Hyper‐CVAD plus nelarabine in newly diagnosed adult T‐cell acute lymphoblastic leukemia and T‐lymphoblastic lymphoma

Nelarabine, a water soluble prodrug of 9‐β‐D‐arabinofuranosylguanine (ara‐G), is a T‐cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T‐ALL) and T lymphoblastic lymphoma (T‐LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper‐CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper‐CVAD alternating with high‐dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m² intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty‐seven patients, including 40 with T‐ALL and 26 with T‐LBL, were enrolled. Complete response rates in both T‐ALL and T‐LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow‐up was 42.5 months. The 3‐year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper‐CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper‐CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T‐ALL/LBL patients.     

Graft loss attributed to possible transfusion‐transmitted ehrlichiosis following cord blood stem cell transplant

We present a case of possible transfusion‐transmitted Ehrlichia chaffeensis infection in a heavily transfused cord blood transplant recipient, resulting in severe infection and graft loss. Transfusion‐transmitted, vector‐borne infections in immunocompromised individuals can have severe consequences, and should be considered in hospitalized patients receiving blood products with unexplained fever or sepsis.     

Biphenotypic acute leukaemia: a case series

Biphenotypic acute leukaemia (BAL) is a rare type of leukaemia. Whether patients with BAL should be treated with regimens designed for acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) or both remain unclear. We have reviewed the clinical data for 31 BAL patients. Most patients co-expressed B-lymphoid and myeloid markers. No specific chromosomal abnormality was identified. The majority of the patients were treated with regimens devised for treating ALL. Seven patients were treated with regimens designed for AML. Complete remission (CR) rates of 78% and 57% were noted respectively. The overall survival probability at 2 years was 60%.     

Protein kinase C does not mediate the inhibitory action of lead on vitamin D3-dependent production of osteocalcin in osteoblastic bone cells

The level of osteocalcin in serum is lower in lead-intoxicated children than in their normal counterparts. To explain this clinical observation, we investigated the mechanism of action of lead on vitamin D3-dependent osteocalcin production. Lead (5-20 microM) blocked the stimulating effects of vitamin D3 on osteocalcin production in cultured rat osteosarcoma cells (ROS 17/2.8). It is often suggested that activation of protein kinase C (PKC) is a critical mediator of the toxic actions of lead. Treatment of ROS cells with G?6976, an inhibitor of PKC alpha and beta isozymes, produced similar effects as lead on vitamin D3-dependent osteocalcin production, while activation of PKC by phorbol-12-myristate-13-acetate (TPA) did not reverse or mimic this effect of lead. Thus activation of PKC is not consistent with the actions of lead on vitamin D3-dependent osteocalcin production. Measurement of PKC enzyme activity showed that 10 microM lead treatment does not activate or inhibit the activity of PKC in ROS cells. Western blot analysis indicated that lead treatment does not translocate PKC alpha, beta, or zeta from cytosol to membrane. Therefore, we concluded that PKC does not mediate the cellular toxicity of lead on vitamin D3-dependent osteocalcin production.     

Outcomes of young adults (aged ≤ 40 years) with newly diagnosed multiple myeloma after up-front autologous stem cell transplant

Multiple myeloma (MM) primarily affects older patients. There are scarce data on the outcomes of young adults undergoing autologous transplantation (auto-HCT). In this single-centre analysis, we included 117 younger patients, with a median age of 37 years (range 22–40) at transplant. Seventeen (15%) patients had high-risk cytogenetics. Before transplant, 10% of patients achieved ≥CR and 44% achieved ≥VGPR. At best post-transplant response, 56% and 77% of patients achieved ≥CR and ≥VGPR respectively. With a median follow-up for survivors of 72.6 months (range 0.9–238.0), median PFS and OS were 43.1 months (95% CI 31.2–65.0) and 146.6 months (95% CI 100.0–208.1) respectively. Patients who underwent auto-HCT after 2010 had better median PFS (84.9 months vs. 28.2 months, p < 0.001) and OS (NR vs. 91.8 months, p < 0.001) compared with those transplanted earlier. In multi-variate analysis, achieving ≥CR as best post-transplant response was associated with improved PFS (HR [95% CI] 0.55 [0.32–0.95], p = 0.032), while achieving ≥VGPR was predictive of superior OS (0.32 [0.16–0.62], p < 0.001). Three patients (3%) developed a second primary malignancy. Younger MM patients had durable survival after auto-HCT, which further improved after the availability of novel anti-myeloma drugs in recent years. Depth of response following transplant remains a key predictor of survival.