Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial.

We report the 12-year follow-up of the prospective randomized EBMT LYM1 trial to determine whether the benefit of brief duration rituximab maintenance (RM) on progression-free survival (PFS) in patients with relapsed follicular lymphoma (FL) receiving an autologous stem cell transplant (ASCT) is sustained. One hundred and thirty-eight patients received RM with or without purging. The median follow-up after random assignment is 12 years (range 10-13) for the whole series. The 10-year PFS after ASCT is 47% (95% CI 40-54) with only 4 patients relapsing after 7.5 years. RM continues to significantly improve 10-year PFS after ASCT in comparison with NM [P = 0.002; HR 0.548 (95% CI 0.38-0.80)]. Ten-year non-relapse mortality (NRM) was not significantly different between treatment groups (7% overall). 10-year overall survival (OS) after ASCT was 75% (69-81) for the whole series, with no significant differences according to treatment sub-groups. 10-year OS for patients who progressed within 24 months (POD24T) was 60%, in comparison with 85% for patients without progression. Thus the benefit of rituximab maintenance after ASCT on relapse prevention is sustained at 12 years, suggesting that RM adds to ASCT-mediated disease eradication and may enhance the curative potential of ASCT.

The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults.

The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.

High hyperdiploidy among adolescents and adults with acute lymphoblastic leukaemia (ALL): cytogenetic features, clinical characteristics and outcome.

High hyperdiploidy (HeH, 51-65 chromosomes) is an established genetic subtype of acute lymphoblastic leukaemia (ALL). The clinical and cytogenetic features as well as outcome of HeH among adolescents and adults have not been thoroughly investigated. Among 1232 B-cell precursor ALL patients (15-65 years) treated in the UKALLXII/ECOG2993 trial, 160 (13%) had a HeH karyotype, including 80 patients aged >24 years. The frequency of HeH was the same in Philadelphia chromosome (Ph)-positive and -negative cases, but Ph-positive patients were older. The cytogenetic profiles of Ph-positive and Ph-negative HeH cases were similar, although trisomy 2 was strongly associated with Ph-positive HeH. Overall, Ph-positive HeH patients did not have an inferior overall survival compared with Ph-negative patients (P=0.2: 50 vs 57% at 5 years). Trisomy of chromosome 4 was associated with a superior outcome in Ph-negative patients, whereas +5 and +20 were associated with an inferior outcome in Ph-positive and Ph-negative patients, respectively. All three markers retained significance in multivariate analysis adjusting for age and white cell count: hazard ratio for risk of death 0.47 (95% CI: 0.27-0.84) (P=0.01), 3.73 (1.51-9.21) (P=0.004) and 2.63 (1.25-5.54) (P=0.01), respectively. In conclusion, HeH is an important subtype of ALL at all ages and displays outcome heterogeneity according to chromosomal gain.

Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008.

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation.

This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkin's lymphoma relapsing following autograft. There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy+/-radiotherapy. One group (n=38) then underwent alemtuzumab-containing RIT. The second group-historical controls (n=34), relapsing before the advent of RIT-had no further high-dose therapy. This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available. Overall survival (OS) from diagnosis was superior following RIT (48% at 10 years versus 15%; P=0.0014), as was survival from autograft (65% at 5 years versus 15%; P< or =0.0001). For the RIT group, OS at 5 years from allograft was 51%, and in chemoresponsive patients was 58%, with current progression-free survival of 42%. Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28-55). These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.

High incidence of avascular necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL XII analysis.

Avascular necrosis (AVN) is a serious complication of acute lymphoblastic leukaemia (ALL) therapy. Little is known of the scope and magnitude of this problem among adults with ALL. We analysed the incidence and risk factors for AVN in 1053 patients on the UKALLXII/ECOG2993 study. AVN affected 99 joints in 42 patients at a median of 2.2 years post-diagnosis, giving a crude incidence rate of 4.0%. Statistically significant risk factors for the development of AVN were age and treatment with chemotherapy. Patients receiving prolonged chemotherapy without stem cell transplant were at significantly greater risk of developing AVN than stem cell transplant recipients (P<0.00005). The actuarial incidence of AVN was 29% at 10 years in patients <20 years old compared to 8% at 10 years in those >20 years old; P=0.0004; odds ratio 0.28 (95% CI=0.14-0.56).

Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia.

ALL in which the Philadelphia (Ph) chromosome is detected is one of the few diseases in which there is almost unequivocal agreement that a matched sibling allogeneic haematopoietic stem cell transplant in first CR is the most appropriate therapy for patients within certain age limits. Extension of allogeneic stem cell transplant to patients without matched sibling donors or to older individuals is increasingly possible due to unrelated donors, umbilical cord blood and reduced-intensity conditioning regimens. Here, we carefully review evidence supporting current practice and examine recent evidence relating to the use of newer allogeneic transplant technologies in Ph-pos ALL. We explore the burgeoning literature on the role of tyrosine kinase inhibitors in this disease and summarize their impact on the transplant practice.

Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study.

To evaluate the outcome of a large series of patients who received high-dose treatment (HDT) for follicular lymphoma (FL), 693 patients undergoing HDT (total-body irradiation (TBI)-containing regimen: 58%; autologous bone marrow (BM)/peripheral blood progenitor cells (PBPCs): 378/285 patients) were included in the study. A total of 375 patients (54%) developed recurrent lymphoma, 10-year progression-free survival (PFS) being 31%. On multivariate analysis, younger age (P=0.003) and HDT in first complete remission (CR1) (P<0.001) correlated with longer PFS. With a median follow-up of 10.3 years, 330 patients died. Ten-year overall survival (OS) from HDT was 52%. Shorter OS was associated on multivariate analysis with older age (P<0.001), chemoresistant disease (P<0.001), BM+PBPC as source of stem cells (P=0.007) and TBI-containing regimens (P=0.004). Thirty-nine patients developed secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), in 34 cases having received TBI as the conditioning regimen. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, older age (P<0.001), refractory disease (P<0.001) and TBI (P=0.04) were associated with a higher NRM. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with HDT. On the downside, TBI-containing regimens are associated with a negative impact on survival.

A second autologous transplant may be efficacious in selected patients with Hodgkin's lymphoma relapsing after a previous autograft.

Treatment options for patients who relapse following autologous transplantation for Hodgkin's lymphoma are limited. There are anecdotal reports of lengthy remissions following second autologous procedures, although treatment-related toxicity can be significant. We report a single centre experience of second autologous transplant performed in seven highly selected patients, who relapsed following initial high-dose therapy. They were all young and had slow tempo disease, which was still sensitive to conventional dose chemotherapy. All received BEAM conditioning for the first transplant, and six of the seven received BEAM for the second. All six of these patients regenerated successfully and with no delay, the final patient dying during the procedure following alternative conditioning. Only one case of presumed carmustine-related pneumonitis was seen, which responded rapidly to corticosteroid therapy. Four patients have subsequently relapsed, of whom three have died at 29, 33, and 38 months postprocedure. One is alive with active disease at 68 months, and the final two are alive and in continuing complete remission at 104 and 68 months.

Use of 18F-FDG positron emission tomography following allogeneic transplantation to guide adoptive immunotherapy with donor lymphocyte infusions.

Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) provides valuable prognostic information in the management of lymphoma patients. However, the utility of (18)F-FDG PET following allografting is unclear. We analysed the use of (18)F-FDG PET after allogeneic reduced-intensity transplantation (RIT) performed in our institution. Between June 1998 and January 2002, 55 patients underwent RIT for either Hodgkin or non-Hodgkin lymphoma. At least one (18)F-FDG PET scan was performed during the post-transplant period (median five studies) in 15 (27.2%) of these 55 patients. PET scans were performed after re-staging computed tomography (CT) and were categorised depending on (18)F-FDG uptake. The first PET scan was informative in 11 of 15 patients (73%) and influenced the administration of donor lymphocyte infusions (DLI) in nine: leading to earlier DLI administration in two patients, earlier dose escalation in one, withholding of DLI administration in five and dose reduction in one. In addition, subsequent monitoring with (18)F-FDG PET scans documented a graft-versus-lymphoma effect in five patients (median post-DLI follow-up 33 months, range 13-36 months). These preliminary data suggest that (18)F-FDG PET has a role in guiding DLI administration and monitoring the immunotherapeutic effect in patients after allogeneic transplantation. This retrospective pilot study forms the basis for a prospective study to clarify the utility of (18)F-FDG PET/CT in these patients.

Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation.

We report the incidence, characteristics and outcome of neurological complications occurring following reduced-intensity conditioning (RIC) in 85 patients who received a related/unrelated donor stem cell transplantation following therapy with alemtuzumab, fludarabine and melphalan. Six patients (probability 8.9%) developed severe neurological complications at a median of 151 days (24-334 days). Five of them presented with progressive peripheral sensori-motor radiculo-neuropathy and/or myelitis, preceded by one or more viral reactivation/infection. Despite treatment with immunoglobulins/plasmapheresis/steroids, four died of respiratory failure due to progressive peripheral neurophathy. Viral infection was identified as the only risk factor for the development of neurological complications. Patients who are treated with alemtuzumab-based RIC may have a lower risk of developing regimen-related neurological complications, but are more susceptible to develop peripheral radiculo-neuropathy or myelitis. This phenomenon may be possibly related to viral infection associated with delayed immunological recovery or immunological dysregulation caused by alemtuzumab-induced T-cell depletion.

Adverse impact of bone marrow transplantation on quality of life in acute myeloid leukaemia patients; analysis of the UK Medical Research Council AML 10 Trial.

The increasing success of intensive consolidation chemotherapy (CCT) as an alternative to bone marrow transplant (BMT) in acute myeloid leukaemia (AML) necessitates comparison of the impact on quality of life (QoL) of these two treatment modalities. Most QoL studies following BMT involve small patient numbers and provide ambivalent results. The present study examines QoL in a large number of patients 1 year from the end of treatment within the United Kingdom Medical Research Council (UK MRC) AML10 trial of BMT versus CCT. Allogeneic-BMT (Allo-BMT) was observed to have an adverse impact on most QoL dimensions compared with Autologous-BMT (A-BMT) and CCT. More patients receiving BMT had mouth dryness problems and worse sexual and social relationships, professional and leisure activities than CCT patients. QoL in A-BMT patients was less impacted than Allo-BMT. Intention-to-treat analysis showed similar results. These results indicate that a reconsideration of treatment strategies is warranted, and that further, good prospective studies are needed to evaluate more clearly the effects of these treatments in long-term survivors.

Bone marrow transplant in Ph+ ALL patients.

Although the outcome for Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) with conventional chemotherapy is poor, the outcome after a sibling-matched allogeneic bone marrow transplantation (BMT) seems to be significantly better. The surprising success of allogeneic BMT may be because of disease response to high-dose chemotherapy combined with a graft-versus-leukemia effect. However, less than 30% of patients have a matched related donor available, and some of them will be too old/not fit for conventional BMT. While young patients who do not have a matched related donor should be considered for matched unrelated donor (MUD) transplant, older patients may be treated with autologous stem cell transplantation (ASCT) or rarely considered for a low-intensity MUD transplant. The efficacy of autologous BMT compared with chemotherapy is still debatable, although the new tyrosine kinase inhibitor Imatinib may be used for pretransplant purging/post-transplant therapy, aiming to improve autologous and allogeneic BMT results. The advantage of low-intensity sib/MUD allograft compared with chemotherapy is not proven either and is currently under investigation. However, if shown to be curative, low-intensity allograft may significantly improve the outcome of older Ph+ ALL patients, who are not eligible for conventional allograft.

An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation.

The role of allogeneic bone marrow transplantation in lymphoma remains uncertain. We have analyzed 1185 allogeneic transplants for lymphoma reported to the EBMT registry between 1982 and 1998 and compared the results with those of 14687 autologous procedures performed over the same period. Patients receiving allogeneic transplants were subdivided according to histology: low-grade non-Hodgkin's lymphoma (NHL) 231 patients; intermediate-grade NHL 147 patients; high-grade NHL 255 patients; lymphoblastic NHL 314 patients; Burkitt's lymphoma 71 patients; and Hodgkin's disease 167 patients. These patients received allogeneic transplants as their first transplant procedure. Actuarial overall survival (OS) at 4 years from transplantation was: low-grade NHL 51.1%; intermediate-grade NHL 38.3%; high-grade NHL 41.2%; lymphoblastic lymphoma 42.0% years; Burkitt's lymphoma 37.1%; and Hodgkin's disease 24.7% years. These outcomes are relatively poor because of the high procedure-related mortality associated with these procedures, particularly in patients with Hodgkin's disease (51.7% actuarial procedure-related mortality at 4 years). Multivariate analysis showed that for all lymphomas apart from Hodgkin's disease, status at transplantation significantly affected outcome. A matched analysis was performed: for all categories of lymphoma, OS was better for autologous than for allogeneic transplantation. Relapse rate was better in the allogeneic group for low-, intermediate- and high-grade, and lymphoblastic NHL. It was equivalent for Burkitt's lymphoma and worse in the allogeneic group for Hodgkin's disease. Allogeneic transplantation appears to be superior to autologous procedures in terms of producing a lower relapse rate. The toxicity of allogeneic procedures must however be reduced before this translates into an improvement in OS.

Non-Hodgkin's lymphomas: clinical governance issues.

Every patient in every part of the world has the right to expect the best possible quality of care from health care providers. Non-Hodgkin's lymphomas (NHL) are an extremely heterogeneous group of conditions which require important decisions to be taken at many points along the treatment pathway. To get this right every time requires that high-quality standards are instituted and adhered to, so that the best possible outcome is achieved. In the past this has not always been the case because of the failure of clinicians sometimes to adhere to an optimal management plan. In 1995, the UK government commissioned an inquiry into the running of cancer services in the United Kingdom, which culminated in a series of recommendations to improve them. Subsequently, these recommendations were implemented as objectives of the NHS Cancer Plan which is the framework by which the UK government wishes to improve cancer services. Concurrently another general concept has emerged which is designed to ensure that the highest quality standards may be achieved for all patients across the whole National Health Service (NHS). This concept, termed 'clinical governance', brings together a corporate responsibility of all health care workers to deliver high quality standards, in the hope that this will translate into better long-term survival of patients with malignant disease. This chapter focuses on the issues surrounding clinical governance and how the principles of this concept relate to non-Hodgkin's lymphomas.

Survival and freedom from progression in autotransplant lymphoma patients is independent of stem cell source: further follow-up from the original randomised study to assess engraftment.

Peripheral blood progenitor cells (PBPCs) have become the stem cell source of choice in autologous transplantation. In a prospective randomised trial, we previously demonstrated that autologous transplantation using filgrastim-mobilised PBPCs resulted in faster haematopoietic recovery with shorter hospitalisation and reduced platelet transfusions compared to bone marrow transplant (BMT). This study is a follow-up analysis evaluating the long-term clinical outcome. Seventy-two patients with advanced Hodgkin's disease or high-grade lymphoma were randomised to receive either filgrastim-mobilised PBPCs (n = 37) or bone marrow (n = 35) after BEAM chemotherapy. Fourteen patients withdrew from the study before commencing high-dose chemotherapy. Fourteen of the 58 patients who received treatment with chemotherapy and transplant have died, 6 (19%) in the ABMT arm and 8 (30%) in the PBPC transplant (PBPCT) arm. Twenty-five patients (81%) in the ABMT arm and 17 (63%) in the PBPCT arm, who received treatment, were in complete remission at the date of last follow-up. Progression-free survival and overall survival (OS) were similar for both arms (OS 81% at 46 months for ABMT versus 63% for PBPC; p = 0.38). Further prospective studies with larger number of patients need to be done to assess which source of stem cells may translate into a long-term clinical benefit for the patient.

ETV6/AML1 fusion by FISH in adult acute lymphoblastic leukemia.

Dual-color interphase fluorescence in situ hybridization (FISH) with ETV6 and AML1 probes was used for the first time on a series of 159 adult patients with acute lymphoblastic leukemia (ALL), for detection of the t(12;21)(p13;q22) translocation. Seven patients (4.4%) were found, with 50-100% of positive cells, of whom one of two tested, proved negative for the fusion product by RT-PCR. Two of them, aged 43 and 50 years, are the oldest patients so far confirmed to have the translocation. Three who relapsed at 10, 11 and 24 months, suggest that adults may not enjoy the good short-term prognosis reported for t(12;21)-positive children. Thirty-one-negative cases had signal numbers differing from the two expected for each gene. In 15 cases these results were consistent with the karyotype. In nine cases with uninformative cytogenetics, the numbers were consistent with those for centromeres and indicated a hidden aneuploidy. Loss of ETV6 genes in two cases and AML1 amplification in three others were not suspected from the cytogenetics. In conclusion, FISH proved to be reliable in defining ETV6/AML1 positivity in this group of patients as well as providing valuable insights into negative cases.