Showing papers by "Vinod Pullarkat published in 2015"

Erythropoietin-mediated expression of placenta growth factor is regulated via activation of hypoxia-inducible factor-1α and post-transcriptionally by miR-214 in sickle cell disease.

Abstract: Placental growth factor (PlGF) plays an important role in various pathological conditions and diseases such as inflammation, cancer, atherosclerosis and sickle cell disease (SCD). Abnormally high PlGF levels in SCD patients are associated with increased inflammation and pulmonary hypertension (PHT) and reactive airway disease; however, the transcriptional and post-transcriptional mechanisms regulating PlGF expression are not well defined. Herein, we show that treatment of human erythroid cells and colony forming units with erythropoietin (EPO) increased PlGF expression. Our studies showed EPO-mediated activation of HIF-1α led to subsequent binding of HIF-1α to hypoxia response elements (HREs) within the PlGF promoter, as demonstrated by luciferase transcription reporter assays and ChIP analysis of the endogenous gene. Additionally, we showed miR-214 post-transcriptionally regulated the expression of PlGF as demonstrated by luciferase reporter assays using wild-type (wt) and mutant PlGF-3′-UTR constructs. Furthermore, synthesis of miR-214, located in an intron of DNM3 (dynamin 3), was transcriptionally regulated by transcription factors, peroxisome proliferator-activated receptor-α (PPARα) and hypoxia-inducible factor-1α (HIF-1α). These results were corroborated in vivo wherein plasma from SCD patients and lung tissues from sickle mice showed an inverse correlation between PlGF and miR-214 levels. Finally, we observed that miR-214 expression could be induced by fenofibrate, a Food and Drug Administration (FDA) approved PPARα agonist, thus revealing a potential therapeutic approach for reduction in PlGF levels by increasing miR-214 transcription. This strategy has potential clinical implications for several pathological conditions including SCD.

Impact of pretransplant serum ferritin level on risk of invasive mold infection after allogeneic hematopoietic stem cell transplantation

Abstract: Invasive mold infections (IMI) are life-threatening complications of allogeneic hematopoietic stem cell transplantation (HSCT) and are mostly caused by Aspergillus species and Mucorales. We examined whether elevated serum ferritin prior to HSCT was associated with increased risk of IMI after allogeneic HSCT. Elevated serum ferritin was defined as values ≥1000 ng/mL. Pretransplant ferritin levels were available for 477 transplants. Nine developed IMI at day 30 and 21 had IMI at day 100 for a cumulative incidence of 1.9% and 4.4%, respectively. Among the high ferritin group, eight of 220 transplant cases (3.6%) developed an IMI within 30 d after HSCT compared with one of 257 (0.4%) in the low ferritin group (P = 0.01). Fourteen of 220 (6.4%) and seven of 257 transplant cases (2.7%) in the high and low ferritin groups, respectively, had developed an IMI by day 100 after HSCT (P = 0.07). Nine of 53 (17%) patients with grades III and IV acute GVHD and iron overload experienced IMI, when compared to three of 37 (8.1%) with high-grade aGVHD, but no iron overload. Among patients without aGVHD, those with elevated ferritin had a 2.7% incidence of IMI compared with 0.9% for patients without elevated ferritin. There was a marginally significant difference in cumulative incidence function between high and low ferritin groups for IMI (P = 0.06). However, elevated serum ferritin (≥1000 ng/mL) was not a significant risk factor for IMI in a multivariate competing risk regression model after adjusting for aGVHD.

Therapy-related ALL: cytogenetic features and hematopoietic cell transplantation outcome.

Abstract: Therapy-related leukemia has been described after chemotherapy, radiation and autologous hematopoietic SCT. The majority of such cases are therapy-related AML/myelodysplastic syndrome (t-AML/MDS) and the cytogenetic and molecular features of these cases are well defined. On the other hand, therapyrelated ALL (t-ALL) has been described infrequently in the literature. The clinical and pathological characteristics as well as treatment outcomes of t-ALL remain poorly defined. Although mixed myeloid leukemia (MLL) gene rearrangement is the most recurrent cytogenetic abnormality associated with t-ALL in the literature, other chromosomal alterations have been described. Herein, we examined the pathologic features and treatment outcomes of a cohort of t-ALL patients who underwent allogeneic hematopoietic cell transplantation (HCT) at our institution in order to better characterize the cytogenetic profile of t-ALL, and to examine outcomes of t-ALL post allogeneic HCT. We reviewed a consecutive case series of adult ALL patients who underwent allogeneic HCT at City of Hope between 1998 and 2014. We excluded patients with prior malignancies who did not receive chemotherapy or/and radiation before ALL onset. Continuous variables were tested between the leukemia cytogenetic abnormality subgroups, namely MLL gene rearrangement-positive and Phpositive, and others (all cases excluding those with MLL gene rearrangement and Ph chromosome) using the Wilcoxon ranksum test. Categorical variables were tested using Fisher’s exact test. Survival estimates were calculated from the date of transplantation, and tested using the log-rank test of Mantel and Haenszel for OS and leukemia-free survival (LFS). Cumulative incidence of relapse (CIR) with non-relapse-related mortality (NRM) as a competing risk was plotted and tested using prevalence methods developed by Gray. Among 596 adults with ALL who underwent allogeneic HCT during the specified period, we identified 28 (4.7%) patients who had a history of chemotherapy and/or radiation before the diagnosis of ALL. The median age was 48 years (range 29–61), and 57% of patients were female. All cases had B-cell phenotype. The median initial WBC was 8.0 × 10/L (range 1.2–323). The median interval from initial diagnosis of malignancy/disease to ALL diagnosis was 7.3 years (range 0.9–50.1). The most common prior diagnosis was breast cancer (N= 9), and this was followed by multiple myeloma (N= 4), sarcoma (N= 4), thyroid cancer/disease (N= 4), lymphoma (N= 3), germ cell tumor (N= 2, including a case of combined germ cell and CLL), melanoma (N= 1) and colon cancer (N= 1). Twenty-nine percent (N= 8) had a prior combination of chemotherapy and radiation therapy, 32% (N= 9) had prior radiation alone and 39% (N= 11) had prior chemotherapy alone. Four patients (14%) had undergone autologous HCT prior to ALL diagnosis. Interestingly, the most common cytogenetic abnormality in our cohort was t(9;22)(q34;q11) (Ph chromosome) in 39% (N= 11) followed by MLL gene rearrangement in 25% (N= 7). MLL gene rearrangement were t(4;11) (N= 5), t(6;11) (N= 1) and t(1;11) (N= 1). Other observed cytogenetics include three cases of normal karyotype and single case of each of the following: complex karyotype; hypodiploidy; 14q32/IGH+; t(1;5); t(12;17); t(1;19); and t(2;7). Therefore, we compared the clinical and pathological features of the three main cytogenetic subgroups: Ph+ t-ALL vs MLL gene-rearranged t-ALL vs t-ALL with other cytogenetic abnormalities. The median age, initial WBC and the type of previous cytotoxic modality were similar among the three cytogenetic subgroups. However, the median interval from the diagnosis of previous malignancy to ALL diagnosis was significantly longer for Ph+ t-ALL and other cytogenetics subgroups compared with the MLL generearrangement subgroup (9.37 vs 7.96 vs 2.07 years; P= 0.0006, respectively; Table 1). The majority of patients were in CR1 at the time of transplantation (71%). Conditioning regimen for HCT was full intensity in 16 patients (57%). Tacrolimus/sirolimus-based GVHD prophylaxis was used in 16 patients (57%). Unrelated donor was the source of graft in 15 patients (54%) and mobilized peripheral blood progenitor cells were used in 23 patients (82%). Disease status at transplant, time from diagnosis to HCT, source of graft, GVHD prophylaxis and conditioning intensity were not different among the cytogenetic subgroups. The 4-year LFS, OS, CIR and NRM for the whole cohort were 47%, 51%, 28% and 25%, respectively. For the patients transplanted in CR1 (N= 20), the 4-year LFS, OS and CIR were 58%, 65% and 23%, respectively, and LFS (P= 0.008) and OS (P= 0.02) were significantly higher for patients transplanted in CR1 compared with those transplanted in non-CR1 (N= 8). Outcomes were not different among the three cytogenetic subgroups (Figure 1). One patient experienced relapse of the initial malignancy (CLL) after allogeneic HCT for t-ALL. Given the fact that t-ALL constitutes a distinct minority among therapy-related leukemias, our study describes a relatively large number of t-ALL treated uniformly with alloHCT. Furthermore, we describe the cytogenetic features of this rare ALL subset and confirm the existence of therapy-related Ph+ ALL as a distinct entity. There are case reports as well as a small case series in the published literature describing the outcome of secondary ALL. However, not all these cases have received prior cytotoxic therapy, and hence, it is difficult to establish a causal relationship between therapy of the prior malignancy and subsequent occurrence of ALL in all of these cases. In contrast, we restricted the definition of t-ALL to cases with prior exposure to chemotherapy or/and radiation. The GIMEMA group identified 21 (2.3%) cases of secondary ALL among 901 adults with ALL recorded in the database, but only 11 patients had prior treatment with cytotoxic therapy before ALL diagnosis. The median latency to development of secondary ALL from prior malignancy diagnosis was 27 months. Normal karyotype was the most common reported cytogenetic characteristic, but Ph chromosome was seen in three cases. The median survival was only 5 months. Shivakumar et al. pooled 101 cases of secondary ALL reported in the literature between the years 1982 and 2005, including 12 cases with no prior cytotoxic therapy. MLL gene rearrangement (N= 37) was the most commonly Bone Marrow Transplantation (2015) 50, 746–748 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15

Prognostic and therapeutic implications of early treatment response assessment in acute myeloid leukemia

Abstract: Early assessment of disease response to induction chemotherapy is important in acute myeloid leukemia (AML) in order to plan future therapy and identify chemorefractory disease. Such assessment is customarily performed by examining the bone marrow at around day 14 after initiation of chemotherapy. However, criteria for assessment of residual leukemia in day 14 bone marrow specimens as well as the significance of partial response on long term outcomes remain unclear. Clinical practices vary regarding the therapeutic intervention for residual disease and include readministration of the original induction therapy or use of a different reinduction regimen. In this article, we critically examine the prognostic significance of residual disease detected on interim bone marrow examination as well as data on reinduction therapy with the original induction regimen versus an alternate regimen. We emphasize the need for standardizing reporting of interim bone marrow assessment as well as evaluating new technologies and biomarkers for early assessment of disease response and chemosensitivity in AML.

Impact of self-administration of romiplostim by patients with chronic immune thrombocytopenia compared with administration by a healthcare provider

Abstract: Objective This post hoc analysis evaluated romiplostim self-administration (SA group) vs. romiplostim administration by a healthcare provider in a clinical setting (HCP group) in patients with chronic immune thrombocytopenia (ITP). Methods Outcomes from 3 ITP trials allowing self-administration in patients achieving a stable romiplostim dose for ≥3 consecutive weeks were compared. Evaluations were conducted for 12-wk treatment intervals. Efficacy endpoints included percentage of patients and weeks with platelets within the target range of 50–200 × 109/L and safety. Results Baseline characteristics suggested less severe disease in the SA groups (n = 563) than in the HCP groups (n = 241). The SA groups had greater proportions of patients achieving the target platelet range (55–58% vs. 40–52%) and greater proportions of weeks with a platelet response (75–88% vs. 47–76%) than the HCP groups. The rate of romiplostim discontinuation was twofold to fivefold lower in the SA groups than in the HCP groups. Rates of duration-adjusted adverse events (AEs), serious AEs and treatment-related AEs were also lower in the SA groups. Conclusions In conclusion, in adults with ITP receiving romiplostim, self-administration was comparable to healthcare provider administration in terms of efficacy and safety profiles, suggesting that self-administration of romiplostim is a feasible option for certain patients with ITP.