Stefan K. Barta

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: A multicenter retrospective analysis

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia.

Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4‐dgRTA) and CD19 (HD37‐dgRTA). Pre‐clinical data demonstrated that Combotox was effective in killing both pre‐B‐ALL cell lines and cells from patients with pre‐B ALL. A clinical study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this study. This study was a Phase I, dose‐escalation trial using Combotox in adults with refractory or relapsed B‐lineage‐ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m2 per dose. Seventeen patients, aged 19–72 years, were enrolled in this multi‐institution study. The maximum tolerated dose was 7 mg/m2/dose (21 mg/m2/cycle) and vascular leak syndrome was the dose‐limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia.

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma.

Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R‐EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)‐associated, aggressive B‐cell, non‐Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.

New antibody approaches to lymphoma therapy

The CD20-directed monoclonal antibody rituximab established a new era in lymphoma therapy. Since then other epitopes on the lymphoma surface have been identified as potential targets for monoclonal antibodies (mAb). While most mAbs eliminate lymphoma cells mainly by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or direct cell death, others counter mechanisms utilized by malignant cells to evade immune surveillance. Expression of PD-L1 on malignant or stromal cells in the tumor environment for example leads to T-cell anergy. Targeting either PD-1 or PD-L1 via mAbs can indirectly eliminate cancer cells by unblocking the host intrinsic immune response. Yet another mechanism of targeted therapy with mAbs are bi-specific T-cell engagers (BiTE) such as blinatumomab, which directly engages the host immune cells. These examples highlight the broad spectrum of available therapies targeting the lymphoma surface with mAbs utilizing both passive and active immune pathways. Many of these agents have already demonstrated significant activity in clinical trials. In this review we will focus on novel CD20-directed antibodies as well as mAbs directed against newer targets like CD19, CD22, CD40, CD52 and CCR4. In addition we will review mAbs unblocking immune checkpoints and the BiTE blinatumomab. Given the success of mAbs and the expansion in active and passive immunotherapies, these agents will play an increasing role in the treatment of lymphomas.

Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma

BACKGROUND We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. PATIENTS AND METHODS We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989-1995), early cART (1996-2000), recent cART (2001-2004), and contemporary cART era (2005-2010). RESULTS Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P < 0.001). While the age-adjusted IPI was a significant predictor of outcome in all time periods, the influence of other factors waxed and waned. Individual HIV-related factors such as low CD4 counts (<50/mm(3)) and prior history of AIDS were no longer associated with poor outcomes in the contemporary era. CONCLUSIONS Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia.

Abstract The outcome for patients with refractory or relapsed acute lymphoblastic leukemia (ALL) treated with conventional therapy is poor. Immunoconjugates present a novel approach and have recently been shown to have efficacy in this setting. Combotox is a mixture of two ricin-conjugated monoclonal antibodies (RFB4 and HD37) directed against CD19 and CD22, respectively, and has shown activity in pediatric and adult ALL. We created a murine xenograft model of advanced ALL using the NALM/6 cell line to explore whether the combination of Combotox with the cytotoxic agent cytarabine (Ara-C) results in better outcomes. In our model the combination of both low- and high-dose Combotox and Ara-C resulted in significantly longer median survival. Sequential administration of Ara-C and Combotox, however, was shown to be superior to concurrent administration. These findings have led to a phase I clinical trial exploring this combination in adults with relapsed or refractory B-lineage ALL (ClinicalTrials.gov identifier NCT01408160).

Diffuse Large B‐Cell Lymphoma with Primary Treatment Failure: Ultra‐high Risk Features and Benchmarking for Experimental Therapies

The outcomes of patients with DLBCL and primary treatment failure (PTF) in the rituximab era are unclear. We analyzed 331 patients with PTF, defined as primary progression while on upfront chemoimmunotherapy (PP), residual disease at the end of upfront therapy (RD) or relapse < 6 months from end of therapy (early relapse; ER). Median age was 58 years and response to salvage was 41.7%. Two‐year OS was 18.5% in PP, 30.6% in RD and 45.5% in ER. The presence of PP, intermediate‐high/high NCCN‐IPI at time of PTF or MYC translocation predicted 2‐year OS of 13.6% constituting ultra‐high risk (UHR) features. Among the 132 patients who underwent autologous hematopoietic cell transplantation, 2‐year OS was 74.3%, 59.6% and 10.7% for patients with 0,1 and 2–3 UHR features respectively. Patients with PTF and UHR features should be prioritized for clinical trials with newer agents and innovative cellular therapy.

A new prognostic score for AIDS-related lymphomas in the Rituximab-era

While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).

Ruxolitinib Withdrawal Syndrome Leading to Tumor Lysis

Case Report A 70-year-old woman with a history of JAK2 V617F mutation– positive post–polycythemia vera (PV) myelofibrosis (MF) presented to the emergency department 4 weeks after discontinuing ruxolitinib with abdominal pain and massive splenomegaly, acute renal failure, hyperkalemia, hyperuricemia, hypocalcemia, and hyperphosphatemia. She was diagnosed with PV 10 years before admission. At that time she had a hemoglobin (Hgb) of 18 g/dL, an elevated red cell mass (51.3 mL/kg; reference range [RR], 24-30 mL/kg), and a hypercellular bone marrow (98%) with clustered megakaryocytes without fibrosis. Cytogenetic analysis showed 70% of cells with trisomy 9 and deletion 20q. She carried the JAK2 V617F mutation, and reverse transcriptase polymer chain reaction was negative for the BCR/ABL transcript. Her WBC count was 25.5 10/ L (RR 4.8-10.8 10/ L), with a platelet count of 210 10/ L (RR, 150-400 10/ L). Abdominal ultrasound showed hepatosplenomegaly, and she was managed with phlebotomy. Six years later she complained of weight loss, night sweats without fever, fatigue, and left upper quadrant abdominal pain resulting from worsening splenomegaly. She was subsequently treated with pegylated interferon, which improved her symptoms and spleen size. Symptoms returned 2.5 years into the course of pegylated interferon and a CBC showed worsening anemia (Hgb, 9.9 g/dL) and thrombocytopenia (platelets, 76 10/ L). A bone marrow biopsy showed hypercellular (100%) marrow with 2/4 reticulin and no significant increase in blasts (Fig 1A, reticulin stain, 40). Cytogenetic analysis revealed no clonal evolution. She subsequently responded to low-dose hydroxyurea, but had recrudescence of symptoms after only 8 months. Red cell morphology was markedly abnormal with poikilocytosis, anisocytosis, and teardrop cells (Fig 2, 100). She was started on low-dose ruxolitinib (10 mg twice daily). Within 5 weeks she experienced improvement in her systemic symptoms and splenomegaly, but had a progressive fall in her Hgb and platelet count with new bruises. Examination of her bone marrow showed marked myelofibrosis with 70% to 80% cellularity (Fig 1B, reticulin stain, 40x), and a new clone with trisomy 8 in addition to the previously seen trisomy 9 and deletion 20q. Again there was no significant increase in blasts. Seven and half weeks after treatment was started, her Hgb dropped to 8.0 g/dL, and platelets decreased to 28 10/ L. The dose of ruxolitinib was reduced to 5 mg twice daily. Despite the low-dose of ruxolitinib, blood counts further deteriorated (Hgb, 7.9 g/dL; platelets, 18 10/ L) and ruxolitinib was stopped after only 9 weeks. Over the next 3 weeks she developed recurrent fever, worsening shortness of breath, diarrhea, and accelerated splenomegaly. She had a gout attack and was treated with prednisone 40 mg daily. A diagnosis of ruxolitinib withdrawal syndrome was considered. Her symptoms deteriorated and she was referred to the emergency department for urgent evaluation. There she was found to be tachycardic with massive splenomegaly and pitting bilateral lower extremity edema. Laboratory tests revealed acute kidney injury (serum creatinine, 2.2 mg/dL; RR, 0.5-1.5 mg/dL; baseline, 1.1 mg/dL), hyperkalemia (potassium, 5.8 mg/dL; RR, 3.5-5.0 mEq/L), hypocalcemia (corrected calcium, 6.6 mg/dL; RR, 8.5-10.5 mg/dL), hyperphosphatemia (phosphorus, 5.9 mg/dL; RR, 2.5-4.5 mg/dL), and hyperuricemia (uric acid, 21.4 mg/ dL; RR, 2.5-8.0 mg/dL). Her lactate hydrogenase was increased at 1,291 U/L (RR, 110-210 U/L), higher than her baseline (756-873 U/L). Her CBC was similar to 1 month prior when ruxolitinib had been stopped (Hgb, 7.1 g/dL; WBC, 30.9 10/ L; platelets, 18 10/ L). An electrocardiogram (EKG) showed peaked T waves without PR prolongation; urine analysis was positive for leukocytes, bacteria, and uric acid crystals. Her chest x-ray was negative for focal infiltrates, vascular congestion, or pleural effusions. She was treated for a presumptive diagnosis of tumor lysis syndrome (TLS) with aggressive hydration and rasburicase (0.2 mg/kg); for hyperkalemia with EKG A