Grant McQuaker

Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies

PURPOSE Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. PATIENTS AND METHODS A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. RESULTS Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. CONCLUSION Nonmyeloablative allogeneic SCT after CAMPATH-1H-containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.

The role of allogeneic SCT in primary myelofibrosis: a British Society for Blood and Marrow Transplantation study

Fifty-one patients with primary myelofibrosis (PMF) received allogeneic haematopoietic stem cell transplants from related (n=33) or unrelated (n=18) donors. Twenty-seven patients, 19–54 years old, were prepared with myeloablative regimens including CY plus BU (n=4) or TBI (n=23). Twenty-four patients, 40–64 years old, received reduced-intensity conditioning (RIC) regimens. All RIC regimens contained fludarabine, combined with melphalan (n=19) or BU (n=5), and alemtuzumab or anti-thymocyte globulin (ATG) in the majority (n=19). Four patients (17%) in the RIC group had primary graft failure. Previous splenectomy reduced time to engraftment in the RIC group (13 versus 20 days; P=0.008). For MA and RIC groups, respectively, at 3 years, overall survival rates were 44 and 31% (P=0.67), progression-free survival 44 and 24% (P=0.87), and actuarial relapse rates 15 and 46% (P=0.06). Non-relapse mortality at 3 years was 41% for the myeloablative and 32% for the RIC group. Acute GVHD occurred in 29 and 38% of patients in the myeloablative and RIC groups, respectively. Extensive chronic GVHD developed in 30 and 35% of evaluable patients, respectively.

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.

The outcome of high‐dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty‐three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60–200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant‐related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6–54 months) and the median time to best response was 6·5 months. Four of 17 evaluable patients (24%) became dialysis‐independent at a median of 5 months post‐HDT/stem cell transplantation. At a median follow‐up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5‐year survival in about one‐third of patients.

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 16 μg/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.

Hypocupremia associated cytopenia and myelopathy: a national retrospective review

Copper is an essential trace element that is involved in a number of important enzymatic processes throughout the body. Recent single case reports and small studies have shown that deficiency of copper can cause reversible haematological changes and irreversible neurological injury. We chose to undertake a national study, looking at all cases of copper deficiency in Scotland over a 5‐yr period using information from a national reference laboratory. From 16 identified patients, we determined that 86% had both haematological and neurological features of copper deficiency, while 18% had haematological features only at presentation. Twelve of the sixteen patients had high serum zinc concentrations (>18 μm/L) nine patients were using zinc‐containing dental fixatives at time of diagnosis. 94% of patients had haematological features as an initial manifestation of copper deficiency, which included anaemia, thrombocytopenia and neutropenia. Patients who underwent later bone marrow testing had appearances in keeping with refractory cytopenia with multilineage dysplasia, refractory anaemia with excess of blasts, unclassified marrow dysplasia or probable myelodysplasia (MDS). 75% of patients had neurological symptoms or signs, including progressive walking difficulties and paraesthesia, or gait difficulties without sensory signs. Clinical examination was in keeping with spastic paraparesis (either with or without sensory neuropathy). Magnetic resonance imaging (MRI) showed multifocal T2 hyper intense foci in the subcortical white matter, and atrophy of the cerebrum and cerebellum was also seen on computerised tomography (CT). MRI of the spinal cord showed signal change in the dorsal columns in either the cervical or thoracic cord. 93% of cytopenias responded to copper replacement and addressing the original cause of the copper deficiency, but only 25% of patients had improvement in their neurological function, while 33% deteriorated and 42% remained unchanged. Our study demonstrates that copper deficiency is an under‐recognised cause of several types of cytopenia, which are reversible but can progress to significant neurological injury if left untreated. We illustrate the importance of identifying these patients early to prevent irreversible neurological injury.

Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation

Purpose To compare the outcome of patients with Hodgkin lymphoma who received post-transplantation cyclophosphamide-based haploidentical (HAPLO) allogeneic hematopoietic cell transplantation with the outcome of patients who received conventional HLA-matched sibling donor (SIB) and HLA-matched unrelated donor (MUD). Patients and Methods We retrospectively evaluated 709 adult patients with Hodgkin lymphoma who were registered in the European Society for Blood and Marrow Transplantation database who received HAPLO (n = 98), SIB (n = 338), or MUD (n = 273) transplantation. Results Median follow-up of survivors was 29 months. No differences were observed between groups in the incidence of acute graft-versus-host disease (GVHD). HAPLO was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%; P = .04). Cumulative incidence of nonrelapse mortality at 1 year was 17%, 13%, and 21% in HAPLO, SIB, and MUD, respectively, and corresponding 2-year cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. On multivariable analysis, relative to SIB, nonrelapse mortality was similar in HAPLO ( P = .26) and higher in MUD ( P = .003), and risk of relapse was lower in both HAPLO ( P = .047) and MUD ( P < .001). Two-year overall survival and progression-free survival were 67% and 43% for HAPLO, 71% and 38% for SIB, and 62% and 45% for MUD, respectively. There were no significant differences in overall survival or progression-free survival between HAPLO and SIB or MUD. The rate of the composite end point of extensive chronic GVHD and relapse-free survival was significantly better for HAPLO (40%) compared with SIB (28%; P = .049) and similar to MUD (38%; P = .59). Conclusion Post-transplantation cyclophosphamide-based HAPLO transplantation results in similar survival outcomes compared with SIB and MUD, which confirms its suitability when no conventional donor is available. Our results also suggest that HAPLO results in a lower risk of chronic GVHD than MUD transplantation.

High dose therapy and autologous stem cell transplantation in patients with POEMS syndrome: A retrospective study of the Plasma Cell Disorder sub-committee of the Chronic Malignancy Working Party of the European Society for Blood & Marrow Transplantation.

POEMS syndrome is a rare para-neoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment can control the disease-related symptom complex. We describe the clinical outcome of autologous stem cell transplantation for patients with POEMS syndrome, determining the impact of patient- and disease-specific factors on prognosis. One hundred and twenty-seven patients underwent an autologous stem cell transplantation between 1997–2010 with a median age of 50 years (range 26–69 years). Median time from diagnosis to autologous stem cell transplantation was 7.5 months with 32% of patients receiving an autologous stem cell transplantation more than 12 months from diagnosis. Engraftment was seen in 97% patients and engraftment syndrome was documented in 23% of autologous stem cell transplantation recipients. Hematologic response was characterized as complete response in 48.5%, partial response in 20.8%, less than partial repsonse in 30.7%. With a median follow up of 48 months (95%CI: 38.3, 58.6), 90% of patients are alive and 16.5% of patients have progressed. The 1-year non-relapse mortality was 3.3%. The 3-year probabilities of progression-free survival and overall survival are 84% and 94%, respectively, with 5-year probabilities of progression-free survival and overall survival of 74% and 89%. In a cohort of graft recipients, detailed organ-specific symptom response demonstrated clear symptom benefit after autologous stem cell transplantation especially in relation to neurological symptom control. The data analyzed in this study demonstrate the clinical utility of autologous stem cell transplantation for patients with POEMS syndrome.

Association of Macroeconomic Factors With Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation for Adults With Acute Lymphoblastic Leukemia: An Analysis From the Acute Leukemia Working Party of the EBMT

PURPOSE From a global perspective, the rates of allogeneic hematopoietic cell transplantation (alloHCT) are closely related to the economic status of a country. However, a potential association with outcome has not yet been documented. The goal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on nonrelapse mortality (NRM) after HLA-matched sibling alloHCT for adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. RESULTS In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21% vs. 16%; p = .07). In a multivariate analysis, the strongest predictive model for day 100 NRM included current HCE greater than the median (hazard ratio [HR], 0.39; p = .002). The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. CONCLUSION Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted.

Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM)–Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin Lymphoma: An Analysis of Outcomes from the British Society of Blood and Marrow Transplantation

The role of allogeneic stem cell transplantation (SCT) in the management of aggressive non-Hodgkin lymphoma (NHL) remains to be defined, but the number of procedures performed continues to increase. We report here the outcomes of allogeneic SCT using carmustine, etoposide, cytarabine, and melphalan (BEAM)-Campath (Genzyme Corporation, Cambridge, MA) conditioning for aggressive NHL as reported to the British Society of Blood and Marrow Transplantation (BSBMT). This retrospective study identified 46 patients who reported to the BSBMT registry as having undergone BEAM-Campath conditioned allogeneic SCT for aggressive NHL between 1999 and 2010. Disease histology was diffuse large B cell lymphoma (DLBCL, n = 25), DLBCL/Burkitt lymphoma (n = 5), and T cell lymphoma (n = 16). At diagnosis, the median age was 42.5 (range, 17 to 59), 37 had advanced stage disease (Ann Arbor III/IV), 28 had 2 or more extra-nodal sites of disease, and 23 had elevated lactate dehydrogenase. International prognostic index was high or high/intermediate in 58%. The median number of prior therapies was 3 (range, 1 to 5) and 5 patients had previously undergone transplantation (4 autologous, 1 allogeneic). The median age at transplantation was 44.8 (range, 18 to 59), with 34 patients demonstrating chemo-sensitive disease and 22 undergoing transplantation in first response. Performance score was good in 40 patients and all engrafted with a median of 14 days (range, 11 to 27) to neutrophil recovery. At latest follow-up, 20 patients were alive with 17 in complete remission. Acute graft-versus-host disease (GVHD) developed in 7 patients and chronic GVHD developed in 13 (7 limited, 6 extensive). Five patients died from nonrelapse causes, with a cumulative incidence of nonrelapse mortality of 7% at 100 days and 11% at 3 and 5 years. Twenty-one patients died after lymphoma relapse, with a cumulative incidence of relapse/progression of 51% at 1 year and 53% at 5 years. Disease status at transplantation had no impact on relapse rate. Progression-free survival was 41% at 1 year and 36% at 5 years. Overall survival was 54% at 1 year and 42% at 5 years. Overall, BEAM-Campath-conditioned allogeneic SCT is well tolerated and able to deliver durable disease-free survival to a subset of patients with aggressive NHL. However, the high relapse rates indicate further investigation is needed to identify those patients most likely to benefit.

Radioimmunotherapy-augmented BEAM chemotherapy vs BEAM alone as the high-dose regimen for autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL): a retrospective study of the EBMT Lymphoma Working Party

Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.