Rakhee Vaidya

DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status

PURPOSE The Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis (PMF) uses five risk factors to predict survival: age older than 65 years, hemoglobin lower than 10 g/dL, leukocytes higher than 25 × 10(9)/L, circulating blasts ≥ 1%, and constitutional symptoms. The main objective of this study was to refine DIPSS by incorporating prognostic information from karyotype, platelet count, and transfusion status. PATIENTS AND METHODS Mayo Clinic databases for PMF were used to identify patients with available bone marrow histologic and cytogenetic information. RESULTS Seven hundred ninety-three consecutive patients were selected and divided into two groups based on whether or not their referral occurred within (n = 428; training set) or after (n = 365; test set) 1 year of diagnosis. Multivariable analysis identified DIPSS, unfavorable karyotype, platelets lower than 100 × 10(9)/L, and transfusion need as independent predictors of inferior survival. Hazard ratio (HR)-weighted adverse points were assigned to these variables to develop a composite prognostic model using the training set. The model was subsequently validated in the test set, and its application to all 793 patients resulted in median survivals of 185, 78, 35, and 16 months for low, intermediate-1 (HR, 2.2; 95% CI, 1.4 to 3.6), intermediate-2 (HR, 4.9; 95% CI, 3.2 to 7.7), and high-risk groups (HR, 10.7; 95% CI, 6.8 to 16.9), respectively (P < .001). Leukemia-free survival was predicted by the presence of thrombocytopenia or unfavorable karyotype (10-year risk of 31% v 12%; HR, 3.3; 95% CI, 1.9 to 5.6). CONCLUSION DIPSS plus effectively combines prognostic information from DIPSS, karyotype, platelet count, and transfusion status to predict overall survival in PMF. In addition, unfavorable karyotype or thrombocytopenia predicts inferior leukemia-free survival.

Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: A comprehensive cytokine profiling study

PURPOSE Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance. PATIENTS AND METHODS Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines. RESULTS In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) -based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories. CONCLUSION This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.

Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study

Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9–27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7–15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ⩾15 × 109/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.

Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients

We have previously identified sole +9, 13q- or 20q-, as ‘favorable’ and sole +8 or complex karyotype as ‘unfavorable’ cytogenetic abnormalities in primary myelofibrosis (PMF). In this study of 433 PMF patients, we describe additional sole abnormalities with favorable (chromosome 1 translocations/duplications) or unfavorable (−7/7q-) prognosis and also show that other sole or two abnormalities that do not include i(17q), −5/5q-, 12p-, inv(3) or 11q23 rearrangement are prognostically aligned with normal karyotype, which is prognostically favorable. These findings were incorporated into a refined two-tired cytogenetic-risk stratification: unfavorable and favorable karyotype. The respective 5-year survival rates were 8 and 51% (hazard ratio (HR): 3.1, 95% confidence interval (CI): 2.2–4.3; P<0.0001). Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)-independent prognostic value of cytogenetic-risk categorization and also identified thrombocytopenia (platelets <100 × 109/l) as another independent predictor of inferior survival (P<0.0001). A similar multivariable analysis showed that karyotype (P=0.001) and platelet count (P=0.04), but not IPSS (P=0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable versus favorable karyotype were 46 and 7% (HR: 5.5, 95% CI: 2.5–12.0; P<0.0001). This study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF.

One thousand patients with primary myelofibrosis: the mayo clinic experience.

OBJECTIVE To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results. PATIENTS AND METHODS One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between November 4, 1977, and September 1, 2011, were considered. The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (N=1000), at initial diagnosis (N=340), and within or after 1 year of diagnosis (N=660). RESULTS To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included median age (66 vs 65 years), male sex (61% vs 62%), red cell transfusion need (24% vs 38%), hemoglobin level less than 10 g/dL (38% vs 54%), platelet count less than 100 × 10(9)/L (18% vs 26%), leukocyte count more than 25 × 10(9)/L (13% vs 16%), marked splenomegaly (21% vs 31%), constitutional symptoms (29% vs 34%), and abnormal karyotype (31% vs 41%). Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2. DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age. Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low- and high-risk patients, respectively. CONCLUSION The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials.

Predictors of greater than 80% 2-year mortality in primary myelofibrosis: a Mayo Clinic study of 884 karyotypically annotated patients

DIPSS-plus (the Dynamic International Prognostic Scoring System-plus) includes 8 risk factors for survival in primary myelofibrosis. In the present study of 884 karyotypically annotated patients with primary myelofibrosis, we sought to identify 1 or 2 parameters that can reliably predict death in the first 2 years of disease. After a median of 8.2 years from time of referral to the Mayo Clinic, 564 deaths (64% of patients in the study) had been recorded. Risk factors associated with > 80% 2-year mortality included monosomal karyotype, inv(3)/i(17q) abnormalities, or any 2 of the following: circulating blasts > 9%, leukocytes ≥ 40 × 10(9)/L, or other unfavorable karyotype. Patients with any 1 of these risk profiles (n = 52) displayed significantly shorter overall survival than those otherwise belonging to a high-risk category per DIPSS-plus (n = 298); respective median survivals were 9 and 23 months (hazard ratio 2.2, 95% confidence interval 1.6-3.1; P < .01). The present information complements DIPSS-plus in the selection of primary myelofibrosis patients for high-risk treatment approaches.

Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival

Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.

Plasma cytokines in polycythemia vera: Phenotypic correlates, prognostic relevance, and comparison with myelofibrosis

Plasma cytokine milieu is abnormal in primary myelofibrosis (PMF) and correlates with disease phenotype and prognosis. In this study, we show that several plasma cytokines are also abnormally expressed in polycythemia vera (PV; n = 65), compared to normal controls (n = 35), but with a significantly different pattern than that of PMF (n = 127). Direct phenotypic correlation in PV included levels of IL‐12 with hematocrit; IL‐1b, IL‐2, IL‐7, FGF‐b, and HGF with leukocytosis; and IFN‐α and IFN‐γ with thrombocytosis. In univariate analysis, levels of 13 cytokines (out of 30 analyzed) correlated with survival but only MIP‐1β remained significant on multivariable analysis that included the other cytokines as covariates. Increased level of MIP‐1β (P < 0.01), older age (P < 0.01), and leukocytosis (P = 0.03) maintained their association with shortened survival, on multivariable analysis. This study provides preliminary observations that warrant a larger scale study and suggests the value of plasma cytokines as prognostic biomarkers in PV. Am. J. Hematol., 2012.

Methemoglobinemia and hemolysis in a patient with G6PD deficiency treated with rasburicase.

A 52-year-old African American male was admitted to the hospital for high-dose chemotherapy for refractory aggressive multiple myeloma (MM). He had previously progressed through bortezomib/dexamethasone and lenalidomide therapy. The most recent bone marrow biopsy showed approximately 90% kappa light chain-restricted plasma cells with a high proliferative rate (3.3% cells in S-phase). Admission labs prior to starting any therapy (Table I) were significant for uric acid 16.1 mg/ dL (reference range, 3.7–8.0), creatinine 2.1 mg/dL (reference range, 0.8–1.3 and his baseline was 1.1), lactate dehydrogenase (LDH) 438 U/L (reference range, 122– 222), phosphorus 6.2 mg/dL (reference range, 2.5–4.5), hemoglobin 7.1 g/dL (reference range, 13.5–17.5), and IgG kappa monoclonal protein of 4.1 g/dL. On admission, baseline pulse oximetry at the bedside was normal at 95% O2 saturation (SpO2). Due to baseline renal insufficiency and anticipated tumor lysis, intravenous (IV) fluids were started immediately followed by 6 mg of rasburicase on Day 1. High-dose IV cyclophosphamide (1,500 mg/m) and 1,000 mg of methylprednisolone were administered in the early morning on Day 2. This patient presents with hyperuricemia and hyperphosphatemia with laboratory levels that meet Cairo–Bishop criteria of tumor lysis syndrome (TLS) even before chemotherapy was initiated [1,2]. In addition, he also has an acute kidney injury (AKI) secondary to TLS occurring in the setting of refractory MM as manifested by high tumor burden, high plasma cell proliferative rate, increased serum LDH, and a very high uric acid with AKI. Given the clinical features and baseline hyperuricemia and AKI, rasburicase should be administered to prevent worsening renal failure. A glucose-6-phosphatase dehydrogenase (G6PD) level is usually obtained in patients receiving rasburicase because rasburicase can induce hemolysis and cause methemoglobinemia in enzyme-deficient individuals. In our patient, the options were to give rasburicase or to provide prophylactic kidney dialysis without rasburicase. We proceeded with rasburicase given the need for immediate chemotherapy. On hospital Day 2, bedside pulse oximetry showed significant hypoxemia (SpO2 75%), triggering an emergency consultation with the critical care team. The patient was evaluated and found to be quite comfortable on room air with a respiratory rate of 16 per minute without the use of accessory muscles of respiration; lung, cardiac, and mucous membrane examinations were normal. An arterial blood gas (ABG) was performed and the arterial blood was noted to be brown in color. ABG showed pH 7.39, pO2 104 mmHg, pCO2 39 mmHg, HCO3 24 mmol/L and methemoglobin 12.9% (normal range, 0–1.5%). At this point, the care team discussed the use of IV methylene blue. Methemoglobinemia is one of the known side effects of rasburicase administration. In the setting of recent rasburicase administration, the low SpO2 with a normal physical examination in an asymptomatic patient makes the diagnosis of methemoglobinemia highly likely. There was no detectable blue skin color due to his African American ethnicity. ABG findings with the normal pO2 and increased methemoglobin confirmed the diagnosis. Rasburicase can induce hemolysis in G6PD-deficient patients. Moreover, G6PD deficient patients who develop methemoglobinemia should not be given methylene blue as it can also induce hemolysis. Immediate treatment with methylene blue was considered in our patient, but avoided given his relatively moderate degree of methemoglobinemia, asymptomatic condition, and his unknown G6PD status at that time on Day 2. Ascorbic acid administration is the alternative method of treatment. The patient was treated conservatively with ascorbic acid therapy 1,000 mg oral daily. The G6PD level returned deficient at 3.3 U/g Hb (normal, 8.8–13.4) and thus the patient did not receive methylene blue. Over the next 4 days, his methemoglobinemia resolved and his O2 saturation normalized (Fig. 1). Unfortunately, during this same time period, he developed progressive anemia requiring red blood cell support. Serum haptoglobin was normal at 69 mg/dL (reference range, 30–200) on Day 3 but became undetectable (<14) by Day 5. Bilirubin increased from 0.6 mg/dL on Day 2 to 3.6 mg/dL (reference range, 0.1–1.0 mg/dL) on Day 5; LDH increased from 438 U/L on Day 1 to 1,555 U/L on Day 5. The patient reported tea-colored urine. He was supported with a total of eight units of packed red blood cells over the next 4 days (Table I). The patient’s low G6PD level explains the moderate hemolysis that he developed after rasburicase administration. It is important to note that there was an hemolysis-free interval between the rasburicase administration and the first clinical and laboratory signs of hemolysis. This is typical and must be remembered or else hemolysis may be missed during a short hospital admission.

Benzodiazepine Use in Breast Cancer Survivors: Findings from a Consecutive Series of 1,000 Patients

Objective: This study reports the percentage of breast cancer survivors receiving ongoing benzodiazepines and the circumstances surrounding their usage. Methods: The medical records of 1,000 consecutive breast cancer survivors who were no longer receiving adjuvant chemotherapy were reviewed. Results: Among those patients, 7.9% (95% confidence interval 6.2–9.6; higher than the 3% rate in the general population) were receiving benzodiazepines. Lorazepam was most commonly prescribed. Sixty-eight patients were cancer free at their last visit, and 51 had not been taking benzodiazepines prior to their cancer diagnosis. Anxiety was the single most frequent reason for initiating and continuing benzodiazepines. Conclusion: Anxiety appears to be a common explanation for relatively high rates of benzodiazepine use in breast cancer survivors. This finding merits further study.