Shirley D'Sa

Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma

The feasibility and efficacy of a triple regimen of oral weekly cyclophosphamide, monthly pulsed dexamethasone and low‐dose Thalidomide (CDT) was studied in 52 patients with relapsed or refractory multiple myeloma (MM). All 52 patients were evaluable for response with a median follow up of 18 (4–29) months. About 17% achieved complete response (CR), 62% partial response (PR), 11% minimal response (MR), 6% stable disease (SD) and 4% progressive disease (PD), resulting in an objective response rate (≥MR) of 90%. Subsequent to successful response, nine patients received high‐dose therapy (HDT) followed by stem cell transplantation (SCT) and 34 received thalidomide monotherapy as maintenance. Response rate was not influenced by disease status, prior HDT or age. The regimen was successfully delivered to all patients except for one patient who developed abnormal liver function at 7 weeks. Infective complications were minimal and there were no infection‐related deaths. The estimated overall and event‐free survival (EFS) at 2 years was 73% and 34%, respectively, and the median time to progression has not been reached. We conclude that the CDT regimen is safe, well tolerated and effective in patients with relapsed and refractory myeloma.

Guidelines for the use of imaging in the management of myeloma

In 2001, reference to the use of imaging in the British Committee for Standards in Haematology guidelines for the diagnosis and management of myeloma was confined to the standard use of plain X‐rays in the diagnostic skeletal survey and emergency use of computed tomography (CT) and magnetic resonance (MR) imaging in the setting of cord compression. Since then, there has been a steady rise in interest in the use of various imaging techniques in the management of myeloma. The purpose of imaging in the management of myeloma includes the assessment of the extent and severity of the disease at presentation, the identification and characterisation of complications, and the assessment of response to therapy. Plain radiography, CT, and MR imaging are generally established examination techniques in myeloma whilst positron emission tomography (PET) and 99Technetium sestamibi (MIBI) imaging are promising newer scanning techniques under current evaluation. These stand‐alone imaging guidelines discuss recommendations for the use of each modality of imaging at diagnosis and in the follow up of patients with myeloma.

T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions

Summary. Immune reconstitution after conventional allogeneic transplantation is a major determinant of survival. We conducted a detailed investigation of T‐ and B‐cell immune reconstitution and clinical outcome in 19 patients with multiple myeloma undergoing reduced‐intensity stem cell transplantation using in vivo T‐cell depletion with alemtuzumab. These patients experienced delayed T‐cell recovery, particularly in the naïve (CD45 RA+) CD4 compartment. T‐cell receptor spectratype analysis showed a reduced repertoire diversity, which improved rapidly after the administration of donor leucocyte infusions and subsequent conversion to full donor T‐cell chimaerism. Post‐transplant recovery of CD19+ B cells was also delayed for up to 18 months. Spectratype analysis of IgH CDR3 repertoire revealed a gradual normalization in IgM spectratype complexity by 6–12 months after transplant. There was a high incidence of viral infection, particularly cytomegalovirus reactivation, but the regimen‐related mortality was low, perhaps because of the very low incidence of acute graft‐versus‐host disease (GVHD; grade I‐II skin GVHD was seen in 5/19 patients). Over 80% of all patients have relapsed at a median of 283 (range 153–895) d after transplant, suggesting that the initially low rate of GVHD comes at a high price with regard to the desired graft‐versus‐myeloma effect.

Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens

This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first‐line salvage therapy (1°ST) and who subsequently receive a second‐line salvage regimen (2°ST) with the intention of ultimately proceeding to high‐dose therapy. The outcome of 57 patients [Hodgkins Lymphoma 17, histologically‐aggressive non‐Hodgkins Lymphoma (NHL) 26, histologically‐indolent NHL 14] who received more than one modality of conventional‐dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1°ST, but subsequently received 2°ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2°ST. Of the 15 patients who had stable disease following 1°ST, 5 (33%) responded to 2°ST. Only one of the 24 (4%) with progressive disease (PD) following 1°ST, responded to 2°ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2‐year progression‐free survival (PFS) and the 3‐year overall survival (OS) for all patients was 24% and 31%, respectively. Long‐term survival was highly dependent on response to 1°ST (P = 0·0001); in patients with PD following 1°ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1°ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.

Assessing diversity: immune reconstitution and T-cell receptor BV spectratype analysis following stem cell transplantation.

Summary. T‐cell receptor (TCR) BV spectratyping provides information concerning immune reconstitution complementary to that derived from monoclonal antibody analysis of surface antigen expression. However, the most appropriate way to analyse and represent these data, the number of subfamilies that should be analysed, and the effects of CD4/8 ratio on observed diversity, remain unclear. A diversity scoring system was developed based on analysis of 11 cord blood (CB) and 12 normal adult BV spectratypes. CB subfamily spectratypes demonstrated minor deviations from a Gaussian pattern consistent with current knowledge about germline TCR rearrangements. Diversity scores were significantly lower in myeloma patients than normal adults (P < 0·001) and fell significantly following stem cell transplantation (P = 0·003). Subsequently increasing diversity was not detected by two previously described complexity scoring systems. The CD4/8 ratio was neither the major determinant of the absolute diversity score nor of the change in score for individual patients, suggesting that analysis of unselected mononuclear cells can provide information largely independent of CD4/8 ratios. There was a relatively low correlation between individual subfamily scores and overall diversity score. The novel and objective diversity scoring system described appears better able to document changes in spectratype patterns than previously described techniques and should aid the standardization of reporting.

Central nervous system involvement by Waldenström macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study.

Bing‐Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi‐centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3‐year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi‐institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.

Elevated lactate dehydrogenase levels detected during routine follow-up do not predict relapse in patients with diffuse large B-cell lymphoma who achieve complete remission after primary treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone-like immunochemotherapy.

Abstract A significant minority of patients with diffuse large B-cell lymphoma (DLBCL) who enter a complete remission following standard first-line immunochemotherapy will relapse. A primary aim of follow-up is to detect early relapse, with the hope of improving outcome following salvage chemotherapy. It is often routine to measure lactate dehydrogenase (LDH) as part of follow-up; however, the evidence for the utility of LDH as a predictor for relapse is scant. A retrospective analysis of the LDH results recorded during the follow-up of 102 patients with DLBCL who achieved a CR following treatment was undertaken in order to determine the utility of LDH as a predictor for relapse (median follow-up 24 months). Despite the fact that the sensitivity of LDH was 69% (95% confidence interval [CI] 39–91), the positive predictive value (PPV) of a raised LDH was only 9/63, 14% (95% CI 6.7–25). Furthermore, in eight of the nine patients who had a raised LDH prior to relapse, symptoms suggestive of relapse were documented simultaneously. As the PPV of a raised LDH is so low and because a raised LDH may cause unnecessary worry, leading to unnecessary radiological investigations, routine evaluation of LDH in patients with DLBCL who achieve CR and who are asymptomatic is not recommended.

Bortezomib‐induced inflammatory neuropathy

Dear Editor, Bortezomib is a proteasome inhibitor licensed in the UK for the treatment of patients with untreated or relapsed/refractory multiple myeloma (MM) who are not candidates for stem cell transplantation. Peripheral neuropathy is a significant non-haematological toxicity associated with bortezomib therapy (Richardson et al., 2006). There remain conflicting data about whether bortezomib neuropathy is dose-related (Richardson et al., 2006; Cata et al., 2007; Chaudhry et al., 2008; Lanzani et al., 2008). Treatment emergent neuropathy usually occurs within the first four cycles, and patients who have not experienced this complication by cycle 5 are unlikely to do so (Richardson et al., 2006). This suggests alternative underlying mechanisms besides classical toxic dose-related axonal insult. For example, Ravaglia et al. (2008) presented a series of five cases of patients treated with bortezomib who developed possible inflammatory polyradiculoneuritis. A severe pulmonary reaction, likely vasculitic, has been reported with bortezomib (Miyakoshi et al., 2006). Bortezomib has also been described as causing cutaneous vasculitis in patients with non-Hodgkin lymphoma (Gerecitano et al., 2006). Interestingly, the response rate to treatment in the subgroup of patients who developed skin vasculitis was improved over bortezomib patients who did not develop skin vasculitis. The appearance of skin vasculitis from bortezomib was not dose dependent. The authors suggest there may be a connection between a vasculitic response and an improved response to treatment in this patient group. We report a case of bortezomib-induced inflammatory neuropathy confined to the peripheral nerves in a patient with refractory MM. In 2005, a 59-year-old man noted epistaxis and fatigue. MM was diagnosed based on an IgG kappa paraprotein (61 g/dl), a heavy infiltrate of monoclonal

Efficacy of rituximab in combination with steroids in refractory chronic lymphocytic leukemia

The optimal salvage treatment for patients with chronic lymphocytic leukemia (CLL) who have failed or relapsed shortly after treatment with purineanalogue based treatment remains undefined. This is especially true in the elderly who may not be able to tolerate treatment intensification. Alemtuzumab, although effective, is associated with a significant risk of infective complications [1] and is only partially effective in patients with bulky lymphadenopathy. Therefore, it was with interest that we read the article by Bowen et al. (December 2007) in which they report their experience with methylprednisolonerituximab as a salvage treatment for patients with relapsed CLL [2]. High-dose methylprednisolone (HDMP) is an established treatment in refractory CLL and can induce responses both in patients with bulky disease and those with p53 mutations [3,4]. The standard HDMP treatment regimen for CLL patients is 1 gm/m intravenously for 5 days in contrast to myeloma, for example, where the standard ‘high-dose’ steroid regimen is dexamethasone 40 mg for 4 days. We recently treated 12 patients (Table I) with mainly advanced/refractory CLL with a combination of rituximab and high-dose steroids (R-HDS) and we observed a similarly high overall response rate to Bowen et al. (details below). However, 50% of our patient group received 40 mg of dexamethasone orally for 4 days in 28 day cycles in place of HDMP. It is worth noting that 10 g of methylprednisolone (the 5-day cumulative dose for a patient with a body surface area of 2) is equivalent to 1875 mg of dexamethasone, almost a 12-fold increase in the total corticosteroid dose. Although twenty-five percent of our patients developed infectious complications there were no patient deaths during treatment in contrast to the mortality rate of 14% during the first month of treatment in the report by Bowen et al. In addition we also looked for evidence of synergistic apoptotic effects by exposing patient CLL cells to R-HDS and other combinations in-vitro. In treating 37 patients with CLL, Bowen et al. noted an objective response in 78% (NCI CLL working group criteria [5]) of patients with 22% of patients achieving a ‘complete clinical response’, but strict complete responses were not recorded. The median time to progression was 12 months. Importantly, their patient group included nine patients with deletion of 17p13.1 (of which five responded) and six with deletion of 11q22.3. The patient group also included five patients with Rai Stage 0 disease. Despite this, they observed infectious complications in 29% of patients and 14% patients died from infectious complications during their first course of treatment although these patients also had serious comorbidities. Anti-viral and anti-Pneumocystis carinii prophylaxis were prescribed for some of the patients. Five patients also required readmission to hospital with non-infectious complications and 38% of patients developed grade 2–3 hyperglycemia. More recently, Dungarwalla et al. [6] reported their experience with this combination in 14 patients with relapsed refractory CLL. They observed an overall response rate of 93% with a median progression-free

Etoposide, methylprednisolone, cytarabine and cisplatin successfully cytoreduces resistant myeloma patients and mobilizes them for transplant without adverse effects

Myeloma remains incurable with a median survival of 4 years, but outcome can be improved by the use of high‐dose therapy. We used the etoposide, methylprednisolone, cytarabine and cisplatin (ESHAP) regimen as second‐line therapy in 42 newly diagnosed myeloma patients who had failed vincristine, adriamycin and dexamethasone (VAD)‐ type therapy (n = 36), responded to first‐line treatment but persisted in having significant residual marrow plasmacytosis (n = 5) or failed prior stem cell harvesting (n = 1), with the dual aim of improving disease response and mobilizing peripheral blood stem cells. Fourteen of 21 (67%) patients with no change or progressive disease after VAD responded to ESHAP; seven of 12 (58%) patients with minor response converted to partial response. Marrow plasmacytosis fell from a median of 52% at diagnosis to 23·5% after primary therapy and to15% after ESHAP. ESHAP chemotherapy was well‐tolerated. There were 11 admissions due to febrile neutropenia (n = 7), nausea and vomiting (n = 2), pneumonia (n = 1) and perforated bowel (n = 1). Renal function deteriorated in 13 of 42 patients after ESHAP, but none required renal support. ESHAP mobilization was performed in 32 patients of whom 87% achieved a CD34+ yield >2 × 106/kg. In all, 38 patients proceeded to high‐dose therapy. The overall survival for all patients was 62% at 4 years following ESHAP. We conclude that ESHAP has acceptable toxicity and efficient stem cell mobilizing capability, effectively cytoreduced this chemoresistant group of patients, and did not appear to adversely affect transplant outcome.