Vikas Gupta

Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

Disease biology rather than age is the most important determinant of survival of patients ≥ 60 years with acute myeloid leukemia treated with uniform intensive therapy

The objectives of the current study were to evaluate the outcome of patients ≥ 60 years with acute myeloid leukemia (AML) treated uniformly with high‐dose daunorubicin containing induction and modified high‐dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival.

Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission

We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 x 10(9)/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 x 10(9)/L. Factors associated with poorer survival included WBC more than 100 x 10(9)/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.

Vascular events associated with alpha Interferon therapy

Alpha Interferon (IFN) is a biological agent used for the therapy of an increasing number of diseases, either as an established effective therapeutic tool or in the context of clinical trials. The use of IFN may be complicated by serious adverse reactions. We describe here the clinical course of a variety of vasculopathic complications in association with IFN-therapy in 12 patients with the diagnosis of chronic myeloid leukemia and 1 patient with malignant melanoma treated at our institute. Vascular manifestations in these patients include Raynauds phenomena, digital ulcerations and gangrene, pulmonary vasculitis, pulmonary hypertension and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). These reactions occurred after 3 months to 3 years of 3-10 million units (MU) daily IFN therapy. Concomitant administration of hydroxyurea (HU) was noted in 5 patients. Discontinuation of IFN and initiation of immunosuppressive therapy brought about a complete resolution or arrested progression of these reactions. IFN-therapy may be complicated by severe vasculopathic/vasospastic complications that usually improve after its discontinuation. Possible underlying mechanisms for these complications are discussed. The early diagnosis of these complications may be vital and IFN should be immediately discontinued when early signs of these complications become evident.

Influence of FLT3-Internal Tandem Duplication Allele Burden and White Blood Cell Count on the Outcome in Patients With Intermediate-Risk Karyotype Acute Myeloid Leukemia

In patients with acute myeloid leukemia (AML), testing for fms‐like tyrosine kinase‐3 (FLT3)–internal tandem duplication (FLT3‐ITD) and nucleophosmin‐1 (NPM1) mutations can allow for further prognostic subclassification, but less is known about the effects of FLT3‐ITD allele burden and presenting white blood cell count (WBC) within molecular subgroups.

Prognostic significance of trisomy 4 as the sole cytogenetic abnormality in acute myeloid leukemia

Trisomy 4 is a recurrent but rare cytogenetic abnormality reported in patients with acute myeloblastic leukemia (AML). The prognostic significance of this abnormality in patients with AML is not clear. We report here four cases of trisomy 4 as the sole cytogenetic abnormality in AML patients treated at our institute during the last 15 years and systematically review all reported cases of trisomy 4 as a solitary cytogenetic abnormality in AML with the aim of studying the disease demography and prognostic significance of this abnormality. Collective data on 30 patients (including four in the present report) showed complete remission (CR) rates of 76.6%. Median relapse free survival and overall survival were 7 months (95% CI 5-17) and 9 months (95% CI 3-17), respectively. Given the limitations of reported literature, the prognosis of AML patients with trisomy 4 appears to be poor compared with the intermediate risk cytogenetics. Collaborations between major institutions and cooperative groups are needed to collect better quality data to understand the prognostic significance of such rare karyotypic abnormalities.

Peripheral blood eosinophilia has a favorable prognostic impact on transplant outcomes after allogeneic peripheral blood stem cell transplantation.

Peripheral eosinophilia after allogeneic stem cell transplant (ASCT) may reflect the activation of the Th2 cytokine pathway. A retrospective analysis was performed to evaluate the impact of early- (before day 100: EEo) or late-onset (beyond day 100: LEo) eosinophilia (> or =0.5 x 10(9)/L in peripheral blood) on transplant outcomes after peripheral blood SCT (PBSCT) in 237 patients. The incidence of EEo and LEo was 43% at day 100 and 62% at 2 years, respectively. Compared with patients without LEo, improved transplant outcomes were observed in patients with LEo: better overall survival (OS; 86% versus 41%, P = 5 x 10(-11)), lower nonrelapse mortality (NRM; 10% versus 37%, P = 3 x 10(-6)), lower relapse incidence (11% versus 31%, P = 3 x 10(-5)), and higher GVHD-specific survival (GSS; 90% versus 64%, P = 1 x 10(-6)) were observed. In addition, similar finding was observed when transplant outcomes were analyzed according to the occurrence of eosinophilia at the onset of cGVHD. The multivariate analyses confirmed a favorable implication of LEo on OS, NRM, and GSS. LEo was associated with: (1) less severe chronic GVHD (cGVHD), (2) higher prevalence of autoantibodies, and (3) rapid lymphocyte count recovery after ASCT. In summary, the development of eosinophila after allogeneic PBSCT seemed to be a prognostic marker for improving transplant outcome.

Outcome of patients who develop acute leukemia or myelodysplasia as a second malignancy after solid tumors treated surgically or with strategies that include chemotherapy and/or radiation

Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy.

A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis.

Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre‐induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 109/l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre‐induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998‐2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1·094 vs. 1·002). A WBC of 34·1 × 109/l had the highest sensitivity (75·6%) and specificity (67·4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 × 109/l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0·0001) and OS (P = 0·0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre‐induction leucoreduction.

Impaired T cell responsiveness to interleukin-6 in hematological patients with invasive aspergillosis.

Invasive mold infections (IMI) are among the most devastating complications following chemotherapy and hematopoietic stem cell transplantation (HSCT), with high mortality rates. Yet, the molecular basis for human susceptibility to invasive aspergillosis (IA) and mucormycosis remain poorly understood. Herein, we aimed to characterize the immune profile of individuals with hematological malignancies (n = 18) who developed IMI during the course of chemotherapy or HSCT, and compared it to that of hematological patients who had no evidence of invasive fungal infection (n = 16). First, we measured the expression of the pattern recognition receptors pentraxin 3, dectin-1, and Toll-like receptors (TLR) 2 and 4 in peripheral blood of chemotherapy and HSCT recipients with IMI. Compared to hematological controls, individuals with IA and mucormycosis had defective expression of dectin-1; in addition, patients with mucormycosis had decreased TLR2 and increased TLR4 expression. Since fungal recognition via dectin-1 favors T helper 17 responses and the latter are highly dependent on activation of the signal transducer and activator of transcription (STAT) 3, we next used phospho-flow cytometry to measure the phosphorylation of the transcription factors STAT1 and STAT3 in response to interferon-gamma (IFN-γ) and interleukin (IL)-6, respectively. While IFN-γ/STAT1 signaling was similar between groups, naïve T cells from patients with IA, but not those with mucormycosis, exhibited reduced responsiveness to IL-6 as measured by STAT3 phosphorylation. Furthermore, IL-6 increased Aspergillus-induced IL-17 production in culture supernatants from healthy and hematological controls but not in patients with IA. Altogether, these observations suggest an important role for dectin-1 and the IL-6/STAT3 pathway in protective immunity against Aspergillus.