Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients.

The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

Correlation of haemophagocytosis with clinical criteria of haemophagocytic lymphohistiocytosis and recommendations for bone marrow reporting.

Haemophagocytic lymphohistiocytosis (HLH) is a rare condition resulting from a dysregulated inflammatory response. Currently there are no guidelines on the reporting of haemophagocytosis on bone marrow biopsy (BM) and lack of evidence on correlation between haemophagocytosis with the clinical diagnostic criteria for HLH. We aimed to assess if the amount of haemophagocytosis identified in the BM correlates with HLH-2004 criteria. Secondary aims were to evaluate inter-observer variability in reporting haemophagocytosis, and to formulate recommendations for screening in bone marrow specimens. A retrospective review of bone marrow biopsies from adult patients under investigation for HLH was undertaken independently by two haematopathologists who were blinded to the original biopsy report. The average number of actively haemophagocytic cells in each slide were quantified. Cases with discordance pertaining to the degree of haemophagocytosis were reviewed by both assessors to reach a consensus. Sixty-two specimens from 59 patients were available for assessment. An underlying haematological condition was identified in 34 cases (58%). There was a significant association between the amount of haemophagocytosis identified on the aspirate samples and the number of HLH-2004 criteria met (p<0.0001). In patients where haemophagocytosis was present (n=31), there was a correlation between the amount of haemophagocytosis and ferritin (p=0.041). Based on our review, we have made recommendations for the reporting of BM haemophagocytosis. Our findings indicate that the amount of haemophagocytosis present on BM samples correlates with the number of HLH-2004 criteria. We found marked interobserver variability which we anticipate can be rectified with our recommendations for reporting.

Treatment of patients with multiple myeloma who are not eligible for stem cell transplantation: position statement of the myeloma foundation of Australia Medical and Scientific Advisory Group.

Options for treatment of elderly patients with multiple myeloma have expanded substantially following the development of immunomodulatory drugs (IMiD), proteasome inhibitors and with enhancement in safety of high-dose therapy and autologous stem cell transplant (HDT + ASCT). The recognition of biological heterogeneity among elderly patients has made delivery of therapy more challenging. An individualised approach to treatment selection is recommended in an era in which highly efficacious treatment options are available for transplant-ineligible patients. Here, we summarise recommendations for patients who are considered unsuitable for HDT + ASCT, including pretreatment considerations, and induction, maintenance and supportive care therapies.

Treatment of patients with multiple myeloma who are eligible for stem cell transplantation: position statement of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

The survival of patients with multiple myeloma (MM) has improved substantially since the introduction in the late 1980s of high-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT). Further improvements have been observed following the availability of immunomodulatory drugs (IMiD) such as thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib. Here, we summarise the recommendations of the Medical Scientific Advisory Group to the Myeloma Foundation of Australia for patients considered suitable for HDT + ASCT as part of initial therapy. These recommendations incorporate the various phases of treatment: induction, HDT conditioning and maintenance therapy.

Management of systemic AL amyloidosis: recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Systemic AL amyloidosis is a plasma cell dyscrasia with a characteristic clinical phenotype caused by multi-organ deposition of an amyloidogenic monoclonal protein. This condition poses a unique management challenge due to the complexity of the clinical presentation and the narrow therapeutic window of available therapies. Improved appreciation of the need for risk stratification, standardised use of sensitive laboratory testing for monitoring disease response, vigilant supportive care and the availability of newer agents with more favourable toxicity profiles have contributed to the improvement in treatment-related mortality and overall survival seen over the past decade. Nonetheless, with respect to the optimal management approach, there is a paucity of high-level clinical evidence due to the rarity of the disease, and enrollment in clinical trials is still the preferred approach where available. This review will summarise the Clinical Practice Guidelines on the Management of Systemic Light Chain (AL) Amyloidosis recently prepared by the Medical Scientific Advisory Group of the Myeloma Foundation of Australia. It is hoped that these guidelines will assist clinicians in better understanding and optimising the management of this difficult disease.

Hepatosplenic T-cell lymphoma, immunosuppressive agents and biologicals: what are the risks?

We present three cases of the rare hepatosplenic T-cell lymphoma (HSTCL); two patients suffering from Crohn disease who developed HSTCL on azathioprine without exposure to biologicals, and a third patient who had psoriasis treated using etanercept, cyclosporine and methotrexate. The evidence for an association between HSTCL and immunosuppressive drugs and biologicals is reviewed. We argue for improved pharmacovigilance processes to help determine the benefit to risk ratios for the use of these and other new agents.

Utilisation of sFLC assays - how well do we comply with guidelines?

INTRODUCTION: There is a paucity of data on the utilisation of the serum-free light chain (sFLC) and compliance with published guidelines. METHODS: Serum-free light chain assays requested at our institute for the diagnosis, prognosis and monitoring of plasma cell dyscrasias from July 2008 to March 2010 were compared with the International Myeloma Working Group (IMWG) consensus guidelines. RESULTS: In total, 1150 assays were performed (4.3 assays per patient, range 1-20). Eight hundred and forty-four (73%) of these were performed for multiple myeloma (MM), 188 (16%) for monoclonal gammopathy of undetermined significance, 72 (6%) for AL amyloidosis and 46 (4%) for smouldering myeloma. Of these, 49.6%, 22.9%, 1.4% and 69.6% of the monitoring assays were outside of IMWG recommendations, respectively. Of the 419 assays performed outside of guidelines for MM patients, 404 (96.4%) were due to monitoring of patients with a measurable M protein, while 24 (5.7%) were due to too frequent requesting (≤14 days) with 15 assays (3.6%) being noncompliant on both grounds. CONCLUSION: Utilisation of the sFLC assay shows reasonable adherence to guidelines within our centre. We propose to further optimise usage of the test with the help of administrative processes and education of clinicians.

Clinical role of flow cytometry in redefining bone marrow involvement in diffuse large B-cell lymphoma (DLBCL) - a new perspective.

AIMS: The clinical role of flow cytometry in staging bone marrow in diffuse large B-cell lymphoma (DLBCL), especially its impact on outcome, remains uncertain. The aim was to determine the contribution of flow cytometry to conventional staging, and to study the impact of this revised staging on survival. METHODS AND RESULTS: One hundred and thirteen cases of DLBCL diagnosed at The Canberra Hospital from 1996 to 2005 were identified. Blinded analysis of bone marrow (BM) morphology and flow cytometric data showed involvement on morphology (M) in 25 (22.1%) cases, on flow cytometry (F) in 21 (18.6%) cases and overall (M + F) in 32 cases (28.3%); discordance was noted in 16 cases (16.1%). Cases with and without marrow involvement on conventional staging alone (M) had no significant difference in survival (P = NS). However, when BM involvement was defined as positivity on morphology and/or flow cytometry (M + F), the median survival of patients with involvement was significantly worse than patients without involvement (P = 0.026). CONCLUSIONS: Flow cytometry-positive cases should be included with those positive on morphology in a summative model to define BM involvement in DLBCL, as it may have a potential impact on predicting outcome.

A comparative study of the quality of DNA obtained from fresh frozen and formalin-fixed decalcified paraffin-embedded bone marrow trephine biopsy specimens using two different methods.

BACKGROUND: Given its prognostic value, there is renewed interest in molecular staging in non-Hodgkin's lymphoma (NHL) using immunoglobulin heavy and light chain (IgH, IgL) gene rearrangements. AIMS: To compare the efficiency of DNA amplification from fresh frozen and formalin-fixed decalcified paraffin-embedded (FFDPE) bone marrow trephines for use in molecular staging using two methods. METHODS: After manually extracting DNA from 13 FFDPE and 14 fresh frozen trephine biopsy specimens, two methods were used to test for amplifiability: use of the amplification control master mix supplied in the In Vivo Scribe immunoglobulin heavy chain (IgH) clonality kit, which creates 5 amplicons between 96-600 base pairs (bp); and real-time amplification of the beta-globin gene. RESULTS: Using the first method, the mean maximum length of amplicons generated from FFDPE trephines was statistically lower at 300 bp compared to fresh frozen samples, all of which generated amplicons up to 600 bp in size (p<0.001). Real-time amplification of the beta-globin gene showed that the mean crossing threshold of fresh frozen samples was statistically lower than that of FFDPE samples (23.48 (95% CI 22.47 to 24.48) vs 33.64 (95% CI 32.15 to 35.12); p<0.001). CONCLUSIONS: Although amplifiable DNA can be extracted from both fresh-frozen and FFDPE trephine samples for IgH/IgL analysis, freshly frozen specimens are superior as a source of template DNA, especially for higher base pair PCR products.

Health-related quality of life in chronic coagulation disorders.

Measurement of health-related quality of life (HR-QoL) is used in patients with haemophilia as a way of assessing the effectiveness of health care, especially as cure is not possible. We report the first such study on patients with chronic coagulation disorders in Australia, using The RAND 36-item Health Survey 1.0 (SF-36), a standardized validated questionnaire combined with a semistructured interview. The mean scores for the eight domains of the SF-36 ranged from 52.5 +/- 42.1 for physical role to 80.0 +/- 20.0 for social functioning. Comparison with normative data obtained from the Australian Bureau of Statistics (ABS) demonstrated a reduction in all domains in this population with statistically significant reductions in general health, physical role limitation and vitality. Comparison with other studies indicates that the HR-QoL of patients with haemophilia and von Willebrand's disorder in Australia is comparable with other Western countries, reflecting the overall similar quality of care available to these patients. This study also provides a good cross-sectional view of the psychosocial factors of life in patients in Australia and recognizes the positive family support available to this population, while raising relevant shortcomings in schools and at the workplace that need to be studied further in a controlled manner.

Autologous peripheral blood stem cell transplantation with in vivo T-cell depletion for life threatening refractory systemic lupus erythematosus.

We report the first Australian application of autologous haemopoietic stem cell transplantation in a 39-year old woman with severe systemic lupus erythematosus (SLE) and multiple life threatening complications, refractory to conventional therapy including intravenous cyclophosphamide. Our transplant technique, although not unique, differs from most published reports, in which an unmanipulated peripheral stem cell graft was used with in vivo lymphocyte depletion using rabbit antithymocyte globulin (ATG). Successful stem cell mobilization was achieved using granulocytecolony stimulating factor mobilization with methylprednisolone cover, after an initial attempt at mobilization was curtailed by respiratory arrest from upper airway obstruction due to cricoarytenoiditis, requiring tracheostomy. Conditioning regimen for the transplantation was cyclophosphamide 50 mg/kg on days -5 to -2 and rabbit ATG 2.2 mg/kg on days -3 and -2. An unmanipulated autograft was infused, with in vivo T-cell depletion achieved through a further dose of ATG given on day +2 postinfusion. The autologous transplant was well tolerated without fever or other serious complication. At 12 months follow-up post-transplantation, there is an objective evidence of near-complete response with SLE disease activity index scores falling from 40 pretransplant to 2. We conclude that HSCT with unmanipulated peripheral stem cell graft and in vivo lymphocyte depletion with ATG is safe and effective therapy for cyclophosphamide refractory SLE.