Nadja Jaekel

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib

The Janus-activated kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib is effective in decreasing symptomatic splenomegaly and myelofibrosis (MF)-related symptoms. However, allogeneic hematopoietic cell transplantation (HCT) remains the only curative option. We evaluated the impact of ruxolitinib on the outcome after HCT. A cohort of 14 patients (median age 58 years) received a subsequent graft from related (n=3) and unrelated (n=11) donors after a median exposure of 6.5 months to ruxolitinib. At HCT, MF risk for survival according to the International Prognostic Scoring System was intermediate-2 or high risk in 86% of patients. Under ruxolitinib, MF-related symptoms were ameliorated in 10 (71.4%) patients and the palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly. Engraftment occurred in 13 (93%) patients. Acute GvHD grade-III occurred in 2 (14%) patients. Median follow-up was 9 months. Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively. Through the anti-JAK-mediated reduction in both cytokines and splenomegaly as well as improvement in performance status, ruxolitinib might improve outcome after allogeneic HCT in patients with MF. The downregulation of inflammatory cytokines might have a beneficial impact on graft failure and acute GvHD.

Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study

Abstract The safety and efficacy of azacitidine (5-day schedule) were assessed in a multicenter study in 40 patients (median age 72 years) with acute myeloid leukemia (AML) medically unfit for (n = 20) or resistant to chemotherapy (n = 20) from April to October 2008. Median marrow blasts were 42%. After a median follow-up of 13 months, response (complete remission [CR]/partial remission [PR]/hematologic improvement [HI]) was 50% and 10% in newly diagnosed and relapsed/refractory patients, respectively (p = 0.008). Median time-to-response was 2.5 months with a median duration of 5.9 months. Median survival was not reached for responders versus 3.8 months for 15 (38%) patients with stable disease (p < 0.045). High-risk cytogenetics was associated with inferior survival (p = 0.05). Lower marrow blasts on day 15 of cycle 1, irrespective of pretreatment count, predicted subsequent response (p = 0.01). Azacitidine is active and well tolerated in elderly patients with newly diagnosed AML.

The role of hypomethylating agents in the treatment of elderly patients with AML

There is a major unmet medical need for treatment options in elderly patients with acute myeloid leukemia (AML) who are deemed ineligible for intensive treatment. The recent approval of decitabine in the European Union for the treatment of patients with AML≥ 65 years old highlights the potential for hypomethylating agents in this setting. Here, we review evidence to support the use of hypomethylating agents in elderly patients and emphasize the importance of tolerability and quality of life considerations. We focus on the rationale for the continued clinical development of the ribonucleoside analog azacitidine in this setting. We discuss potential differences in the activity of azacitidine and decitabine in different patient subgroups that could possibly be explained by important differences in mechanism of action. Finally, we assess practical challenges that will be faced when integrating hypomethylating agents into clinical practice, such as how to define ineligibility for intensive treatment.

Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation

Elevated serum ferritin contributes to treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The multicenter DE02 trial assessed the safety, efficacy and impact of deferasirox on iron homeostasis after allogeneic HSCT. Deferasirox was administered at a starting dose of 10 mg/kg per day to 76 recipients of allogeneic HSCT, with subsequent dose adjustments based on efficacy and safety. Deferasirox was initiated at a median of 168 days after HSCT, with 84% of patients still on immunosuppression. Baseline serum ferritin declined from 2045 to 957 ng/mL. Deferasirox induced a negative iron balance in 84% of patients. Hemoglobin increased in the first 3 months, and trough serum cyclosporine levels were stable. Median exposure was 330 days, with a median compliance rate of >80%. The most common investigator-reported drug-related adverse events (AEs) were increased blood creatinine (26.5%), nausea (9.0%) and abdominal discomfort (8.3%). Fifty-four (71.1%) patients experienced drug-related AEs, which occasionally resulted in discontinuation (gastrointestinal (n=6), skin (n=3), elevated transaminases (n=1) and creatinine (n=1)). The incidence of AEs appeared to be dose related, with 7.5 mg/kg per day being the best-tolerated dose. Low-dose deferasirox is an effective chelation therapy after allogeneic HSCT, with a manageable safety profile, even in patients receiving cyclosporine.

Pretreatment long interspersed element (LINE)-1 methylation levels, not early hypomethylation under treatment, predict hematological response to azacitidine in elderly patients with acute myeloid leukemia.

Background Epigenetic modulations, including changes in DNA cytosine methylation, are implicated in the pathogenesis and progression of acute myeloid leukemia (AML). Azacitidine is a hypomethylating agent that is incorporated into RNA as well as DNA. Thus, there is a rationale to its use in patients with AML. We determined whether baseline and/or early changes in the methylation of long interspersed element (LINE)-1 or CDH13 correlate with bone marrow blast clearance, hematological response, or survival in patients with AML treated with azacitidine. Methods An open label, phase I/II trial was performed in 40 AML patients (median bone marrow blast count was 42%) unfit for intensive chemotherapy treated with azacitidine 75 mg/m2/day subcutaneously for 5 days every 4 weeks. Bone marrow mononuclear cell samples were taken on day 0 (pretreatment) and day 15 during the first treatment cycle; LINE-1 and CDH13 methylation levels were quantified by methylation-specific, semiquantitative, real-time polymerase chain reaction. Results Treatment with azacitidine significantly reduced LINE-1 but not CDH13 methylation levels over the first cycle (P < 0.0001). Absolute LINE-1 methylation levels tended to be lower on day 0 (P = 0.06) and day 15 of cycle 1 (P = 0.03) in patients who went on to achieve subsequent complete remission, partial remission or hematological improvement versus patients with stable disease. However, the decrease in LINE-1 methylation over the first treatment cycle did not correlate with subsequent response (P = 0.31). Baseline methylation levels of LINE-1 or CDH13 did not correlate with disease-related prognostic factors, including cytogenetic risk, relapsed/refractory AML, or presence of NPM1 or FLT3 mutations. No correlation was observed between LINE-1 or CDH13 methylation levels and overall survival. Conclusion Analysis of baseline LINE-1 methylation levels may help identify elderly AML patients who are most likely to respond to azacitidine therapy.

Miliary tuberculosis after initiation of ibrutinib in chronic lymphocytic leukemia

Dear Editor, Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disease and associated with high morbidity and mortality [1]. The Bruton’s tyrosine kinase inhibitor ibrutinib was recently approved for relapsed/refractory CLL and mantle cell lymphoma after at least one prior therapy and for CLL patients with del(17p) based on its efficacy data [2–4]. Ibrutinib blocks B cell receptor signaling and is generally well tolerated. However, infections mainly of the upper respiratory tract and neutropenias were commonly reported [2–5]. In the extended follow-up of the PCYC-1102-trial, pneumonia grade ≥3 occurred in 25 % of relapsed/refractory CLL [5]. We, hereby, report on a patient who developed miliary tuberculosis (TB) shortly after initiation of ibrutinib. Ibrutinib was started in a 64-year-old Caucasian male living in Germany because of progressive lymphadenopathy with bulky disease in December 2014 after seven lines of standard immunoand chemotherapies for CLL including an allogeneic stem cell transplantation (SCT). The patient has no previous diagnosis of TB. Prior to ibrutinib, absolute neutrophil count (ANC) was normal, immunosuppression was discontinued, and prophylactic antiviral and intravenous immunoglobulins were continued. One month later, the patient had a dramatic clinical response but complained of back pain and ataxia without fever. Biopsy of the MRI-detected lesions in the lumbar spine revealed a non-caseating granuloma with negative PCR for mycobacterium tuberculosis species. However, an interferon-γ release assay from the peripheral blood was positive. Further imaging revealed intracerebral and disseminated micronodular lesions in the lung. Finally, PCR for mycobacterium tuberculosis species was positive in the bronchoalveolar lavage. Interestingly, no neutropenia developed during ibrutinib treatment, and the CD3+, CD3+/ CD4+−, as well as CD3+/CD8+− cell counts were normal at the time of TB diagnosis. Standard TB therapy was started with rifampicin/isoniazid/ethambutol/pyrazinamide and ibrutinib discontinued. This is the first case of miliary TB reported under ibrutinib. Whether this was a reactivation of latent TB or a new infection remains speculative. Although our patient was heavily pretreated, he is comparable in terms of age and number of previous CLL therapies to patients included in the ibrutinib trials [2–4]. Noteworthy, TB developed shortly after initiation of ibrutinib which is in accordance with the occurrence of infectious complications reported previously [5]. B cell dysfunction and neutropenia account for infections in patients with CLL. Additionally and despite normal T cell counts, the T cell compartment in CLL is often profoundly impaired [6]. Due to the impaired cell-mediated immunity after SCT, TB is seen in recipients of allogeneic grafts mainly in endemic areas mostly within the first 90 days of SCT [7]. It is unlikely that SCT crucially contributed to the occurrence of TB because of the long interval between SCT and ibrutinib, the absence of immunosuppression, and normal T cells. Song-Yau Wang and Thomas Ebert contributed equally to this work.