Jennifer L. Byrne

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial

Summary Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137–632) before disease progression, with a median of 3·7 years follow-up (IQR 2·9–4·7). Zoledronic acid reduced mortality by 16% (95% CI 4–26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74–0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2–20) versus clodronic acid (HR 0·88, 95% CI 0·80–0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0–38·0 vs 17·5 months, IQR 8·5–34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]). Interpretation Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits. Funding Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0–65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.

Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial.

Summary Background Bisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events. Methods Patients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001). Interpretation The results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline. Funding Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation.

Summary:We treated 17 patients with refractory (n=7) or relapsed lymphoid malignancy (n=10) following allogeneic HSCT with donor lymphocyte infusions (DLI). Patients with low-grade disease received DLI alone (n=7) or following radiotherapy (n=1). Patients with aggressive disease (n=9) received prior chemotherapy. Nine out of 15 patients receiving DLI from sibling donors responded after one (n=6), two (n=2) and three (n=1) infusions. Both MUD recipients achieved CR after two and three DLI. In all, 10/17 patients achieved CR including 3/4 patients with chronic lymphatic leukaemia (CLL), 4/4 with mantle cell lymphoma (MCL), 3/4 with follicular NHL but 0/5 with aggressive NHL/Richters. The median CD3 cell dose to achieve CR for siblings was 2 × 107/kg. One patient with CLL had a second transplant following DLI-induced aplasia and is in CR at 14 months giving a final CR rate of 64%. Grade II–IV acute GVHD developed in 45% and chronic GVHD in 8/9 evaluable patients. Of the 11 patients finally achieving CR, one patient with MCL relapsed at 18 months post-DLI but all others remain in remission with a median follow-up of 40 months (range 12–64 months). Low-grade NHL and MCL have a high response rate and sustained remissions following DLI. Aggressive disease responds poorly however, despite pre-DLI chemotherapy.

The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia.

unrelated donor (ud) transplantation is the only potentially curative therapy for many leukaemia patients but is associated with a high mortality and morbidity. we sought to identify factors that could be optimised to improve outcome following ud transplantation in adults. data was retrospectively analysed on 55 patients sequentially receiving ud transplants for cml or acute leukaemia (al), all of whom received serotherapy for the prevention of gvhd and rejection. all patients received standard conditioning regimens. the first 28 patients transplanted also received combined pre- and post-transplant serotherapy with campath 1g (days −5 to +5) and standard dose csa plus mtx as gvhd prophylaxis (protocol 1). the subsequent 27 patients received a 5-day course of pre-transplant serotherapy alone either with atg (cml patients) or campath 1g (al patients) on days −5 to −1 inclusive, with high-dose csa plus mtx (protocol 2). the incidence of acute gvhd was low with no patient receiving either protocol developing >grade 2 disease. The use of protocol 2 and the administration of a bone marrow cell dose above the median (2.17u2009×u2009108/kg) were the most important factors predicting engraftment (P = 0.03 and P = 0.001, respectively) but this only remained significant for cell dose in multivariate analysis (P = 0.03). Overall survival for the group was 45% at 3 years and was influenced by both age (P = 0.02) and disease status at transplantation (P = 0.001). Receiving a cell dose above the median was also associated with a trend towards better survival (P = 0.08), due primarily to a reduction in the TRM to 8.2% compared with 54.5% in those receiving a lower cell dose (P = 0.002). We conclude that pre-transplant serotherapy alone is highly effective at preventing acute GVHD following UD BMT and that additional post-transplant serotherapy does not confer any benefit. Furthermore, a high marrow cell dose infused has a major effect in reducing transplant-related mortality following UD BMT. Bone Marrow Transplantation (2000) 25, 411–417.

A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation

This open-label, dose-escalation study assessed the maximum tolerated dose (MTD) of the new antifungal micafungin in patients undergoing haematopoietic stem cell transplantation (HSCT). Participants received 3, 4, 6 or 8u2009mg/kg/day micafungin intravenously from 7 days to a maximum of 28 days or until neutropaenia resolved. The MTD was defined as the highest dose not causing the same Grade 3 or 4 adverse event in three or more patients. All 36 participants received ⩾8 days treatment for a median of 18 days (range: 8–28); 1 patient withdrew consent and a further 11 discontinued to receive another systemic antifungal agent for a suspected infection. No case of confirmed invasive fungal infection occurred. Adverse events were those expected for patients undergoing HSCT and showed no evidence of dose-related toxicity. Criteria for MTD were not met; no patient had a Grade 3 or 4 adverse event considered causally related to micafungin. Thus, the MTD of micafungin can be inferred to be 8u2009mg/kg/day or higher.

Outbreaks of infectious diseases in stem cell transplant units: a silent cause of death for patients and transplant programmes

Summary:Following the closure of the National Blood and Bone Marrow Transplant Unit in Dublin, because of an outbreak of vancomycin-resistant enterococcal infection, a survey was carried out by the EBMT to investigate the occurrence of outbreaks of infection in SCT units and the impact on patient morbidity, mortality and the administration of the transplant programme over a 10-year period from 1991 to 2001. A total of 13 centres reported 23 outbreaks of infection involving 231 patients: 10 bacterial, eight viral and five fungal outbreaks were reported and 56 deaths were attributed to infection. All fungal and bacterial deaths and the majority of viral deaths occurred in allograft recipients. In all outbreaks, the infection was reported to be hospital acquired and in all the viral, and half the bacterial infections, cross-infection was a major factor. All viral, four of 10 bacterial and three of five fungal outbreaks occurred in HEPA filtered rooms. A total of 12 SCT units reported a partial or total closure. The introduction of mandatory quality management systems such as JACIE should result in a change in attitude to ‘incident reporting’ and together with future surveys should reduce the incidence of infectious outbreaks in SCT units.

Stem cell mobilisation in lymphoproliferative diseases

A number of different regimens have evolved for the mobilisation of peripheral blood stem cells for autologous transplantation in patients with lymphoma or myeloma. A successful regimen could be defined as one which consistently resulted in the collection of an optimal number of CD34+ cells with a minimum number of apheresis procedures with minimal toxicity. Initial protocols, which used chemotherapy alone as a mobilising agent, have now been replaced by regimens involving the use of haematopoietic growth factors either alone or in combination with variable doses of cyclophosphamide. Although there is good evidence that high-dose cyclophosphamide (6–7 g/m2) is an effective mobilising agent it is associated with significant toxicity and many groups have now utilised lower doses of cyclophosphamide with reduced toxicity which have still proven to be effective in the majority of patients. More recently a number of ‘second generation’ combined salvage chemotherapy and mobilisation regimens have been reported for use in the lymphomas which have the advantage of avoiding a specific stem cell mobilisation step and at the same time appear more consistently effective at mobilising stem cells than cyclophosphamide and G-CSF. These regimens are associated with fewer ‘poor-mobilisers’ and indeed some patients who have failed previous mobilisation with cyclophosphamide and G-CSF have been successfully re-mobilised. It is clear that in both lymphoma and myeloma patients the success of PBSC mobilisation is affected by the amount and type of previous chemotherapy and radiotherapy and probably other pre-treatment factors as exemplified by variability seen in normal donors mobilised with G-CSF alone. In myeloma most groups have utilised cyclophosphamide in variable doses in combination with G-CSF or GM-CSF. However, recent randomised studies have confirmed that G-CSF alone is an effective and non-toxic alternative although it appears that the efficacy of G-CSF as a single agent is related to the dosage used with daily doses of 16u2009μg/kg/day or greater being most effective. Thus, disease-specific mobilisation strategies appear to be emerging and these will undoubtedly be modified further as more is understood concerning the biology of blood stem cell mobilisation.

Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma

The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)‐alemtuzumab allogeneic HSCT (BEAM‐allo) (nu2003=u200344) or BEAM‐autologous HSCT (BEAM‐auto) (nu2003=u200382). The BEAM‐allo group had a younger median age (48u2003years vs. 56u2003years, Pu2003<u20030·001) but received a higher median number of therapies pretransplant (Pu2003=u20030·015) compared with the BEAM‐auto group. There was a higher non‐relapse mortality (NRM) in the BEAM‐allo group compared with the BEAM‐auto group at 1u2003year (20% vs. 2%, Pu2003=u20030·001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM‐allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, Pu2003=u20030·01) at 3u2003years with BEAM‐alemtuzumab, with no relapses after 2u2003years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (Pu2003=u20030·99) or disease‐free survival (DFS) (Pu2003=u20030·90) was identified at 3u2003years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM‐allo group was observed. Furthermore, the ability to re‐induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.