Sameer A. Parikh

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.

Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist, for Patients With Myelofibrosis

BACKGROUND Myelofibrosis (MF) is a disease characterized by the overexpression of the antiapoptotic BCL-2 family of proteins (eg, BCL-XL and MCL-1). PATIENTS AND METHODS We conducted a multicenter, open-label, noncomparative phase II study of obatoclax mesylate, a small-molecule pan-BCL-2 antagonist, in patients with MF. Obatoclax was administered as a 24-hour infusion (on an outpatient basis) every 2 weeks at a fixed dose of 60 mg. RESULTS A total of 22 patients were enrolled, with a median age of 63 years (range, 43-89 years). Twelve were men, and all 22 patients were previously treated (median of 2 previous therapies). Ten patients (45%) had a Lille score of 1, and 9 patients (41%) had a Lille score of 2. Thirteen (59%) were red blood cell transfusion dependent. A median of 7 cycles of obatoclax were administered. No patient achieved complete or partial response according to International Working Group criteria. One patient (4%) demonstrated a clinical improvement (in terms of hemoglobin and platelet count) after 7 cycles of therapy. The improvement was sustained for 4 cycles of therapy, after which he underwent allogeneic stem cell transplantation. The most common adverse events included low-grade ataxia and fatigue in 50% of the patients. Dose reduction because of toxicity was required in 1 patient, whereas 2 patients were taken off the study because of grade 3 ataxia and grade 3 heart failure. Grade 3/4 anemia and thrombocytopenia were evident in 6 (27%) and 4 (18%) patients, respectively. CONCLUSION Obatoclax exhibits no significant clinical activity in patients with MF at the dose and schedule evaluated.

Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL

Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a median follow-up time of 11 months, the median overall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated. This trial was registered at www.clinicaltrials.gov as #NCT02332980.

Chronic Myeloid Leukemia: Mechanisms of Resistance and Treatment

Imatinib mesylate has revolutionized the treatment landscape for patients with newly diagnosed chronic myeloid leukemia. Follow-up has shown excellent response rates, progression-free survival, and overall survival after 8 years. However, some patients develop resistance to imatinib treatment because of a multitude of reasons. Strategies to overcome resistance include dose escalation of imatinib or switching to a second-generation tyrosine kinase inhibitor or to one of the newer non-tyrosine kinase inhibitors. This article guides the treating physician with a rational approach in the management of patients with chronic myeloid leukemia who fail initial treatment with imatinib or lose response while on therapy with imatinib.

Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis

Since the first description of the natural history of chronic lymphocytic leukemia (CLL) by David Galton in 1966, the considerable heterogeneity in the disease course has been well recognized. The Rai and Binet staging systems described ∼40 years ago have proven to be robust prognostic tools. Over the past 2 decades, several novel biological, genetic, and molecular markers have been shown to be useful adjuncts to the Rai and Binet staging systems. In this systematic review, we examined the role of immunoglobulin heavy-chain variable region gene (IGHV) mutation status and genetic abnormalities determined by interphase fluorescence in situ hybridization (FISH) in patients with newly diagnosed CLL. The cumulative evidence presented in this systematic review is sufficient to recommend that FISH and IGHV be performed as standard clinical tests for all patients with newly diagnosed CLL in those countries with the resources to do so. In addition to clinical stage, these parameters could represent the minimal standard initial prognostic evaluation for patients with CLL. This approach will allow the application of powerful, recently developed prognostic indices (all of which are dependent on IGHV and FISH results) to all patients with newly diagnosed CLL.

Experience with everolimus (RAD001), an oral mammalian target of rapamycin inhibitor, in patients with systemic mastocytosis

KIT D816V mutation has been observed in more than 90% of patients with systemic mastocytosis (SM). This mutation constitutively activates the mammalian target of rapamycin (mTOR) signaling pathway. We tested the efficacy of everolimus (RAD001), a novel oral mTOR inhibitor, at a dose of 10 mg daily in an open label, non-comparative Phase II trial for patients with SM. Ten patients were enrolled from April 2007 to October 2008. Median age was 55 years, four were males, seven had indolent and three aggressive SM, and six were previously treated with other agents. Median duration of therapy was 4 months (range 0.2–18). No objective responses were noted. Four patients had a short-lasting subjective improvement in symptoms for a median duration of 3 months (range 3–15). Grade 1–3 diarrhea, mucositis, and neutropenia were the most common adverse effects. No Grade 4 toxicity was noted. In conclusion, everolimus does not result in appreciable clinical activity in patients with SM.

The Great Imitator: Systemic Nocardiosis Mimicking Richter's Transformation in Relapsed Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) with relapsed disease and high-risk disease features are at risk for transformation of their disease into a more aggressive form of large-cell lymphoma or Richter’s transformation. Such patients usually present with constitutional symptoms (fever, night sweats, and weight loss), rapidly progressive lymphadenopathy, and lesions on positron emission tomography (PET) scan with increased metabolic activity. Here, we discuss a patient who presented with these features but turned out to have an entirely different diagnosis. A 59-year-old African American male was initially diagnosed with CLL in 2002 and intermittently treated with rituximab alone or in combination with chemotherapy (fludarabine and cyclophosphamide) until 2009 at an outside facility. In January 2010, he was admitted to a local hospital for treatment of presumed community-acquired pneumonia. After discharge, he presented to The University of Texas M. D. Anderson Cancer Center in February 2010 and was admitted with progressively worsening shortness of breath, fatigue, weight loss of 10 pounds, night sweats, low-grade fevers, and multiple subcutaneous and axillary nodes that had developed over approximately 4 weeks. His other pertinent past medical history included coronary artery disease, atrial fibrillation, hyperlipidemia, and seizure disorder. He smoked half a pack of cigarettes daily for 20 years and was a retired construction worker. His family history was noncontributory, and he denied any unusual hobbies or pets. Physical examination revealed the presence of a 16 12 cm right axillary mass (Fig 1A), an 8 6 cm erythematous mass on the left flank (Fig 1B), and a 2 3 cm tender erythematous nodule on the left anterior chest. Multiple small lymph nodes measuring 2 cm in the largest dimension were palpated in the axillary and cervical chains bilaterally. No hepatosplenomegaly was appreciated. Further diagnostic work-up demonstrated CLL with high-risk disease features. His WBC count was 51 10/L with 80% lymphocytes and 13% neutrophils; he had anemia with a hemoglobin level of 12.9 g/dL and thrombocytopenia with 36,000 platelets/ L. His serum lactate dehydrogenase was 766 U/L. Bone marrow revealed CLL with the presence of 83% CLL cells in an interstitial pattern. His CLL cells displayed unmutated immunoglobulin heavy-chain variable region

Role of cd20 monoclonal antibodies in previously untreated chronic lymphocytic leukemia

Monoclonal antibodies (MoAbs) directed against the CD20 antigen on B cells have dramatically altered the treatment landscape for patients with chronic lymphocytic leukemia (CLL). Rituximab, a chimeric mouse/human MoAb, was the first antibody to be approved for the treatment of indolent B-cell lymphomas. Although single-agent, standard-dose rituximab has limited activity as first-line therapy for patients with CLL, it has synergistic therapeutic activity when combined with chemotherapy. Indeed, chemoimmunotherapy with combined fludarabine (F), cyclophosphamide (C), and rituximab was shown to improve both progression-free and overall survival in a randomized phase III clinical trial compared with FC in previously untreated patients with CLL. In this article, we review important clinical trials that have incorporated rituximab with other agents for treatment-naive patients with CLL. We also highlight second- and third-generation CD20 MoAbs approved or in development for the treatment of CLL.

Peripheral Blasts on Day 21 of Induction Chemotherapy in a Patient With Core Binding Factor Acute Myeloid Leukemia: More Than Meets the Eye

The combination of fludarabine, high-dose cytarabine, gemtuzumab ozogamicin, and granulocyte colony-stimulating factor (G-CSF), the FLAG-GO protocol, has resulted in excellent response rates and superior relapse-free survival as first-line therapy for patients with core binding factor acute myeloid leukemia (AML). A side effect of administration of G-CSF is an increase in peripheral white blood cell count and blast cell percentage during the recovery phase of the bone marrow after induction chemotherapy. A 60-year-old man with inversion 16 AML was admitted for induction chemotherapy with the FLAG-GO protocol at our institution. On day 21 of his induction regimen, he was noted to have blasts in both the peripheral smear and in the bone marrow that resolved on their own without any intervention by day 28. Our case report underscores the importance of recognizing this phenomenon associated with the administration of G-CSF, and waiting for 5-7 days before administering re-induction therapy or classifying the disease as primary refractory AML.

Clinical Management of Relapsed/Refractory Acute Myeloid Leukaemia

In a study of 243 patients with relapsed/refractory AML by Keating et al., 33% patients obtained a complete remission (CR), 24% died prior to achieving a response and 43% were resistant to their first salvage regimen. The median survival was 18 weeks and five-year survival was only 5%. Whereas prior therapy with cytarabine or stem cell transplant (SCT) did not influence prognosis, duration of first remission was significantly associated with subsequent outcome.