Dyke, Daniel L. Van

BACKGROUND Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. METHODS All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. RESULTS Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III‐IV; P = .001) and higher expression of CD49d ( P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. CONCLUSIONS Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long‐term follow‐up. The presence of hypogammaglobulinemia does not appear to impact overall survival. Cancer 2015;121:2883–2891. © 2015 American Cancer Society .

Key Points Deep sequencing identifies a significant reservoir of subclonal mutations affecting key genes in CLL pathogenesis. Convergent evolution of genetic lesions in tumor subclonal populations is recurrently found in CLL.

SummaryDetection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1‐ (17p‐) and 11q22.3‐ (11q‐) occurring in the same cell (clonal 17p‐/11q‐) would confer a worse prognosis than either 17p‐ or 11q‐. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p‐, 11q‐, or clonal 17p‐/11q‐. Twenty (1%) patients had clonal 17p–/11q‐, 158 (7%) had 17p‐ (including 4 with 17p‐ and 11q‐ in separate clones), 247 (11%) had 11q‐, and 1759 (81%) had neither 17p‐ nor 11q‐. Eleven of 15 (73%) tested patients with clonal 17p‐/11q‐ had dysfunctional TP53 mutations. Overall survival for clonal 17p‐/11q‐ was significantly shorter (1·9 years) than 17p‐ (3·1 years, P = 0·04), 11q‐ (4·8 years, P ≤ 0·0001), or neither 17p‐ nor 11q‐ (9·3 years, P ≤ 0·0001). Clonal 17p‐/11q‐ thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very‐high risk patients.

Abstract 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 × 109/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.

Abstract 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.

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.

Abstract Among 200 patients with primary myelofibrosis, karyotype at diagnosis was abnormal in 83 (42%). To assess their individual prognostic impact, specific cytogenetic abnormalities with more than or equal to 5 informative cases were identified and the rest grouped separately as “other abnormalities.” Median survival in patients with sole +9 (n = 6), sole 20q− (n = 21), sole 13q− (n = 8), normal karyotype (n = 117), “other abnormalities” (n = 28), complex karyotype (n = 13), and sole +8 (n = 7) were “not reached,” 112, 105, 80, 46, 34, and 28 months, respectively (P = .01). Accordingly, 4 cytogenetic risk groups were considered: (1) favorable (sole +9, 20q−, or 13q−), (2) normal, (3) unfavorable (complex karyotype or sole +8), and (4) “other abnormalities.” Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)–independent prognostic value of both 4-way and 2-way (ie, favorable/normal vs unfavorable/other abnormalities; IPSS-adjusted hazard ratio = 0.37; 95% confidence interval, 0.24-0.58) cytogenetic risk categorization (P < .01). The ability to prognostically dissect a specific IPSS category has major therapeutic implications.

To determine the clinical fate of patients with de novo deletion 17p13.1 (17p−) chronic lymphocytic leukemia (CLL), we retrospectively studied the outcome of 99 treatment-naive 17p− CLL patients from the M. D. Anderson Cancer Center (n = 64) and the Mayo Clinic (n = 35). Among 67 asymptomatic patients followed for progression, 53% developed CLL requiring treatment over 3 years. Patients who had not progressed by 18 months subsequently had stable disease, with 3 of 19 patients progressing after follow-up of up to 70 months. Risk factors for progressive disease were Rai stage of 1 or higher and unmutated immunoglobulin variable region heavy chain (IgVH). The overall survival rate was 65% at 3 years. Rai stage 1 or higher, unmutated IgVH, and 17p− in 25% or more of nuclei were adverse factors for survival. The 3-year survival rates of patients with 1 or fewer, 2, and 3 of these factors were 95%, 74%, and 22%, respectively (P < .001). Response rates to therapy with rituximab (n = 6); purine analogues and rituximab (n = 25); and purine analogues, rituximab, and alemtuzumab (n = 16) combinations were 50%, 72%, and 81%, respectively. Patients with 17p− CLL exhibit clinical heterogeneity, with some patients experiencing an indolent course. Survival can be predicted using clinical and biologic characteristics.