Imad A. Tabbara

Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review.

Allogeneic hematopoietic stem cell transplantation provides many patients, with hematological and malignant diseases, hope of remission and in some cases cure. Because the toxicities of this approach are severe, its use has been limited to younger healthier patients. Nonmyeloablative and reduced intensity conditioning regimens depend more on donor cellular immune effects and less on the cytotoxic effects of the conditioning regimen to eradicate the underlying disease. This approach is based on the induction of host tolerance to donor cells followed by the administration of scheduled donor T-lymphocytes infusions. Accumulated clinical data have been encouraging, and prospective studies are underway to compare this approach to conventional myeloablative allogeneic stem cell transplantation with regard to outcome, durability of responses, effects on the immune system, and the consequences of late complications such as chronic graft-versus-host disease.

Small-cell carcinoma of the head and neck : a novel treatment regimen

Four patients with small-cell carcinoma (SCC) of the head and neck were treated in a pilot Phase I-II study to evaluate the response rate and toxicity of weekly non-cross-resistant combination chemotherapy administered as primary therapy in small-cell carcinomas. All four patients had locoregional disease without evidence of distant metastasis. The treatment regimen consisted of dose-intensive chemotherapy administered for 16 weeks. One or two of six cytotoxic agents (cisplatin, vincristine, methotrexate, Adriamycin, cyclophosphamide, and etoposide) were used weekly in different combinations followed by radiotherapy and/or surgical resection. To date, three of the four patients have completed therapy and achieved a complete response. The fourth patient is currently receiving chemotherapy and has achieved a partial response. Our treatment regimen appears effective in producing high initial response rates in SCC of the head and neck.

The Role of Granulocyte Colony-Stimulating Factor in Hematopoietic Stem Cell Transplantation

Recombinant granulocyte colony-stimulating factor (G-CSF) has been shown to decrease the duration of severe neutropenia, the incidence of febrile neutropenic episodes, the overall duration of intravenous antibiotic therapy, and the length of hospitalization in patients receiving myelosuppressive chemotherapy. G-CSF has also been shown to accelerate myeloid recovery after autologous and allogeneic bone marrow transplantation, and to mobilize stem cells in peripheral blood for hematopoietic rescue. However, the optimal dose, schedule, and method of administration of G-CSF in these settings remain to be standardized. This review focuses on the role of G-CSF in bone marrow and peripheral blood stem cell transplantation, and in hematopoietic stem cell mobilization.

The Role of Mutant IDH1 and IDH2 Inhibitors in the Treatment of Acute Myeloid Leukemia.

For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. Inhibition of various classes of αKG-dependent dioxygenases results in dramatic epigenetic changes in hematopoietic cells, which has been found to directly impair differentiation. In addition to a global dysregulation of gene expression, other mechanisms have been described through which R2-HG promotes leukemic transformation including the induction of B cell lymphoma 2 dependency and stimulation of the EglN family of prolyl 4-hydroxylases (EglN). Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors. More recently, the FDA approved the first mutant IDH2 inhibitor, enasidenib (AG-221), for patients with relapsed or refractory IDH2-mutated AML (RR-AML). This has brought a lot of excitement to researchers, clinicians, and patients, especially because the treatment of AML remains challenging and is still associated with a high mortality.

Primary cutaneous anaplastic large-cell lymphoma.

Since the recognition of the anaplastic large-cell lymphomas in the 1980s, much has been learned about the diagnosis, clinical presentation, and treatment of these malignant conditions. The systemic and primary cutaneous types of anaplastic large cell lymphomas have been differentiated on clinical and immunophenotypical findings, but further research is required to elucidate their exact etiologies and pathogeneses. Primary cutaneous anaplastic large-cell lymphoma has a 95% disease-specific 5-year survival, owing partly to the relatively benign course of the disease and partly to the variety of effective treatments that are available. As with many other oncological diseases, new drugs are continually being tested and developed, with immunotherapy and biological response modifiers showing promise.

Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study

Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8xa0months. Despite a median platelet count of 49u2009×u2009109/L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (nu2009=u20091), asymptomatic QT prolongation (nu2009=u20091), and bradycardia (nu2009=u20091) occurred in three patients within the first 3xa0months of retreatment. One death due to catheter-associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3—NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment-limiting thrombocytopenia.

PD-1 signaling and inhibition in AML and MDS

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

Lymphocyte-predominant Hodgkin disease: A comprehensive overview

Lymphocyte-predominant Hodgkin disease is a rare form of Hodgkin lymphoma that is recognized as a separate histopathological entity. This disease tends to have multiple relapses, but has an overall good prognosis. Owing to its rarity, and the prolonged time period between recurrence and transformation events, there is no consensus regarding optimal management. However, the National Comprehensive Cancer Network guidelines indicate that for early stages, appropriate treatment is radiotherapy. Several management options have been reported including observation, radiation, chemotherapy, combined chemoradiotherapy, and anti-CD20 antibody therapy. Salvage therapy remains effective in inducing prolonged remission in patients with relapsed/refractory disease.

Ceftazidime and Ciprofloxacin as Empiric Therapy in Febrile Neutropenic Patients Undergoing Hematopoietic Stem Cell Transplantation

This pilot study was done to assess the efficacy and toxicity of intravenous ceftazidime and ciprofloxacin in patients developing febrile neutropenia while undergoing high-dose myeloablative therapy and hematopoietic stem cell transplantation (HSCT). All patients undergoing high-dose chemoradiotherapy and HSCT for leukemias, lymphomas, multiple myeloma, and solid tumors received open-label ceftazidime 2 g intravenously every 8 hours and ciprofloxacin 400 mg intravenously every 12 hours if they developed fever while they were neutropenic. Success with or without modification of this regimen was defined as survival through the neutropenic period; failure was defined as death secondary to infection. Among 45 patients treated with this regimen, the success rate was 98%. Sixty-two percent (28 of 45) of the patients achieved defervescence within 48 to 72 hours and remained afebrile without regimen modification. In 16 patients (36%) the regimen was modified because of persistent fever. The combination of ceftazidime and ciprofloxacin as initial empiric antibacterial therapy in febrile neutropenic patients undergoing myeloablative therapy and HSCT appears to be highly effective and is associated with minimal toxicity.

Safety of BTZ retreatment for patients with low-grade peripheral neuropathy during the initial treatment

ObjectiveNeuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment.MethodsCharts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug.ResultsAmong the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (nxa0=xa052, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN.ConclusionThe results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug.