Kazunori Ohnishi

Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate

Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1–17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.

High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

A questionnaire survey of pharmacists regarding the clinical practice guidelines for the appropriate use of granulocyte-colony stimulating factors

BackgroundClinical practice guidelines should be user-friendly and confirming their penetration rate and compliance are critical.MethodsWe conducted a nationwide web-based questionnaire survey among pharmacists regarding the 2013 guidelines for the appropriate use of granulocyte-colony stimulating factors (G-CSFs) (version 2, published by the Japan Society of Clinical Oncology [JSCO]) between August 24 and September 6, 2015.ResultsA total of 301 pharmacists responded; 96.0% belonged to hospitals and were board-certified pharmacists in oncology pharmacy (n = 133) and palliative pharmacy (n = 78). In addition, 61.5% of respondents (n = 185) worked for designated cancer care hospitals. The observation that 75.7% of respondents knew that the JSCO guidelines are available on the internet indicated that several pharmacists used this guideline. A high degree of usability by pharmacists was also demonstrated, as 98.0% and 51.5% of respondents, respectively, agreed with the statements “it is useful for the work of pharmacists” and “it is referred to in the actual work of pharmacists”. However, more than half of the respondents (58.4%) agreed with the phrase “there are differences from the actual work of pharmacists”.ConclusionsTheir responses indicated that the respondents used the G-CSF guidelines and viewed them positively; however, the observation that about half of the respondents reported feeling that the guidelines do not match their current practice requires additional follow-up in future studies. The use of these guidelines should be routinely assessed in order to introduce novel cancer chemotherapy regimens and long-acting G-CSF in clinical practice.

Imatinib: Clinical Pharmacology and Therapeutic Results

Imatinib has a remarkable long-term efficacy in patients with chronic myelogenous leukemia (CML) in the chronic phase. Reported rates of 5-year progression-free survival and overall survival associated with imatinib therapy (400 mg daily) have ranged between 83–94% and 83–97%, respectively. Imatinib is generally well tolerated, and adverse events are typically manageable. Current evidence does not support the extensive use of high-dose imatinib (800 mg daily) as a frontline treatment in patients with CML, and also the excessive dose reductions to less than 300 mg imatinib should be avoided, even in patients who are intolerant to 400 mg imatinib. Addition of pegylated interferon α to imatinib offers additional benefits for CML treatment; however, its addition does not appear to improve PFS or OS. The early molecular response (BCR-ABL1 transcript level of ≤10% at 3 months) is reportedly associated with improved prognosis in several studies. Furthermore, approximately 40% of patients who exhibited sustained deep molecular response could maintain treatment-free remission after discontinuation of imatinib. Treatment-free remission is now considered to be a new goal of tyrosine kinase inhibitor therapy in patients with CML in the chronic phase.