Chronic graft versus host disease burden and late transplant complications are lower following adult double cord blood versus matched unrelated donor peripheral blood transplantation.

Adult umbilical cord blood transplantation (CBT) has emerged as an important option for patients lacking matched related (MRD) and matched unrelated donors (MUD). We compared chronic GVHD (cGVHD) incidence, immunosuppression burden and late infections and hospitalizations in consecutive patients undergoing CBT (n=51) versus peripheral blood MUD transplant (n=57) at our center between June 2009 and April 2014. At 3 years post transplantation, the cumulative incidence (CI) of moderate to severe cGVHD was 44% following MUD versus 8% following CBT (P=0.0006) and CI of any cGVHD was 68% following MUD versus 32% following CBT (P=0.0017). Median time to being off immunosuppression among CB patients was 268 days versus not reached among MUD patients (P<0.0001). Late infections and late hospitalized days were reduced in CB patients (P=0.1 and <0.001, respectively). Three-year CI of transplant-related mortality (TRM) and relapse as well as 3-year overall survival (OS) were similar following CB and MUD transplantation. We demonstrate a significantly lower incidence of cGVHD, immunosuppression burden and late complication rate following UCB versus peripheral blood MUD transplant without decreased OS, increased relapse or early TRM. Combined with the rapid availability of UCB, these findings have led our center to move primarily to UCB over peripheral blood MUD when a MRD is not available.

Omacetaxine mepesuccinate for the treatment of chronic myeloid leukemia.

Omacetaxine mepesuccinate is a protein synthesis inhibitor that causes apoptosis of chronic myeloid leukemia cells without binding to the BCR-ABL tyrosine kinase that is implicated in the pathogenesis of this disease. It has been approved for the treatment of chronic myeloid leukemia in patients with resistance to two or more tyrosine kinase inhibitors and is emerging as an important agent in countering the highly resistant T315I mutation. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of omacetaxine mepesuccinate in the current milieu of tyrosine kinase inhibitor-dominant therapy of chronic myeloid leukemia.

Ponatinib for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Ponatinib is a novel, next-generation, small-molecule tyrosine kinase inhibitor with potent activity against the BCR-ABL fusion oncogene as well as all other ABL kinase domain mutations that confer resistance to earlier generation tyrosine kinase inhibitors. Due to its unique structure, it is the only tyrosine kinase inhibitor with the capability to counter the highly resistant T315I or gate-keeper mutation in leukemic cells that express the Philadelphia chromosome. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive adult acute lymphoblastic leukemia.

Adjusting DLCO for Hb and its effects on the Hematopoietic Cell Transplantation-specific Comorbidity Index.

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is used to counsel patients regarding the risk of transplantation and selection of conditioning regimens. Pulmonary disease, most frequently demonstrated by a decreased diffusion capacity of carbon monoxide (DLCO), is the most prevalent comorbidity captured by the HCT-CI. The HCT-CI was validated using the Dinakara method for adjusting DLCO for Hb, but our institution and others utilize the Cotes method. The purpose of this study was to determine the impact of using the Cotes method rather than the Dinakara method on the HCT-CI score. We reviewed pre-transplant pulmonary function tests in 73 patients who underwent allogeneic hematopoietic SCT. Patients were stratified into low, intermediate or high-risk groups based on HCT-CI scores of 0, 1-2 or 3, respectively. We found that compared with the Dinakara method, the Cotes method increased the HCT-CI score in 45% of patients and resulted in total HCT-CI scores predictive of higher non-relapse mortality in 33% of patients. These results indicate that if an institution uses the Cotes method to adjust DLCO for Hb, their patients may be counseled to expect a higher risk of mortality than is actually predicted by the HCT-CI, and may be excluded from transplantation. Therefore, unless the HCT-CI is validated using other methods for correcting DLCO for Hb, the Dinakara method should be used.

Double umbilical cord blood transplantation in patients with hematologic malignancies using a reduced-intensity preparative regimen without antithymocyte globulin.

Reduced-intensity conditioning (RIC) regimens in cord blood transplant (CBT) are increasingly utilized for older patients and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Antithymocyte globulin (ATG) has been incorporated into conditioning regimens in order to decrease the risk of graft failure; however, use of ATG is often associated with infusion reactions and risk of post-transplant complications. We report the results of a non-ATG-containing RIC regimen, where patients received 2 Gy TBI unless they were considered to be at higher risk of graft failure, in which case they received 3 Gy of TBI. Thirty patients underwent CBT using this protocol for high-risk hematological malignancies. There was only one case of secondary and no cases of primary graft failure. At 1 year, estimates of non-relapse mortality, OS and PFS were 29%, 53% and 45%, respectively. The cumulative incidences of grade III-IV acute and chronic GVHD were 14% and 18%, respectively. In summary, the results of this study demonstrate that this non-ATG-containing conditioning regimen provides a low incidence of graft failure without increasing regimen-related toxicity.

Autologous transplantation followed closely by reduced-intensity allogeneic transplantation as consolidative immunotherapy in advanced lymphoma patients: a feasibility study.

We report outcomes in advanced lymphoma patients (n = 32) who enrolled in a trial of prospectively planned combined autologous/reduced-intensity transplantation (RIT) (n = 25) or who received RIT shortly after prior autografting because of high relapse risk or progressive disease (n = 7). Nine patients on the autologous/RIT transplant protocol did not proceed to planned RIT because of patient choice (n = 4), disease progression (n = 3), toxicity (n = 1), or no adequate donor (n = 1). Among the 23 other patients, RIT was started a median of 59 days (range 31-123) after autologous transplant. Fifteen patients had related donors, five patients had unrelated donors, and three patients had cord blood donors. Among all patients completing RIT, the median overall survival time was 385 days (95% CI 272-792), and the median relapse-free survival time was 157 days (95% CI 119-385). At the time of reporting, six patients (26%) remain alive and three patients (13%) remain alive without relapse. The 100-day transplant-related mortality (TRM) was 9% among all patients and was 0% among matched sibling donors. Overall TRM was 43%. Tandem transplant is feasible in advanced lymphoma with low early TRM. However, practical challenges associated with the strategy were significant and high levels of late TRM due to graft-versus-host disease and infections suggest that modifications of the procedure will be needed to improve outcomes and patient retention.

Disopyramide-induced heart block.

A 57-year-old woman with right bundle branch block +LPH and ventricular premature contractions developed complete heart block (CHB) following administration of disopyramide phosphate (Norpace). The ECG at the onset of CHB suggested block to have occurred in the trifascicular conduction system. On rechallenging the patient with the drug following the implantation of a permanent pacemaker, intermittent complete heart block developed. This case suggests that disopyramide should be used with caution in patients with bifascicular block patterns on ECG.