Efficient bone marrow irradiation and low uptake by non-haematological organs with an yttrium-90-anti-CD66 antibody prior to haematopoietic stem cell transplantation.

We report the results of a Phase I radiation dose escalation study using an yttrium-90 (90Y) labelled anti-CD66 monoclonal antibody given with standard conditioning regimen for patients receiving haematopoietic stem cell transplants for myeloid leukaemia or myeloma. The 90Y-labelled anti-CD66 was infused prior to standard conditioning. In total, 30 patients entered the trial and 29 received 90Y-labelled mAb, at infused radiation activity levels of 5, 10, 25, or 37.5 megaBequerel (MBq)/kg lean body weight. A prerequisite for receiving the 90Y-labelled mAb was favourable dosimetry determined by single-photon emission computerised tomography (SPECT) dosimetry following administration of indium-111 (111In) anti-CD66. Estimated absorbed radiation doses delivered to the red marrow demonstrated a linear relationship with the infused activity of 90Y-labelled mAb. At the highest activity level of 37.5 MBq/kg, mean estimated radiation doses for red marrow, liver, spleen, kidneys and lungs were 24.6 ± 5.6 Gy, 5.8 ± 2.7 Gy, 19.1 ± 8.0 Gy, 2.1 ± 1.1 and 2.2 ± 0.9, respectively. All patients engrafted, treatment-related mortality 1-year post-transplant was zero. Toxicities were no greater than those anticipated for similar conditioning regimens without targeted radiation. The ability to substantially intensify conditioning prior to haematopoietic stem cell transplantation without increasing toxicity warrants further testing to determine efficacy. clinicaltrials.gov identifier: NCT01521611.

Allogeneic hematopoietic stem-cell transplantation for patients with Richter transformation: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3-63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9-11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54-77) and 39% (27-51) and 53% (41-65) and 29% (18-40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs. 21%, p = 0.032). Cumulative incidences of grade II-IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29-53) and chronic GVHD at 3 years was 53% (95% CI 41-65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26-50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required.

Venetoclax-based low intensity therapy in molecular failure of NPM1-mutated AML.

ABSTRACT: Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax-based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy.

Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion.

Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).

Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival.

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.

UK consensus statement on the use of plerixafor to facilitate autologous peripheral blood stem cell collection to support high-dose chemoradiotherapy for patients with malignancy.

Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte-colony stimulating factor [G-CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re-mobilization after a failed mobilization attempt with G-CSF, and rescue or pre-emptive mobilization in patients in whom mobilization with G-CSF is likely to fail. Pre-emptive use has the advantage that it avoids the need to re-schedule the transplant procedure, with its attendant inconvenience, quality-of-life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre-emptive plerixafor is associated with an incremental drug cost of less than £2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 µl-1 at the time of recovery after chemomobilization or after four days of G-CSF treatment, or an apheresis yield of <1 × 106 CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre-emptive plerixafor.

Use of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization: an analysis of mobilization and engraftment.

Peripheral blood haematopoietic progenitor cell mobilization has become a standard procedure prior to autologous stem cell transplantation. Biosimilar granulocyte colony-stimulating factors (GCSF) have recently been awarded European Union (EU) licences for stem cell mobilization but data for their use in this context remain limited. The biosimilar GCSF, Ratiograstim(®) (Ratiopharm, Ulm, Germany) was granted an EU licence in September 2008 and incorporated into clinical practice in the Wessex Blood and Marrow Transplantation Programme in December 2008. Data were retrospectively collected for 154 consecutive patients undergoing peripheral blood stem cell harvest between January 2009 and December 2011 using the biosimilar GCSF. 131 consecutive patients from the preceding 3 years, who had received Neupogen(®) , were used as a control. We analysed both parameters relevant to stem cell collection and engraftment data, where patients proceeded to transplantation. We found no statistically significant difference between the two groups when comparing CD34 predictors, total number of CD34(+) stem cells collected, number of days required for collection, or for time to engraftment. This is, to our knowledge, the largest direct comparison of a biosimilar GCSF with originator GCSF for stem cell mobilization. The use of biosimilar GCSF can produce a significant cost saving, allowing investment in other areas of stem cell transplantation.

Mumps virus encephalomyelitis in a 19-year old male patient with an undefined severe combined immunodeficiency post-haematopoietic bone marrow transplantation: a rare fatal complication.

We describe a rare case of fatal mumps encephalomyelitis occurring in 19-year old male following matched unrelated donor peripheral blood haematopoietic stem cell transplantation (HSCT). The indication for HSCT was for an undefined form of severe combined immunodeficiency (SCID). Molecular typing of the mumps viral RNA isolated from neural tissue indicated that the infection was acquired at the time of a mumps outbreak in England and Wales that occurred between 2004 and 2006. This case highlights the importance of considering mumps in the differential diagnosis of central nervous system infection in highly immunosuppressed patients.

A randomized controlled trial of an appearance-related smoking intervention.

OBJECTIVES: To investigate whether exposure to a smoking-related facial age-progression technique impacts on quit smoking cognitions, nicotine dependence, and self-reported and objectively assessed smoking in young women in a randomized controlled trial. METHODS: eighteen- to 34-year-old women smokers (n = 70) were allocated at random to either an appearance-related intervention (plus usual care) or control (usual care) group. Women completed questionnaires assessing attitudes, subjective norms, perceived behavioral control and intention to quit smoking immediately before, immediately after, and four weeks after receiving the intervention or usual care. At the first and last time points they also completed measures of nicotine dependence and self-reported and objectively assessed smoking (breath carbon monoxide levels). RESULTS: The two groups were well matched at baseline. Using intention to treat analyses and baseline as a covariate, women in the appearance-related intervention group compared to the control group had significantly more positive attitudes, subjective norms, perceived behavioral control, and intentions to quit smoking immediately after exposure. Only the effects on quit smoking attitudes remained significant at four weeks postintervention. Nicotine dependence and self-reported smoking (total cigarettes in last seven days), but not objective smoking, were significantly lower in the intervention compared with control group at four weeks. CONCLUSIONS: This study suggests that an appearance-related smoking intervention may be a useful adjunct to traditional cessation programs with young women smokers.

Women smokers' experiences of an age-appearance anti-smoking intervention: a qualitative study.

OBJECTIVES: This study was designed to investigate women's experiences of engaging in an age-appearance anti-smoking intervention. METHODS: Ten 18- to 34-year-old women gave accounts of their experiences after engaging in an age-appearance facial morphing anti-smoking intervention in interviews (n= 7) and a focus group (n= 3), and 37 women gave their accounts while they were engaged in the intervention. Transcripts were analysed using a thematic analysis broadly informed by the procedures of Grounded Theory. RESULTS: Women were very concerned about the impact of ageing on their faces in general, and in particular the additional impact of smoking on their skin. Women were concerned about other people's reactions to them as older smokers with wrinkled skin, and many experienced a physical shock reaction (including reports of nausea) to seeing how they would age if they continued to smoke. They reported that seeing their own face aged on the computer screen increased their perceived risk of skin wrinkling. Women reported being highly motivated to quit smoking as a result of the intervention, and many reported that they would take active steps to quit having seen how they would look if they continued to smoke. This was linked with increased perceived personal responsibility for quitting. CONCLUSIONS: Results are discussed in relation to suggestions for anti-smoking interventions aimed at women in the 18- to 34-year-old age group. It is concluded that interventions incorporating age-appearance morphing techniques are likely to be effective in helping women to take active steps to quit smoking.

Long-term silicone central venous catheters impregnated with minocycline and rifampin decrease rates of catheter-related bloodstream infection in cancer patients: a prospective randomized clinical trial.

PURPOSE: To evaluate the efficacy of long-term nontunneled silicone catheters impregnated with minocycline and rifampin (M-R) in reducing catheter-related bloodstream infections. PATIENTS AND METHODS: This prospective, randomized, double-blind clinical trial was conducted at M.D. Anderson Cancer Center, a tertiary care hospital in Houston, TX. All patients in the trial had a malignancy. RESULTS: Between September 1999 and May 2002, 356 assessable catheters were used: 182 M-R and 174 nonimpregnated. The patients' characteristics were comparable between the two study groups. The mean (+/- standard deviation) duration of catheterization with M-R catheters was comparable to that of nonimpregnated catheters (66.21 +/- 30.88 v 63.01 +/- 30.80 days). A total of 17 catheter-related bloodstream infections occurred during the course of the study. Three were associated with the use of M-R catheters and 14 were associated with the nonimpregnated catheters, with a rate of catheter-related bloodstream infection of 0.25 and 1.28/1,000 catheter-days, respectively (P = .003). Gram-positive cocci accounted for the majority of the organisms causing the infections. There were no allergic reactions associated with M-R catheters. CONCLUSION: Long-term nontunneled central venous catheters impregnated with minocycline and rifampin are efficacious and safe in reducing catheter-related bloodstream infections in cancer patients.

Current Perspectives on the Use of Growth Factors in the Therapy of Acute Myeloid Leukaemia; Malignancy.

Recombinant haematopoietic growth factors have been available for clinical use for over a decade, however their role in the management of patients with acute myeloid leukaemia (AML) has yet to be established. There are several potential roles for the use of growth factors in the management of patients with AML, including reduction in the infective complications associated with the underlying disease and its treatment, use as mobilising agents in stem cell transplantation and as priming agents with chemotherapy. Clinical trials have failed to give clear indications for the use of growth factors following chemotherapy, mainly due to the variability of patient populations, chemotherapy and growth factor schedules used. G-CSF appears to be associated with no negative impact on remission rate or survival but clear benefits in terms of infection-related endpoints were not universally seen. Three studies did show a reduction in duration of hospitalisation, particularly when G-CSF was used following consolidation chemotherapy and economic analyses have also shown financial advantages to the administration of G-CSF. GM-CSF had a variable impact on survival and only two studies demonstrated reduction in serious infections or antimicrobial therapy use. These trials also showed economic benefits for the use of GM-CSF. Clinical studies which have attempted to exploit possible potentiation of chemotherapeutic activity by recruitment of leukaemic cells into the cell cycle have generally been disappointing. Use of growth factors for this purpose, outside the context of randomised clinical trials cannot be recommended. GM-CSF may have a role in modulating the cellular immune response against cancer cells but experimental data on its activity against leukaemia cells is limited. Augmentation of white cell function by G-CSF or GM-CSF may also be of clinical benefit in patients with suspected or confirmed fungal infection and further trials are underway.