CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes.

Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.).

Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies.

CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes.

The efficacy and tolerance of azacitidine in higher-risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA-001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of <30% cellularity were considered hypocellular with data evaluable from 299 patients (azacitidine n = 154, CCR n = 145); 13% (n = 39) hypocellular, 87% (n = 260) non-hypocellular. Patient characteristics were balanced between cellularity and treatment groups. Most patients (90-100%) had 2-3 cytopenias at baseline. Median (range) azacitidine treatment cycle lengths were 35·5 (28-54) and 33·0 (15-75) d in hypocellular and non-hypocellular groups, respectively. At 33 months, median OS was not reached (NR) [95% confidence interval (CI): 19·2, NR] in hypocellular patients receiving azacitidine versus 16·9 months (95% CI: 11·1, 19·3) with CCR (P = 0·001); and in non-hypocellular patients, it was 21·1 months (95% CI: 16·2, 34·7) versus 15·3 months (95% CI: 9·3, 17·6) (P = 0·012). Azacitidine tolerance was similar regardless of cellularity. Grade 3-4 thrombocytopenia and neutropenia occurred similarly in hypocellular patients treated with azacitidine versus CCR (80% vs. 92% and 88% vs. 75%). Azacitidine OS results are consistent with those from AZA-001, regardless of cellularity, and demonstrate its safety and efficacy in higher-risk myelodysplasia with hypocellular BM.

Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index.

Anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the most prevalent forms of anemia and often occur concurrently. Standard tests of iron status used in differential diagnosis are affected by inflammation, hindering clinical interpretation. In contrast, soluble transferrin receptor (sTfR) indicates iron deficiency and is unaffected by inflammation. Objectives of this prospective multicenter clinical trial were to evaluate and compare the diagnostic accuracy of sTfR and the sTfR/log ferritin index (sTfR Index) for differential diagnosis using the automated Access(®) sTfR assay (Beckman Coulter) and sTfR Index. We consecutively enrolled 145 anemic patients with common disorders associated with IDA and ACD. Subjects with IDA or ACD + IDA had significantly higher sTfR and sTfR Index values than subjects with ACD (P < 0.0001). ROC curves produced the following cutoffs for sTfR: 21 nmol/L (or 1.55 mg/L), and the sTfR Index: 14 (using nmol/L) (or 1.03 using mg/L). The sTfR Index was superior to sTfR (AUC 0.87 vs. 0.74, P < 0.0001). Use of all three parameters in combination more than doubled the detection of IDA, from 41% (ferritin alone) to 92% (ferritin, sTfR, sTfR Index). Use of sTfR and the sTfR Index improves detection of IDA, particularly in situations where routine markers provide equivocal results. Findings demonstrate a significant advantage in the simultaneous determination of ferritin, sTfR and sTfR Index. Obtaining a ferritin level alone may delay diagnosis of combined IDA and ACD.

Serum transferrin receptor.

Transferrin receptors (TfRs) are the conventional pathway by which cells acquire iron for physiological requirements. Under iron-deficient conditions there is an increased concentration of surface TfR, especially on bone marrow erythroid precursors, as a mechanism to sequester needed iron. TfRs are also present in the circulation, and the circulating serum TfR (sTfR) level reflects total body TfR concentration. Under normal conditions erythroid precursors are the main source of sTfR. Disorders of the bone marrow with reduced erythroid precursors are associated with low sTfR levels. The sTfR concentration begins to rise early in iron deficiency with the onset of iron-deficient erythropoiesis, and continues to rise as iron-deficient erythropoiesis progressively worsens, prior to the development of anemia. The sTfR level does not increase in anemia of chronic inflammation, but is increased when anemia of chronic inflammation is combined with iron deficiency. The sTfR level is also increased in patients with expanded erythropoiesis, including hemolytic anemias, myelodysplastic syndromes, and use of erythropoietic stimulating agents. The ratio of sTfR/ferritin can be used to quantify the entire spectrum of iron status from positive iron stores through negative iron balance, and is particularly useful in evaluating iron status in population studies. The sTfR/log ferritin ratio is valuable for distinguishing anemia of chronic inflammation from iron deficiency anemia, whether the latter occurs alone or in combination with anemia of chronic inflammation.

CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia.

Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 109/L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 109/L and 198 × 109/L, respectively. Grade 3-4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values <25 × 109/L. Overall response rates were 38% and 46% in the Low Platelets and High Platelets groups, respectively. Five thrombocytopenic patients attained complete remission and 9 attained platelet hematologic improvement. In both cohorts, platelet counts dropped during the first CC-486 treatment cycle, then increased thereafter. Extended CC-486 dosing was generally well tolerated and induced hematologic responses in these patients regardless of pretreatment thrombocytopenia.

Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care.

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51-0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31-46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

Is there a plateau in the survival curve after autologous transplantation in patients with intermediate and high-risk acute myeloid leukemia? A 20-year single institution experience.

In an attempt to examine whether autologous SCT provides long-term disease control in patients with intermediate and high-risk AML where a suitable donor is not available, we analyzed the outcomes of autologous SCT in patients with intermediate and high-risk AML from 1986 to 2005. No relapses occurred after 2.2 years. The overall survival curve appears to have developed a plateau after 2.2 years. In conclusion, autologous SCT in patients with AML in whom an allogeneic transplantation is not feasible appears to be a safe alternative and a plateau in the survival curve indicates cure in a small proportion of patients.

A retrospective analysis of long-term survival in severe aplastic anemia patients treated with allogeneic bone marrow transplantation or immunosuppressive therapy with antithymocyte globulin and cyclosporin A at a single institution.

Severe aplastic anemia can be treated with either bone marrow transplantation (BMT) or immunosuppressive therapy (IST). A retrospective review of patients with severe aplastic anemia treated with both of these modalities was conducted. Fifteen BMT and 16 IST patients were available for analysis, and follow-up of 22 and 15 years was available for the BMT and IST groups, respectively. Median survival was limited to 4.3 months in BMT patients vs. 135.2 months in IST patients, despite the older median age of the latter (22 vs. 55 years). Actuarial survival at 1 and 5 years was 87% and 78% for the IST patients and 40% and 33% for the BMT patients. Hematologic response rates, as defined by achievement of transfusion independence, were similar for the two groups. Long-term responses and survival are possible with antithymocyte globulin/cyclosporin A.

A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura.

BACKGROUND: Photochemical treatment of fresh-frozen plasma (FFP) with amotosalen and ultraviolet (UV) A light (PCT FFP) results in inactivation of a broad spectrum of pathogens while retaining coagulation factor activity, antithrombotic proteins, and von Willebrand factor-cleaving protease (VWF-CP) activity. STUDY DESIGN AND METHODS: A randomized, controlled, double-blind Phase III trial was conducted with PCT FFP or control FFP for therapeutic plasma exchange (TPE) in patients with thrombotic thrombocytopenic purpura (TTP). Owing to the rarity of this diagnosis, the trial was not powered to demonstrate small differences between treatment groups. Patients were treated with study FFP for a maximum of 35 days until remission was achieved (for a maximum of 30 daily study TPEs with no remission) plus an additional 5 days after remission. RESULTS: Among the 35 patients treated, the primary endpoint, remission within 30 days, was achieved by 14 of 17 (82%) PCT patients and 16 of 18 (89%) control patients (p = 0.658) The 90 percent confidence interval for treatment difference in remission rate for test - control was (-0.291 to 0.163). Time to remission, relapse rates, time to relapse, total volume and number of FFP units exchanged, and number of study TPEs were not significantly different between groups. Improvement in VWF-CP and inhibitors was similar for both groups. The overall safety profile of PCT FFP was similar to control FFP. No antibodies to amotosalen neoantigens were detected. CONCLUSION: The comparable results between treatment groups observed from this small trial suggest that TPE with PCT FFP was safe and effective for treatment of TTP.

Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura.

Several reports have defined nonfamilial thrombotic thrombocytopenic purpura (TTP) as an autoimmune disorder caused by antibodies to von Willebrand's factor-cleaving protease (vWF-CP). This raises the possibility that rituximab, a monoclonal antibody against CD20 present in B-lymphoid cells, may have utility in the treatment of TTP. We report five consecutively treated patients with relapsed TTP who responded rapidly to immune suppression by rituximab at our institution. These two male and three female patients had a median age of 37 years (27-70). The median time from diagnosis to therapy was 24 months (8-60). Prior therapies included plasma exchange and corticosteroids in all cases, splenectomy (4), vincristine and aspirin (3), and azathioprine (2). The median number of plasma exchanges received prior to therapy was 59 (21-158). The cohort had a median platelet count of 48 x 10(9)/l (23-110), median hemoglobin of 9 g/dl (8-11), and median lactate dehydrogenase of 632 IU/l (311-945) prior to administration of rituximab. Analysis of vWF-CP activity demonstrated absent or decreased activity with detectable inhibitors in four patients. All patients attained a complete response. The median time to response after the first dose of rituximab was 5 weeks. Responses are maintained in all patients from 10 to 21 months after treatment. This report adds to the evidence that rituximab has efficacy in nonfamilial TTP and warrants further study.

Autologous transplantation in patients with relapsed or high-grade follicular lymphoma provides long term disease-free survival and best median duration of response.

The best treatment option for patients with relapsed or high-grade follicular lymphoma (FL) is unknown. In spite of major advances in the therapy for FL, disease-free survival remains short, and median time to progression is just over a year. Autologous stem cell transplantation in patients with relapsed FL is safe and appears to improve disease-free survival. In an attempt to examine whether autologous stem cell transplantation provides long-term disease control in patients with relapsed or high-grade FL, we retrospectively evaluated our experience and analyzed the outcomes of autologous stem cell transplantation in patients with FL from 1991 to 2003. Seventeen men and seven women (n=24) of median age 47.5 years (range 28-64 years) were treated. Three patients with high-risk FL were in first remission. Twenty-one patients were salvaged after relapse with second-line chemotherapy. Of these, 14 were in CR at the time of transplantation, and seven patients were transplanted with active disease. Bone marrow was used in six patients as the source of stem cells prior to 1995 and peripheral blood stem cells were used in 18 patients. Twenty-three of 24 patients engrafted (96%). Median time for neutrophil recovery was 11.5 days (range 9-35 days) and 15 days (range 10-40 days) for platelets. Median duration of follow-up was 6 years (range 7 months-8 years). Of the 24 patients, six have died-with one patient death due to transplant-related pulmonary complications. Overall survival (OS) and disease-free survival (DFS) of all evaluable patients were 71.6 and 40%, respectively. Median duration of response was 4.3 years. OS and DFS in patients transplanted in CR were 80 and 57%, respectively. For those transplanted with disease, a complete response was achieved in 43% of patients, with the OS and DFS of 57 and 19%, respectively. Disease status at transplantation was not a significant variable for survival (p>0.3). Three patients developed moderate to severe treatment-related toxicity, two with grade III mucositis and one with life-threatening infection. When these results are compared with historical controls or patients treated with other modalities, autologous stem cell transplantation appears to be providing the longest disease-free survival and best duration of response.

The quantitative assessment of body iron.

Current initiatives to reduce the high prevalence of nutritional iron deficiency have highlighted the need for reliable epidemiologic methods to assess iron status. The present report describes a method for estimating body iron based on the ratio of the serum transferrin receptor to serum ferritin. Analysis showed a single normal distribution of body iron stores in US men aged 20 to 65 years (mean +/- 1 SD, 9.82 +/- 2.82 mg/kg). A single normal distribution was also observed in pregnant Jamaican women (mean +/- 1 SD, 0.09 +/- 4.48 mg/kg). Distribution analysis in US women aged 20 to 45 years indicated 2 populations; 93% of women had body iron stores averaging 5.5 +/- 3.35 mg/kg (mean +/- 1 SD), whereas the remaining 7% of women had a mean tissue iron deficit of 3.87 +/- 3.23 mg/kg. Calculations of body iron in trials of iron supplementation in Jamaica and iron fortification in Vietnam demonstrated that the method can be used to calculate absorption of the added iron. Quantitative estimates of body iron greatly enhance the evaluation of iron status and the sensitivity of iron intervention trials in populations in which inflammation is uncommon or has been excluded by laboratory screening. The method is useful clinically for monitoring iron status in those who are highly susceptible to iron deficiency.