent data obtained using a nonmyeloablative (NMA) conditioning regimen are scarce. We retrospectively collected data from 38 relapsed MM patients who received a NMA allo-SCT from October 2001 to January 2008. In total, 18 patients (48%) were transplanted using a matched unrelated donor. The median follow-up is 2.3 years. In 16 patients (42%) the response improved and eight patients (21%) were rapidly progressive within 6 months after allo-SCT. In total, 15 patients (39%) were in CR after allo-SCT. The median PFS was 1.4 years (range, 0.1-4.9), and having a CR after allo-SCT or having chronic GVHD resulted in longer PFS. Median OS was 3.1 years (range, 0.2-7.2) and again having a CR after allo-SCT or chronic GVHD was associated with a better OS. Six patients (16%) have died from treatment-related diseases. These results indicate that NMA allo-SCT is a treatment option in relapsed MM patients and that results may be improved by strategies that enhance the CR rate after allo-SCT.

High level of perforin expression in T cells: An early prognostic marker of the severity of herpesvirus reactivation after allogeneic stem cell transplantation in adults.

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus reactivations are frequent complications of hematopoeitic allogeneic stem cell transplantation (SCT) because of a lack of T cell control after immunosuppression. Early diagnosis of reactivation and subsequent preemptive therapy relies on frequent viral load measurement. Additional virus-specific T cell reconstitution data could improve the predictive value of viral load detection for viral complications after transplantation. Here, we studied perforin expression in CD8(+) T cells as a measure of cytotoxic T cell capacity in relation to the occurrence of viral reactivation. METHODS: In a prospective study, we monitored 40 patients during the first 3 months after transplantation and measured viral loads in combination with intracellular perforin expression in CD8(+) T cells. RESULTS: Median perforin expression in CD8(+) T cells throughout follow-up was higher in patients with viral reactivations than in patients without viral reactivations (4.9% vs 2.3%; P = .001). The median percentage of perforin-expressing CD8(+) T cells in patients with high viral reactivations exceeding 1000 copies/mL (10.7%) was statistically significantly higher than that in patients with minor reactivations of 50-1000 copies (4.0%), that in patients with detectable EBV loads that did not exceed the detection limit of 50 copies/mL (2.9%), and that in patients without reactivations (0.8%). Patients with high viral reactivations reached a high percentage of perforin-expressing CD8(+) T cells (>10.2%) more often and faster than did patients with low viral loads (1000 copies/mL) or without viral reactivations. High perforin expression preceded high viral loads. CONCLUSION: Perforin-expressing CD8(+) T cells may be useful as an easy-to-measure prognostic marker for identifying patients at risk for severe viral reactivation very soon after SCT.

New developments in the treatment of patients with multiple myeloma.

Much progress has been made in the treatment of patients with multiple myeloma (MM). The introduction of new drugs such as thalidomide, bortezomib and lenalidomide has created more possibilities for patients than many years before. In addition, autologous peripheral blood stem cell transplantation after high-dose melphalan has become the standard of care for younger patients. Allogeneic stem cell transplantation is an experimental option for those younger patients with a human leucocyte antigen identical donor. Because of these rapid developments and many treatment options we need good quality clinical studies that can guide us in what to do in everyday practice. This review will focus on those studies that have changed the treatment guidelines for patients with MM.

Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome.

Recent literature suggests that after non-myeloablative allogeneic (NMA) stem cell transplantation (SCT), the incidence of extramedullary (EM) relapse in multiple myeloma (MM) patients is increased and that these relapses have a poor prognosis. However, numbers on incidence and treatment outcome are scarce. We collected data from 54 relapsed MM patients from a total group of 172 treated with sequential autologous and allogeneic NMA SCT at seven transplantation centres. There were 43 (79.6%) systemic relapses, including 6 with concurrent EM localisation. Five patients had a local EM relapse only. Six patients relapsed with only bone involvement. Patients with deletion of chromosome 13 had a higher incidence of EM relapse (30.8 versus 5.6%, P=0.06). EM relapses were treated with donor lymphocyte infusion, radiotherapy, or chemotherapy, especially with novel agents. The response rate was 45.5%, which was not different when compared to patients without EM disease (54.1%). Overall survival and progression-free survival were not significantly different in patients with EM disease, when compared to those without EM disease. In conclusion, the incidence of relapse with EM disease following allogeneic NMA SCT was 20.4%. There was no negative impact of EM relapse on response rate, overall survival and progression-free survival.