Jamile M. Shammo

Multicenter Analysis of 80 Solid Organ Transplantation Recipients With Post-Transplantation Lymphoproliferative Disease: Outcomes and Prognostic Factors in the Modern Era

PURPOSE Adult post-transplantation lymphoproliferative disease (PTLD) has a reported 3-year overall survival (OS) of 35% to 40%. The impact of rituximab on the outcome of PTLD is not well defined. METHODS We examined the clinical features and outcomes among a large cohort of solid organ transplantation (SOT) -related patients with PTLD who were recently treated at four Chicago institutions (from January 1998 to January 2008). Results Eighty patients with PTLD were identified who had a median SOT-to-PTLD time of 48 months (range, 1 to 216 months). All patients had reduction of immunosuppression as part of initial therapy, whereas 59 (74%) of 80 patients received concurrent first-line rituximab with or without chemotherapy. During 40-month median follow-up, 3-year progression-free survival (PFS) for all patients was 57%, and the 3-year overall survival (OS) rate was 62%. Patients who received rituximab-based therapy as part of initial treatment had 3-year PFS of 70% and OS 73% compared with 21% (P < .0001) and 33% (P = .0001), respectively, without rituximab. Notably, of all relapses, only 9% (4 of 34 patients) occurred beyond 12 months from PTLD diagnosis. On multivariate regression analysis, three factors were associated with progression and survival: CNS involvement (PFS, 4.70; P = .01; OS, 3.61; P = .04), bone marrow involvement (PFS, 2.95; P = .03; OS, 3.14; P = .03), and hypoalbuminemia (PFS, 2.96; P = .05; OS, 3.64; P = .04). Furthermore, a survival model by multivariate CART analysis that was based on number of adverse factors present (ie, 0, 1, > or = 2) was formed: 3-year PFS rates were 84%, 66%, 7%, respectively, and 3-year OS rates were 93%, 68%, 11%, respectively (P < .0001). CONCLUSION This large, multicenter, retrospective analysis suggests significantly improved PFS and OS associated with early rituximab-based treatment in PTLD. In addition, clinical factors at diagnosis identified patients with markedly divergent outcomes.

Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS.

Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) ⩾8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI ⩾8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI ⩾8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI ⩾8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression.

Clinical Presentation, Diagnosis, and Prognosis of Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) comprise a group of underrecognized hematologic clonal malignancies with variable propensity for leukemic transformation that can present a diagnostic challenge because they lack hallmark symptoms. MDS can present with varying degrees of anemia, neutropenia, and thrombocytopenia, and at presentation can range from indolent to life threatening. The clinician should have a heightened level of suspicion when treating elderly patients and those with prior exposure to chemotherapy, radiation, and environmental toxins in the presence of unexplained cytopenias. Chronic anemia should not be considered a natural consequence of aging. Approximately 1 in 6 patients with unexplained anemia may have findings compatible with MDS, suggesting that MDS should be considered higher in the differential diagnosis. Primary care physicians are encouraged to conduct comprehensive evaluations to exclude non-MDS-related causes for persistent cytopenias. Patients with pancytopenia, bicytopenia, or any persistent and unexplained isolated cytopenia (and particularly unexplained macrocytic anemia) should be referred to a specialist to establish a diagnosis.

Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma.

BACKGROUND We conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas. PATIENTS AND METHODS We enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m(2) on days 1-3, mitoxantrone 12 mg/m(2) on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m(2) on day 1. After 6-8 weeks, responders received (90)Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m(2) weekly × 4 doses, repeated every 6 months for 2 years). RESULTS After R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received (90)Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient. CONCLUSION R-FM with (90)Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas.

Granulocyte-macrophage colony stimulating factor-induced immune priming of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab chemoimmunotherapy in previously untreated patients with diffuse large B-cell lymphoma and mantle cell lymphoma

Abstract Granulocyte-macrophage colony stimulating factor (GM-CSF) has been shown to enhance CD20 antigen expression, augment antibody-dependent cell-mediated cytotoxicity, and stimulate immune cell proliferation. This may lead to an improved anti-tumor effect of rituximab while reducing the severity of chemotherapy-induced myelosuppression. We evaluated the safety and efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in sequential combination with GM-CSF priming and rituximab in previously untreated patients (n = 39) with diffuse-large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). CHOP was administered every 21 days on day 1, GM-CSF 250 μg/m2/day on days 9 through 15, and rituximab 375 mg/m2 on day 15 of each cycle. The overall response rate was 87%, with complete response in 64%. At a median follow-up of 84.3 months, the overall and progression-free survival rates were 54% and 49%, respectively. The most common toxicity was myelosuppression. Sequential combination of CHOP with GM-CSF priming and rituximab was feasible and effective, warranting further evaluation.

Erratum: Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS (Leukemia (2014) 29 (1033-1040) DOI: 10.1038/leu.2013.305)

Correction to: Leukemia (2014) 28, 1033–1040; doi:10.1038/leu.2013.305 Since the publication of this article it has been noted that there was an omission in the listing of conflict of interest. JM Bennett was listed as having no conflict of interest; however, the authors would like to correct this to read:

An examination of educational gaps in the diagnosis and treatment of myelodysplastic syndromes.

BACKGROUND Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies, with an incidence rate of 3.4 cases per 100,000 in the United States. MDS affects patients predominantly over 60 years of age. As these syndromes are not well understood by many medical practitioner, patients with MDS may be underrecognized or underdiagnosed. The availability of new MDS treatment options further establishes the need to more closely assess gaps in clinical practice and underscores the necessity to develop educational activities to address those gaps. METHODS A multidisciplinary panel was convened to examine current educational needs and gaps. A group consensus approach incorporating a modified nominal group technique was utilized to prioritize and review needs identified in the pre-meeting survey and to evaluate data provided by panelists prior to the meeting. RESULTS The panel identified and prioritized seven educational areas of need: (1) MDS disease awareness, (2) diagnosis, (3) classification and risk stratification, (4) treatment issues, (5) referral to stem cell transplantation or new treatment protocols, (6) clinical monitoring and toxicity management, and (7) translation of new data into patient care. CONCLUSIONS In-depth knowledge is critical to the timely diagnosis and optimal care of MDS patients. A number of key educational needs exist. Educational programs should be practical in orientation to integrate data into practice, and they should be tailored for the intended audience. In addition, an effective educational program must be easily applied by participants.

RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia

The roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.1, and with CDK9/P-TEFb to recruit RNA-polymerase-II at nascent RNA, leading to formation of 5-Azacitidine (5-AZA)-sensitive chromatin structure. In contrast, NSUN1 binds BRD4 and RNA-polymerase-II to form an active chromatin structure that is insensitive to 5-AZA, but hypersensitive to the BRD4 inhibitor JQ1 and to the downregulation of NSUN1 by siRNAs. Both 5-AZA-resistant leukaemia cell lines and clinically 5-AZA-resistant myelodysplastic syndrome and acute myeloid leukaemia specimens have a significant increase in RNA:m5C and NSUN1-/BRD4-associated active chromatin. This study reveals novel RNA:m5C/RCMT-mediated chromatin structures that modulate 5-AZA response/resistance in leukaemia cells, and hence provides a new insight into treatment of leukaemia.Resistance to chemotherapy is a serious issue that can be influenced by RNA epigenetics and chromatin structure. Here, the authors show in leukaemia cells that RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) mediate chromatin structures that can modulate 5-Azacitidine response and resistance.

Phase 2 study of CHOP‑R‑14 followed by 90Y‑ibritumomab tiuxetan in patients with previously untreated diffuse large B‑cell lymphoma

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.

Impact of insulin-like growth factor 1 and insulin-like growth factor binding proteins on outcomes in acute myeloid leukemia.

Our objective was to explore associations of circulating factors implicated in insulin-like growth factor- 1 receptor (IGF-1R) signaling with clinical outcomes of patients with acute myeloid leukemia (AML). Pretreatment blood samples from patients with non-M3 AML (n = 30) were collected prospectively and levels of IGF binding proteins (IGFBPs) 1–7 and IGF-1 (free and total) were established at diagnosis and statistically evaluated. Baseline levels of IGFBP-1 and -6 below respective thresholds of 8.8 ng/mL and 237 ng/mL were associated (p = 0.0347 and 0.0099, respectively) with superior progression-free survival, whereas baseline levels of IGFBP −1, −2, −6 and −7 below the respective thresholds of 8.8, 28.8, 237 and 119 ng/mL were strongly associated (p = 0.0004, 0.0085, 0.0031, 2.46 × 10− 7, respectively) with improved overall survival. These findings provide promising evidence that IGFBP signatures could be used as predictive tools in AML, with applications in remission surveillance and the development of IGFBP-directed biologic therapy.