Understanding quality of life issues in patients with advanced melanoma: Phase 1 and 2 in the development of the EORTC advanced melanoma module.

AIMS: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy. METHODS: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module. RESULTS: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates. Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items. CONCLUSION: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.

"One more chance to survive": the experiences of patients with advanced melanoma and their partners with tumor-infiltrating lymphocyte therapy-a qualitative study and recommendations for future care.

PURPOSE: Patients with advanced melanoma refractory to first-line treatment have a need for effective second-line treatment options. A recent phase 3 trial showed promising results for adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) as second-line therapy in patients with advanced melanoma. However, it remains unknown how patients and their partners experience TIL therapy, which is key to evaluate and improve the quality of care. METHODS: Semi-structured interviews about the experience of TIL therapy were conducted with patients with advanced melanoma and their partners 2-4 weeks post-treatment (short term) and >6 months after treatment (long term). RESULTS: In total, 25 interviews were conducted with advanced melanoma patients treated with TIL (n=13) and their partners (n=12), with the majority being short-term interviews (n=17). Overall, patients and partners experienced TIL therapy as intense (uncertainty of successful TIL culture, multiple treatment-related toxicities, and extensive hospitalization). Patients and partners with young children or other caregiving responsibilities encountered the most challenges during TIL therapy. All patients, however, reported a recovery of all treatment-related toxicities within 2-4 weeks (except fatigue). CONCLUSION: Clinical data justify the role of TIL therapy in the treatment of advanced melanoma. With the distinct nature of TIL therapy compared to the current standard of care, we have provided patient-centered recommendations that will further enhance the quality of TIL therapy. IMPLICATIONS FOR CANCER SURVIVORS: As more patients with advanced melanoma are expected to receive TIL therapy in the future, our findings could be incorporated into survivorship care plans for this novel group of advanced melanoma survivors treated with TIL.

Health-state utilities in long-term advanced melanoma survivors comparable with the general population.

BACKGROUND: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors. METHODS: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores. RESULTS: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (ß = - .82, p = .022) and fatigue burden (ß = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07). DISCUSSION: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Late mortality after hematopoietic SCT for a childhood malignancy.

Hematopoietic SCT (HSCT) has been used as a curative therapy for pediatric malignancies. Survivors of HSCT are at risk for disease recurrence, late morbidity and mortality. We assessed late mortality (≥2 years post-HSCT) in a population-based cohort of children who underwent HSCT for a malignancy. Mortality outcomes were determined by linking a clinical transplant database with the Canadian province of Ontario's pediatric cancer mortality files. Seven hundred and fifty-four children underwent HSCT (371 allogeneic, 383 autologous). Of the 479 (63.5%) who were alive ≥2 years post HSCT, 98 (20.5%) suffered a late death. Late mortality in the allogeneic HSCT group was 14.9% (median follow-up 10.0 years; range: 2.0-25.6 years), mainly due to relapse of the primary malignancy (64.7%). Chronic GVHD and second malignancies were not major causes of late mortality. A total of 25.5% suffered a late death following autologous HSCT (median follow-up 6.7 years; range: 2.0-22.2 years). Recurrence of the primary malignancy accounted for 87.5% of these deaths. Recurrence of the primary malignancy is the predominant cause of late mortality after HSCT. In contrast to studies of adult patients, non-relapse mortality is less common in children, and death due to chronic GVHD and secondary malignancies is uncommon.

Acute gut GVHD in children: does skin involvement matter?

Gut GVHD (G-GVHD) is frequently the most severe and difficult to treat compared with skin GVHD. It is unknown if skin involvement with G-GVHD has prognostic significance. To compare the prognosis of acute isolated G-GVHD vs acute gut and skin GVHD (GS-GVHD) in children following allo-SCT. Allo-SCT recipients from Jan 2000-Dec 2009 were included and patients who underwent endoscopy and gut biopsy for G-GVHD were identified. Four hundred and fifty children (0-18 years) underwent allo-SCT during the study period. Seventy-nine (17.5%) patients underwent endoscopy and biopsy. At least stage II was required for skin involvement. Forty nine patients had G-GVHD and 30 had combined, GS-GVHD. The majority of patients received CsA and MTX for GVHD prophylaxis. Sixty-seven percent of patients with GS-GVHD had grade III-IV while only 31% had grade III-IV in the G-GVHD group. Median follow-up was 6.3 years (range 3.6-11.9 years). Relapse rate was similar in both the groups. However, children with G-GVHD had a significantly higher risk of dying from GVHD related complications (37% vs 16%) resulting in superior survival for those with skin involvement (79% vs 49% P=0.02). Extension of G-GVHD to the skin may suggest a better outcome.

Chest health surveillance utility in the early detection of bronchiolitis obliterans syndrome in children after allo-SCT.

To prospectively assess whether periodic chest health surveillance is beneficial for the early detection of bronchiolitis obliterans syndrome (BOS) in children after allo-SCT. Children up to 18 years of age receiving allo-SCT from September 2009 to September 2011 were included. Surveillance consisted of the following: a 7-item respiratory system questionnaire of cough, wheeze and shortness of breath; focused physical examination; and pulmonary function test (PFT) conducted before SCT and at 1, 3, 6, 9, 12, 18 and 24 months after SCT. Thirty-nine patients were enrolled. Five children developed BOS at a median time of 192 days (range 94-282). Positive response comparisons between the BOS group vs the non-BOS group were NS for history questionnaire (P=0.2), heart rate (P=0.3), respiratory rate (P=0.3) and oxygen saturation monitoring (P=0.8). Differences between the two groups for chest auscultation and PFT were statistically significant (P=0.03 and P=0.01, respectively). However, chest auscultation in the BOS group was only positive after BOS diagnosis. PFT reduction was evident in the asymptomatic phase (BOS group 33%; non-BOS group 4.5%, P=0.01). Changes in PFT, but not history/physical examination, allow the early detection of BOS in children after SCT. Our study is limited by the small sample size.

A retrospective comparison of autologous and unrelated donor hematopoietic cell transplantation in myelodysplastic syndrome and secondary acute myeloid leukemia: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Hematopoietic cell transplantation (HCT) is an effective treatment for myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML). In this study, outcome of 593 patients with MDS/sAML after autologous and allogeneic HCT from a matched unrelated donor (MUD) were compared. A total of 167 (28%) patients received HCT from MUD without prior chemotherapy (MUD-U). The rest received HCT in first complete remission (CR1) (Autologous (Auto-CR1), n=290 (49%), HCT from MUD (MUD-CR1), n=136 (23%)). Survival at 3 years was best in MUD-CR1 (50%) compared to Auto-CR1 (41%) and MUD-U (40%) (P=0.01). Similarly, disease-free survival was 44% for MUD-CR1 compared to Auto-CR1 (28%) and MUD-U (34%) (P=0.03). Treatment-related mortality was 17% in Auto-CR1 compared to MUD-CR1 (38%) and MUD-U (49%) (P<0.001). Relapse for Auto-CR1 was 62% compared to 24 and 30% for MUD-CR1 and MUD-U, respectively (P<0.001). Outcome was best for patients with low tumor burden transplanted 6-12 months after diagnosis. Factors influencing outcome at 3 years were mainly significant in the first 6 months. Only, relapse after autologous HCT remained constant over time. Outcomes after allogeneic HCT in patients of 20-40 and >40 years were similar. Autologous and Allogeneic HCT from MUD offer the possibility of long-term survival to patients with MDS/sAML.

Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis.

Fifty-seven patients receiving unrelated donor (UD) BMT were matched for disease and stage with 57 recipients of genotypically matched related donor (MRD) BMT. All UD recipients were matched serologically for A and B and by high resolution for DR and DQ antigens. All patients received CsA and 'short course' methotrexate with folinic acid. Unrelated donor BMT patients also received thymoglobulin 4.5 mg/kg (6 mg/kg if <30 kg) in divided doses over 3 days pretransplant. For UD and RD BMT, respectively, incidence of acute GVHD grade II-IV was 19 +/- 6% vs 36 +/- 8%, grade III-IV 10 +/- 6% vs 18 +/- 7%, chronic GVHD 44 +/- 8% vs 51 +/- 8%, non-relapse mortality 15 +/- 5% vs 8 +/- 4% at 100 days, 28 +/- 8% vs 36 +/- 7% at 3 years. At 3 years, relapse was 45 +/- 7% vs 42 +/- 7%, and disease-free survival 39 +/- 7% vs 37 +/- 7%. None of these differences are significant. Three-year overall survival was identical at 42 +/- 7%. For 29 patients with low/intermediate risk leukemia, disease-free survival was 68 +/- 10% after UD BMT vs 59 +/- 9% for RD BMT recipients (P = NS). Corresponding figures for high risk patients were 14 +/- 7% and 21 +/- 8%, respectively. We conclude that UD BMT recipients matched as above and given pretransplant ATG have similar outcomes to recipients of MRD BMT using conventional drug prophylaxis. Unrelated donor BMT should be considered in any circumstance where MRD BMT is routine.

Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: influence of stem cell source on outcome.

We have compared the outcomes of 87 patients with acute myelogenous leukemia (AML) and myelodysplasia (MDS) receiving matched sibling transplants with stem cells from peripheral blood (blood cell transplant, BCT) or bone marrow (BMT). In good risk patients (AML in CR1) granulocytes recovered to 0.5 x 10(9)/l a median of 14 days after BCT compared with 19 days after BMT (P < 0.0001). For patients with poor risk disease (AML beyond CR1 and MDS) corresponding figures were 16 vs 26 days (P < 0.0001). Platelet recovery to 20 x 10(9)/l was also faster after BCT (good risk 12 vs 20 days, P < 0.0001; poor risk 17 vs 22 days, P = 0.04). Red cell transfusions were unaffected by cell source, but BCT recipients required less platelet transfusions (good risk 1 vs 5, P = 0.002; poor risk 5 vs 11, P = 0.004). Blood cell transplants resulted in more chronic GVHD (86% vs 48%, P = 0.005) and a significantly higher proportion of recipients with KPS of 80% or less (48% vs 5%, P = 0.004). Disease-free survival at 4 years was 23% for both groups of poor risk patients but outcome in good risk patients was better after BCT (93% vs 62%, P = 0.047) related mainly to less relapse. While disease-free survival may be better after BCT than BMT for AML in CR1, quality of life may be relatively impaired.

Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.

BACKGROUND: Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic abnormalities in neuroblastoma to determine their prognostic value. METHODS: We used Southern blot analysis to study the allelic loss of chromosomes 1p, 4p, 11q, and 14q, the duplication of chromosome 17q, and the amplification of the N-myc oncogene in 89 neuroblastomas. We also determined the nuclear DNA content of the tumor cells. RESULTS: Allelic loss of chromosome 1p, N-myc amplification, and extra copies of chromosome 17q were significantly associated with unfavorable outcome. In a multivariate analysis, loss of chromosome 1p was the most powerful prognostic factor. It provided strong prognostic information when it was included in multivariate models containing the prognostic factors of age and stage or serum ferritin level and stage. Among the patients with stage I, II, or IVS disease, the mean (+/- SD) three-year event-free survival was 100 percent in those without allelic loss of chromosome 1p and 34 +/- 15 percent in those with such loss; the rates of three-year event-free survival among the patients with stage III and stage IV disease were 53 +/- 10 percent and 0 percent, respectively. CONCLUSIONS: The loss of chromosome 1p is a strong prognostic factor in patients with neuroblastoma, independently of age and stage. It reliably identifies patients at high risk in stages I, II, and IVS, which are otherwise clinically favorable. More intensive therapy may be considered in these patients. Patients in stages III and IV with allelic loss of chromosome 1p have a very poor outlook, whereas those without such loss are at moderate risk.

Immunosuppression: preliminary results of alternative maintenance therapy for familial hemophagocytic lymphohistocytosis (FHL).

Hemophagocytic lymphohistiocytosis (HLH) describes a group of disorders with similar clinical features that are associated with a very high mortality rate. Patients with HLH, and particularly the infantile form referred to as familial hemophagocytic lymphohistiocytosis (FHL), are often treated with multiple courses of epipodophyllotoxins, such as etoposide, for prolonged periods of time. Because of the concern regarding the risk of epipodophyllotoxin-induced acute myelogenous leukemia (AML) we have explored the use of immunosuppression as maintenance therapy for patients with FHL while they await the only known definitive treatment, i.e., bone marrow transplantation (BMT). We report 2 infants with FHL who had significant central nervous system involvement at diagnosis. Both were initially treated with etoposide, methotrexate, and glucocorticosteroids. Once clinical improvement was achieved these patients were successfully maintained in clinical remission of FHL on daily cyclosporine A (CSA) and glucocorticosteroids along with intermittent intrathecal methotrexate for 5 months until appropriate unrelated donors could be identified for BMT.