Citations

Transplant‐associated thrombotic microangiopathy (TA‐TMA) is a rare clinical syndrome associated with significant mortality. Although the use of plasma exchange (PE) in TA‐TMA continues to be explored, evidence for its efficacy is debated. We performed a single institution, retrospective study to evaluate the efficacy of PE in treating TA‐TMA patients. Special attention was given to efficacy in relation to the timing of presentation with TA‐TMA since transplant. Thirty‐three patients diagnosed with TA‐TMA and treated with PE between January 1999 and December 2010 were included in the study. Clinical improvement was seen in eight patients (24%); four patients achieved complete resolution while the remaining four achieved partial resolution. All‐cause day‐30 and day‐100 mortality was 33 and 55%, respectively. There was a trend toward a better outcome (complete/partial) for those presenting ≥ 100 days after transplantation (42%) vs. < 100 days after transplantation (14%; P‐value = 0.15). Similarly, those presenting at ≥ 100 days had better, but not significantly, 30‐day and 100‐day all‐cause mortality rates (17 and 33%, respectively) than those presenting at < 100 days (43 and 67%, respectively) (P‐value = 0.25 and 0.08, for 30‐ and 100‐day all‐cause mortality, respectively). This is the first study looking at the efficacy of PE while considering the time of presentation since transplantation and is one of the largest single institution series of TA‐TMA. The overall efficacy of PE is poor; however, patients who present with TA‐TMA ≥100 days after transplant may have better outcome and lower mortality. J. Clin. Apheresis 30:147–153, 2015. © 2014 Wiley Periodicals, Inc.

Disease Overview: Chronic neutrophilic leukemia (CNL) is a myeloproliferative neoplasm characterized by sustained, mature neutrophilic leukocytosis, splenomegaly, and bone marrow granulocytic hyperplasia. Diagnosis: Key diagnostic criteria include leukocytosis of >25 × 109/l (of which >80% are neutrophils) with <10% and <1% circulating immature granulocytes and myeloblasts, respectively. There should be no dysplasia, monocytosis, molecular evidence of BCR‐ABL1, PDGFRA, PDGFRB, or FGRF1 rearrangements and no identifiable cause for physiologic neutrophilia or, if present, demonstration of myeloid clonality. Developments in Molecular Genetics: Recently, CNL has been shown to be specifically driven by somatic activating mutations of CSF3R, most commonly CSF3R T618I. As such, the diagnosis of CNL will no longer be one of exclusion only, and revision of the current WHO classification is anticipated to include the molecular criterion of mutated CSF3R. Am. J. Hematol. 89:651–658, 2014. © 2014 Wiley Periodicals, Inc.

In childhood acute lymphoblastic leukemia (ALL), a rapid decline of circulating leukemic blasts in response to induction chemotherapy or prednisone is one of the most important prognostic factors, not only for achieving remission but also for relapse-free survival (RFS). However, in acute myeloid leukemia (AML) parameters of chemosensitivity have been restricted mainly to the rapidity of achievement of complete remission (CR) or the assessment of residual leukemic bone marrow blasts during aplasia. We hypothesized that the time to circulating peripheral blood blast clearance, as a potential surrogate for in vivo chemosensitivity, would have prognostic relevance in AML also. In a retrospective analysis of a cohort of 86 adult patients with AML receiving uniform induction and consolidation chemotherapy, we demonstrate that the time to clearance of circulating blasts during induction chemotherapy is an independent prognostic marker of RFS, superseding other known or established risk factors, including karyotype and number of inductions to achieve CR.

Abstract Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

AbstractThe immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor protein has been crude. We evaluated the utility of the FLC assay in a retrospective analysis of patients with AL undergoing peripheral blood stem cell transplantation (PBSCT). Ninety-three such patients had serial FLC measurements performed. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were studied. There was a significantly higher risk of death in patients with higher baseline FLC (hazard ratio 2.6, P < .04). Baseline FLC correlated with serum cardiac troponin levels, and higher FLC levels were associated with more organs involved by amyloid, suggesting that high FLC levels may be associated with more advanced disease. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. Normalization of FLC level after PBSCT predicted for both organ response and complete hematologic response. Achievement of FLC response was a better predictor of survival than achievement of complete hematologic response or normalization of the FLC ratio. FLC measurements both before and after PBSCT are important predictors of patient outcome.

AbstractPrimary systemic amyloidosis (AL) is a fatal plasma cell disorder. Pilot data suggest survival is better in patients undergoing peripheral blood stem cell transplantation (PBSCT), but the selection process makes the apparent benefit suspect. We have reported that circulating cardiac biomarkers are the best predictors of survival outside of the transplantation setting. We now test whether cardiac troponins (cTnT and cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are prognostic in transplant recipients. In 98 patients with AL undergoing PBSCT, serum cardiac biomarkers were measured (cTnT, 98 patients; cTnI, 65 patients; and NT-proBNP, 63 patients). Elevated levels of cTnT, cTnI, and NT-proBNP were present in 14%, 43%, and 48% of patients, respectively. At 20 months median follow-up, median survival has not been reached for patients with values below the thresholds; in patients with values above the thresholds, median survival is 26.1 months, 66.1 months, and 66.1 months, respectively. Our previously reported risk systems incorporating these markers were also prognostic, notably the cTnT/NT-proBNP staging. Using this system, 49%, 38%, and 13% of patients were in stage I, stage II, and stage III, respectively. Determining levels of circulating biomarkers may be the most powerful tool for staging patients with AL undergoing PBSCT.

AbstractPrimary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 μmol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.

Single-agent thalidomide (THAL) at “conventional” doses (> 100 mg/d) has been evaluated in myelofibrosis with myeloid metaplasia (MMM) based on its antiangiogenic properties and the prominent neoangiogenesis that occurs in MMM. THAL monotherapy at such doses produces approximately a 20% response rate in anemia but is poorly tolerated (an adverse dropout rate of > 50% in 3 months). To improve efficacy and tolerability, we prospectively treated 21 symptomatic patients (hemoglobin level < 10 g/dL or symptomatic splenomegaly) with MMM with low-dose THAL (50 mg/d) along with a 3-month oral prednisone (PRED) taper (beginning at 0.5 mg/kg/d). THAL-PRED was well tolerated in all enrolled patients, with 20 patients (95%) able to complete 3 months of treatment. An objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 × 109/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In 4 of 21 patients (19%), spleen size decreased by more than 50%. Responses observed were mostly durable after discontinuation of the PRED. The dose of THAL in this study (50 mg/d) was better tolerated than the higher doses used in previous studies. Adverse events associated with corticosteroid therapy were mild and transient. Clinical responses did not correlate with improvements in either intramedullary fibrosis or angiogenesis. THAL-PRED is well tolerated and preliminarily appears to be a promising drug regimen for treating cytopenias in patients with MMM.

In a phase 2 study, 23 patients with myelofibrosis with myeloid metaplasia were treated with imatinib mesylate at a constant dose of 400 mg/d. Treatment was held in 16 patients (70%), after 1 to 12 weeks, because of side effects (neutropenia, 6 patients; musculoskeletal pain, 5 patients; thrombocytosis, 4 patients; edema, 3 patients; diarrhea and hyperbilirubinemia, 1 patient). Including patients in whom retreatment at a reduced dose was possible, 11 patients (48%) were able to continue treatment beyond 3 months. None of the patients experienced a response in anemia, and only 2 had partial responses in splenomegaly. A greater than 50% increase in platelet count was documented in 11 (48%) patients, but not in those with baseline platelet counts of less than 100 × 109/L. In vitro, imatinib mesylate caused variable degrees of growth suppression of myeloid and erythroid progenitors that unfortunately did not translate into clinical benefit.