Jenny L. Byrne

Allogeneic stem cell transplantation in the myelodysplastic syndromes: interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens

Summary. Conventional allogeneic stem cell transplantation (SCT) for myelodysplastic syndrome (MDS) is associated with excessive procedure‐related mortality. The outcome following volunteer‐unrelated donor (VUD) or sibling allogeneic SCT was therefore evaluated in 23 MDS patients conditioned with reduced‐intensity regimens (fludarabine/busulphan/Campath‐1H) because of advanced age (48 vs 37 years, P = 0·002) and/or co‐morbidity (19 vs 3, P < 0·0001) which precluded conventional transplantation, and compared with 29 treated with standard protocols [busulphan/cyclophosphamide (Bu/Cy); Bu/Cy/total‐body irradiation/Campath‐1G]. Graft‐versus‐host disease (GVHD) prophylaxis comprised of cyclosporine/methotrexate. One hundred per cent donor engraftment (variable number tandem repeat analysis/cytogenetics/fluorescence in situ hybridization) was achieved in 18/19 (95%) evaluable patients receiving reduced‐intensity regimens, although six (32%) have subsequently shown mixed chimaerism. Reduced‐intensity conditioning was associated with significantly reduced duration of aplasia, less mucositis, fever, antibiotic, analgesia, parenteral nutrition use, less acute and chronic GVHD, and lower early procedure‐related mortality [two (9%) vs nine (31%), P < 0·05]. Six patients relapsed (two standard, four reduced‐intensity) and two (reduced‐intensity) experienced late graft failure. The 2 year actuarial overall/disease‐free survival (OS/DFS) was 48/39% in the reduced‐intensity arm and 44/44% in the standard group. The 2 year non‐relapse mortality was 31% and 50% respectively. In VUD recipients, OS was superior in the reduced‐intensity arm (49%vs 34%). Predictors of DFS included good/intermediate‐risk karyotype, low/intermediate‐1 International Prognostic Scoring system score, human leucocyte antigen compatibility and attainment of complete remission. Our data demonstrates that VUD or sibling allogeneic SCT following reduced‐intensity conditioning is feasible in high‐risk MDS patients considered unsuitable for standard transplantation and is associated with comparable 3·5 year DFS to those receiving conventional regimens.

Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM–CAMPATH conditioning: an effective regimen with low procedure‐related toxicity

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure‐related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti‐CD52 antibody CAMPATH‐1G from day −5 to day −1.

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.

Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial

Disease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8+ T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8+ T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8+ T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8+ T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial.

Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission

Summary. Imatinib mesylate (IM, STI 571, Glivec®) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT‐PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony‐stimulating factor [rHu‐G‐CSF; 10 µg/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11·5/µl (range 0–108/µl), and 43/58 (74%) patients underwent a median of two (range 1–3) apheresis procedures. A median dose of 2·1 × 106/kg CD34+ cells (range 0·1–6·5 × 106/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR‐ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 × 106/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph– CD34+ cells from IM‐treated patients in CCR is possible using rHu‐G‐CSF alone.

Allogeneic Haemopoietic Stem Cell Transplantation for Multiple Myeloma or Plasma Cell Leukaemia Using Fractionated Total Body Radiation and High-dose Melphalan Conditioning

We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients <50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, <50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.

Ifosphamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilisation regimen for transplant-eligible patients with non-Hodgkin lymphoma and Hodgkin disease.

A total of 143 patients with relapsed (n =  90), primary refractory (n = 32) and first line chemotherapy responsive (n = 21) non‐Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were treated with IVE (ifosphamide, etoposide and epirubicin) chemotherapy with the intent to proceed to high‐dose therapy with either autologous or allogeneic transplantation, following peripheral blood stem cell mobilisation. A major response (complete/partial response) to IVE was seen in 115 patients (80·4%) with 5‐year overall survival (OS) and event free survival (EFS) of 53% and 43%, respectively. Subgroup analysis showed overall response rates of 93·1% for HD with a 5‐year OS and EFS of 62% and 52% respectively, while NHL showed response rates of 78·0% with 5‐year OS and EFS of 50% and 39% respectively. The median number of CD34 +ve cells mobilised following IVE was 7·86 × 106 (range 1·72–42·91 × 106), with 60% mobilising >2 × 106/kg in a single collection. Grade IV neutropenia was seen in 79·6% patients and 77/270 cycles required intravenous antibiotic treatment. We conclude that IVE has a high response rate across a range of refractory and relapsed lymphoma with acceptable toxicity and excellent PBSC mobilising characteristics.

Second-generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia in whom imatinib therapy has failed

Background It has not been clearly established whether second-generation tyrosine kinase inhibitors actually improve the survival of patients with chronic myeloid leukemia in chronic phase who are given nilotinib or dasatinib therapy after treatment failure with imatinib. Design and Methods To address this issue we compared the survival of 104 patients in whom first-line therapy with imatinib failed and who were then treated with second-generation tyrosine kinase inhibitors with the outcome of 246 patients in whom interferon-α therapy failed and who did not receive tyrosine kinase inhibitor therapy. Results Patients treated with second-generation tyrosine kinase inhibitors had longer overall survival than the interferon controls (adjusted relative risk= 0.28, P=0.0001). However this survival advantage was limited to the 64.4% of patients in whom imatinib failed but who achieved complete cytogenetic response with the subsequent tyrosine kinase inhibitor (adjusted relative risk =0.05, P=0.003), whereas the 35.6% of patients who failed to achieve complete cytogenetic response on the second or third inhibitor had similar overall survival to that of the controls (adjusted relative risk=0.76, P=0.65). Conclusions Patients in whom imatinib treatment fails who receive sequential therapy with second-generation tyrosine kinase inhibitors have an enormous advantage in survival over controls (palliative therapy); this advantage is, however, limited to the majority of the patients who achieve a complete cytogenetic response.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

BACKGROUND Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. METHODS We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. FINDINGS Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib. INTERPRETATION TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted. FUNDING Newcastle University and Bloodwise.

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.