Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we ...determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational “hot-spot” but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.
In the phase III QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent significantly prolonged overall and relapse-free survival vs. placebo among patients with AML in first ...remission after induction chemotherapy (IC). Gastrointestinal (GI) events were the most frequent adverse events (AEs) with CC-486.
Assess GI AE rates with CC-486 over time and associated management strategies.
Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics, and ECOG-PS scores ≤ 3. Patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) after IC ± consolidation and were not transplant candidates. Within 4 months of CR/CRi, patients were randomized 1:1 to once-daily CC-486 300-mg or placebo on days 1-14 of repeated 28-day cycles. Safety was assessed in patients who received ≥1 dose, through 28 days after the last dose. Prophylaxis and treatment of GI AEs was allowed but not mandatory.
236 patients received CC-486 and were evaluated for safety. Median age was 68 years (range, 55-86). Rates of any-grade nausea, vomiting, and diarrhea were 65%, 60%, and 50%, respectively; few patients experienced grade 3 (3%, 3%, and 5%) or serious (0.4%, 0.8%, and 1.3%) events, and only 1 grade 4 event (diarrhea) was reported. Rates were highest during initial treatment and decreased thereafter: in cycles 1-2, 3-4, and 5-6, nausea was reported in 53%, 17%, and 15% of patients, respectively; vomiting in 49%, 15%, and 10%; and diarrhea in 29%, 16%, and 11%. 5-HT3-antagonists, metoclopramide, lactulose, and loperamide were the most common concomitant medications; use of these agents also decreased over time. GI events required CC-486 dose-reductions for 6% of patients, treatment interruptions for 13%, and discontinuation for 5%.
Most GI AEs with CC-486 were low-grade, and events decreased in frequency after initial cycles. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486. Few patients discontinued CC-486 due to GI AEs, indicating these events were easily managed. Clinicians and patients should be aware of possible GI events during early CC-486 treatment; prophylaxis and symptomatic intervention may facilitate treatment adherence to promote better outcomes.
Background
CPX‐351 is approved for the treatment of therapy related acute myeloid leukemia (t‐AML) and AML with myelodysplastic related changes (MRC‐AML). The benefits of this treatment over standard ...chemotherapy has not been addressed in well matched cohorts of real‐life patients.
Methods
Retrospective analysis of AML patients treated with CPX‐351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry.
Results
Median age of 79 patients treated with CPX‐351 was 67 years old (interquartile range 62–71), 53 were MRC‐AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX‐351 was 52%, 60‐days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3‐year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX‐351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX‐351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18–0.59), p < 0.001.
Conclusion
Larger post‐authorization studies may provide evidence of the clinical benefits of CPX‐351 for AML in the real‐life setting.
We report the results of CPX‐351 treatment in a group of 79 non‐selected patients reported to the PETHEMA epidemiologic registry and compared the main outcomes with a matched cohort among 765 historical patients receiving intensive chemotherapy. After propensity score matching, no differences in complete remission (60% vs. 54%) and median overall survival (10.3 months vs. 9.1 months) were observed between cohorts, although more patients were bridged to allogeneic transplant in the CPX‐351 group (35% vs. 12%). The results were confirmed when only 3 + 7 treated patients were included in the historical cohort.
Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents ...such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA.
To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA.
Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available.
This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease.
This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.
To assess the prevalence, risk factors, clinical causes and outcome of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 275 patients was undertaken. ...ARF was diagnosed in 72 patients (26%) and occurred in 81.9% within the first month. The three main clinical causes were multifactorial (36%), nephrotoxic (29%), and veno-occlusive disease of the liver (VOD) 15%. The prevalence was higher in allogeneic BMT (36%) than in autologous BMT (6.5%). Risk factors related to the development of ARF wee preexisting VOD and age older than 25 years. Logistic regression in allogeneic BMT confirmed this association (VOD, odds ratio 3.8; age offer than 25, odds ratio 1.9). Underlying disease, graft-versus-host disease, sepsis, conditioning therapy, and sex were not associated with ARF. Seventeen cases of ARF required hemodialysis (24%) mainly in association with VOD (70.5%). The overall morality from ARF was 45.8%, the dialyzed group having the highest mortality (88%). Survival in the ARF group was continuously worse up to 3 months and the actuarial survival at 10 years was 29.7 versus 53.2%. We conclude that ARF is a common complication mainly in allogeneic BMT and carries a grave prognosis. VOD and age were risk factors for ARF.
Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of ...quick availability, easy programation and logistics, and a committed donor. This procedure has shown promissing results in patients diagnosed with relapsed or refractory Hodgkin´s disease (Burroughs LM et al. Biol Blood Marrow Transplant 2008; 14:1279-1287).
We retrospectively evaluate the results of HAPLO-HSCT with RIC regimens (Fludarabine 30 mg/m2 x5 days (-6 to -2), Cyclophosphamide14,5 mg/kg x2 days (-6 to -5), Busulfan IV 3,2 mg/kg x 1-2 days (BUX, days -3 to -2) or 200 cGy TBI on day -1) and GVHD prophylaxis based on HD-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5 performed in GETH centers to patients diagnosed with relapsed or refractory Hodgkin´s disease.
From March-2009, 29 HAPLO-HSCT have been performed in patients diagnosed with relapsed or refractory Hodgkin´s disease in 11 GETH centers. Median age was 31 years (18-53), 19 were males and all were in advanced phases of their disease. Autologous HSCT was previously employed in 90% of them, and allogeneic HSCT in 10%. Disease status at HAPLO-HSCT evaluated by PET was complete remission in 8 (28%) and persistent disease in 21 (72%). Bone marrow was the stem cell source in 15 (52%) and peripheral blood in 14 (48%), without T-cell depletion in all cases. The haploidentical donor was the patient´s mother (13), father (2), brother (8), sister (5) or daughter (1). The RIC regimens employed included 1 dose BUX (11), 2 doses BUX (14) or 200cGy TBI (4). Median neutrophils engraftment was day +17 (11-44) and platelets >20K was day +26 (11-150). Main toxic complications were grade II-III muchositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a transplant related mortality rate of 7% (2/29) at day +100 and 17% (5/29) at 6 months post-transplant. Acute GVHD grade II-IV affected to 7/28 patients at risk (25%), with grade III-IV in 3/28 (11%). Chronic GVHD was present in 3/19 (16%), being extensive in 1/19 (5%). After a median follow-up of 9 months (0.3-49), 13/22 (59%) remain alive and in complete remission. Relapse or progression occured in 6/28 (21%). Immune reconstitution was fast and complete in those evaluated.
HAPLO-HSCT with HD-CY is a useful tool in the treatment of patients with relapsed or refractory Hodgkin´s disease, rendering long-lasting remissions with limited toxicity, low GVHD incidence and early immune reconstitution.
No relevant conflicts of interest to declare.
Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. Only one third of them have an HLA identical sibling donor and around 60-70% will find an ...unrelated donor, that´s why HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of quick availability, easy programation and logistics, and a committed donor.
We retrospectively evaluate the results of HAPLO-HSCT with reduced conditioning or myeloablative regimens and GVHD prophylaxis based on HD-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5 performed in GETH centers.
From Dec-2007, 80 HAPLO-HSCT have been done in 14 centers. Median age was 37 years (16-66), 67.5% were males and all were in advanced phases of their disease or presented high risk features (29 Hodgkin´s, 22 AML, 9 ALL, 8 MDS, 5 NHL, 4 myeloma and 2 myelofibrosis). Previous HSCT has been employed in 65%, autologous in 38 and allogeneic in 15 (5 siblings, 3 unrelated and 7 cord blood transplants), and in 35% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was CR in 45%, with persistent disease in 55%. Bone marrow was the graft source for 51% and peripheral blood for 49%, non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21), father (7), brother/sister (35) or offspring (17). Non-myeloablative conditioning was employed in 77.5% and myeloblative in 22.5%. Median neutrophils engraftment was reached at day +18 (13-45) and platelets >50K at day +27 (11-150). Main toxic complications were grade II-III muchositis in 36%, febrile neutropenia in 75% and CMV reactivations in 62%, with a transplant related mortality rate of 12.5% at day +100 and 19% at 6 months post-transplant. Acute GVHD grade II-IV affected to 24/73 patients at risk (33%), with grade III-IV in 10/73 (14%). Chronic GVHD was present in 12/51 (24%), being extensive in 6/51 (12%). After a median follow-up of 9 months (0.3-49), 26/80 patiens have died due to relapse in 13, infections in 10 and GVHD in 3 cases. Event-free survival and overall survival at 1 year were 48% and 60% respectively. Immune reconstitution was fast and complete in those evaluated.
HAPLO-HSCT with HD-CY is a useful tool in the treatment of high risk hematologic malignancies, rendering long-lasting remissions with limited toxicity, low GVHD incidence and early immune reconstitution.
No relevant conflicts of interest to declare.
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