Comparison of intermittent intravenous tacrolimus to continuous tacrolimus in adult allogeneic stem cell transplant recipients.

Introduction: Initial continuous intravenous (CIV) tacrolimus (0.03 mg/kg/day based on ideal body weight [IBW]) has been favored for graft versus host disease (GVHD) prevention in allogeneic stem cell transplant patients due to the consistent, steady-state degree of immunosuppression; however, this method poses many logistical challenges. We implemented intermittent (IIV) tacrolimus at a starting dose of 0.015 mg/kg IBW twice daily over 4 h. To our knowledge this is the first retrospective comparison of CIV to IIV tacrolimus. Objectives: The primary objective was to evaluate the safety of IIV tacrolimus in comparison to CIV with respect to nephrotoxicity and neurotoxicity. The secondary objectives were to compare the incidence of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at day +180, outcomes including relapse and overall survival, cell engraftment, and reactivation of cytomegalovirus and Epstein-Barr virus. Methods: This retrospective, single-center review evaluated adults who received an allogeneic stem cell transplant patients between January 1, 2020, and December 31, 2022. Results: Fifty-one unique patients were eligible for evaluation - 28 in the IIV cohort and 23 in the CIV group. The number of patients who developed nephrotoxicity and neurotoxicity were comparable between groups with no significant differences noted. No severe neurotoxicity was identified in either population. Secondary objectives revealed no significant difference in GVHD incidence or survival outcomes. Conclusion: IIV tacrolimus is comparable to CIV in terms of safety while also maintaining similar outcomes at day +180. IIV is a safe and feasible alternative to CIV in adult allogeneic stem cell transplant recipients.

Urinary bother, Urinalysis, and Two-Year Efficacy Follow-Up Results of Phase I Trial of Intravesical Bacillus Calmette-Guérin Combined with Intravenous Pembrolizumab in Recurrent or Persistent High-Grade Non-Muscle-Invasive Bladder Cancer after Previous Bacillus Calmette-Guérin Treatment.

OBJECTIVE: To report urinary bother, urinalysis changes, disease-free survival (DFS), and overall survival (OS) over 2 years for subjects enrolled in a phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab for recurrent or persistent high-grade non-muscle invasive bladder cancer (HGNMIBC). METHODS: Eighteen patients consented to the study. Five were screen failures. Clinical activity was determined using cystoscopy and cytology with a biopsy of suspicious lesions. Urinalysis and International Prostate symptom score were assessed at pre-treatment, Week 10 (during combined BCG and pembrolizumab treatment), and 3 and 6 months from treatment completion. IPSS was analyzed using a mixed-model repeated measures analysis. A Chi-square test was used to compare urinalysis results at each interval. RESULTS: The pathologic disease stage after restaging transurethral resection and before treatment was pTa in 6 (46.2%), CIS in 6 (46.2%), and pT1 in 1 (7.7%). There was no increase in reported urinary bother throughout treatment. Quality of life measurements demonstrated no change in subjective burden. On urinalysis, we did not observe significant differences at 3 months compared to baseline evaluation. At 12 months, the DFS and OS were 69.23% and 92.31%, respectively. At 24 months, the DFS and OS were 38.46% and 92.31%, respectively. CONCLUSIONS: Treatment with BCG combined with intravenous pembrolizumab is not showing increased urinary bother or adverse urinalysis changes. Two-year response data is promising and await confirmation in the phase III study (Keynote 676).

Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment.

OBJECTIVES: We conducted the first phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab in patients with high-grade non-muscle-invasive bladder cancer (HGNMIBC) who had persistent or recurrent disease after prior intravesical therapy with BCG. The primary endpoint was the safety of this combination. The secondary endpoint was clinical activity at three months following BCG treatment. METHODS: Eighteen patients were consented for the study, five of which were screen failures. Six doses of pembrolizumab were administered every 3 weeks over 16 weeks concurrently with six weekly doses of BCG beginning at week 7. Patient safety was evaluated from the time of consent through 30 days following pembrolizumab treatment. Clinical activity was determined using cystoscopy and biopsy of suspicious lesions. RESULTS: Treatment-related adverse events included one grade 4 adverse event (AEs) (adrenal insufficiency). There were nine grade 3 AEs (chest discomfort, pulmonary embolism, arthritis, wrist edema, injection site reaction, bilateral wrist pain, cardiomyopathy, hypokalemia, urinary tract infection). There were 49 grade 1 and 30 grade 2 AEs (88% of AEs). Eleven patients finished the treatment, and two patients died during the study. Of 13 patients treated, nine patients (69%) had no evidence of disease at 3 months following BCG treatment. CONCLUSIONS: We report for the first time that combining BCG and pembrolizumab in treating HGNMIBC is safe allowing complete treatment of most patients. A phase III trial has opened to test the efficacy of this combination in HGNMIBC (KEYNOTE-676).

Protocol for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high-risk non-muscle invasive bladder cancer.

INTRODUCTION: The initial treatment for high-risk non-muscle invasive bladder cancer (NMIBC) is endoscopic resection of the tumour followed by BCG therapy. In those who develop recurrence, the standard treatment is radical cystectomy. Despite the advancement in surgical technique and postoperative care, the degree of morbidity associated with radical cystectomy remains high, therefore less invasive treatment modalities are desirable. Therapies targeting the programmed death (PD) pathway have shown promise in urothelial carcinoma. We undertook the current study to determine the safety and efficacy of administering pembrolizumab (a monoclonal antibody targeting the interaction between PD-1 and its ligand) in combination with BCG in high-risk NMIBC. METHODS: This is a single-centre phase I safety and efficacy study of pembrolizumab used in combination with intravesicular BCG treatment for subjects with pathologically documented high-risk NMIBC despite having received two courses of induction therapy or BCG treatment followed by maintenance BCG. Fifteen subjects will be enrolled, patients will receive treatment with 200 mg of pembrolizumab every 21 days, starting 2 weeks from the initial endoscopic resection and continuing for 6 weeks after the final dose of BCG. The primary objective is to determine the safety of administering pembrolizumab at a fixed dose of 200 mg every 3 weeks in conjunction with intravesicular BCG treatment in patients with high-risk NMIBC who have failed previous treatment. Secondary objectives are to determine the 19 weeks and the 3, 12 and 24 months post-treatment completion complete response rate with combined pembrolizumab and intravesicular BCG therapy in the aforementioned patients. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Henry Ford Hospital. The results of this study will be published in a peer-reviewed journal and presented at a scientific conference. TRIAL REGISTRATION NUMBER: NCT02324582.

A Case of Synchronous Bone Marrow Chronic Myelomonocytic Leukemia (CMML) and Nodal Marginal Zone Lymphoma (NMZL).

BACKGROUND Leukemias and lymphomas can arise from myeloid or lymphoid stem cells. Combined myeloid leukemia and non-Hodgkin's lymphoma (NHL), either synchronous or metachronous, rarely occur in the same patient. This report is of a 67-year-old man with a synchronous diagnosis of both bone marrow chronic myelomonocytic leukemia (CMML) and nodal marginal zone lymphoma (NMZL), which a peripheral low-grade B-cell NHL. CASE REPORT A 67-year-old Caucasian man, who was a long-term cigarette smoker, presented with a five-year history of leukocytosis and cervical lymphadenopathy. He had no symptoms of night sweats, fever, or weight loss. Review of his medical records showed a progressively increasing leukocytosis with a peak of 58×109/L. Computed tomography (CT) imaging of the chest and abdomen showed lymphadenopathy, including enlarged cervical, axillary, mediastinal, and retroperitoneal lymph nodes. Bone marrow biopsy and histology showed CMML. Lymph node biopsy and histology showed NMZL. The patient was treated for NMZL with weekly intravenous rituximab infusions. Although his CMML was stable, the patient requested an evaluation for treatment with hematopoietic allogeneic stem cell transplantation (ASCT). At the time of this report, the patient remains asymptomatic. CONCLUSIONS The synchronous occurrence of bone marrow CMML and NMZL in a single patient is rare and may be attributed to a genetic mutation common to both. There are no current treatment guidelines for this group of patients, and treatment strategies should be individualized to provide an optimum outcome or symptomatic improvement.

Systemic Mastocytosis in Association with Small Lymphocytic Lymphoma.

BACKGROUND Systemic mastocytosis with an associated hematologic non-mast cell lineage disease is a rare entity, and the majority of systemic mastocytosis cases are associated with myeloid neoplasm. Lymphoproliferative disorders are less commonly associated with systemic mastocytosis and a few cases of systemic mastocytosis associated with chronic lymphocytic leukemia have been described in the literature. CASE REPORT We present a case of indolent systemic mastocytosis associated with small lymphocytic lymphoma. The bone marrow biopsy demonstrated mast cells in the form of clusters and perivascular distribution on immunohistochemistry for tryptase, CD2, and CD25 markers. In addition, 30% involvement by small lymphocytic lymphoma was discovered in the form of interstitial lymphoid aggregates composed of small lymphocytes. Flow cytometry showed B-cells positively stained for CD19, CD20, CD5, CD23, and kappa light chains, and the CD38 expression was <5%. CONCLUSIONS In systemic mastocytosis with an associated hematologic non-mast cell lineage disease, the combination of systemic mastocytosis associated with small lymphocytic lymphoma is rare and the management strategy follows the principle of treating the two entities individually as if they are not related. Clinical surveillance is indicated for indolent systemic mastocytosis and low-risk small lymphocytic lymphoma to monitor for disease progression.

Clinical trials in the management of anal cancer.

Our understandings of anal canal cancer pathogenesis and treatment have undergone significant changes due to continuing research into its pathogenesis and the results of major clinical trials conducted over the past 20 years. Anal canal cancer can be cured by combined modality chemoradiation therapy, a treatment that preserves continence and reserves abdominoperineal resection of the rectum and anal canal in patients with recurrent or residual disease after primary chemoradiotherapy. The research into more effective, less toxic therapies is continuing. Future challenges include an increasing incidence of human papillomavirus infection, the AIDS epidemic, diagnosis of early disease, and optimization of chemotherapy and radiation regimens. This article aims to provide a summary of recently completed and ongoing clinical trials in the management of anal canal cancer.

Assessing the impact of tissue devitalization time on genome-wide gene expression analysis in ovarian tumor samples.

The utilization of genome-wide gene expression microarray technology in tumor stratification has proven a powerful tool to identify gene expression signatures associated with cancer prognosis and is currently under evaluation in clinical laboratories. Standardized protocols, including tumor tissue postoperatively handling guidelines are yet to be defined. We aimed at assessing a systematic effect of devitalization in ovarian tumors' gene expression profiling, using high-density oligonucleotide microarrays, under a standardized protocol following strict quality control criteria. Residual tissue from the surgical pathology specimen was divided into 5 samples. Half of each was immediately snap frozen in liquid nitrogen. The remaining halves were kept at room temperature for 0, 15, 30, 60, and 120 minutes, at which time the tissue was snap frozen in liquid nitrogen, and stored at -80 degrees C until RNA extraction. The entire process from RNA extraction through feature intensity distribution was rigorously monitored for quality. Identification of altered gene expression among each pair of snap frozen and devitalized samples per ovarian tumor specimen was assessed by using the Significance score (S-score) method. We identified only 4 probe sets that seemed to correlate with devitalization time in one of the ovarian tumor specimens, suggesting that they are not likely to have an impact on gene expression profiling tumor stratification. Our study suggests that with proper sample handling and rigorous quality control procedures for RNA extraction and microarray analysis, tumor classification based on global gene expression data will not be adversely affected if devitalization times are kept within a 120-minute window.

Applicability of international prognostic index in non Hodgkin's lymphoma in Pakistan.

BACKGROUND: Aggressive non Hodgkin's Lymphomas (NHL) are common in Southeast Asia, Middle East and Africa. Data on survival with relation to prognostic factors is scarce. The primary objective of the study was to evaluate the applicability of International Prognostic Index (IPI) to predict overall survival (OS) and disease free survival (DFS) in developing countries. METHODS: Two hundred and nineteen patients of NHL consecutively presenting to the Department of Oncology, Jinnah Hospital Lahore between August 1998 to July 2000 were analyzed. All patients underwent initial staging according to Ann Arbor staging system. The patients were categorized by five independent risk factors: patient age, disease stage, serum lactate dehydrogenase (LDH) levels, performance status, and number of extranodal sites involved. Patients were divided into three risk categories Low (0 or one risk factors), Intermediate (2 risk factors) and High (3 or more risk factors). RESULTS: According to IPI low risk category comprised of 15%, intermediate 21% and high 64% of patients, Overall survival (OS) for 2 years and 5 years (n=197) was (69%), (51%), (32%) and (64%), (46%), (13%) respectively (p=0.0008). Disease free survival (DFS) for 2 years and five years (n=197) was (66%), (43%), (34%) and (66%), (43%), (18%) respectively. Age adjusted (60) DFS for 2 and 5 years (n=164) was (70%), (45%), (40%) and (63%), (45%) (19%) respectively. OS for 2 and 5 years (n=164) was (71%), (52%), (34%) and (64%), (46%), (11%) respectively (p=0.0013). CONCLUSIONS: The IPI accurately predicted survival in our population. Modification of treatment protocols according to specific risk groups will be beneficial to the developing countries with limited resources.

Cancer treatment in Pakistan: challenges & obstacles.

INTRODUCTION: There is no population based tumor registry in Pakistan except for Karachi. A Department based tumor registry was established to determine the patterns of cancers in Pakistan especially Punjab. Other objectives were to determine socioeconomic status, disease stage, co-morbid conditions. We also tried to determine if patients had received optimal treatment on diagnosis. MATERIALS & METHODS: 3,274 patients presented to the Department of Oncology between 1995-2000. All patients had histopathologically confirmed diagnosis of cancer. Demographic data included age, sex, socioeconomic status, smoking, other co-morbid and occupation. RESULTS: The Oncology Department drains a catchment area of approximately 400 square kms in Punjab. Breast cancer was the most common cancer in females while leukemias and lymphomas were most common in males. Poor socio-economic status was present in 89% of cases. Illiteracy was present in 76%. Comorbid conditions like hepatitis B & C were present in 37% of patients. Advanced disease was documented in 59% patients. Optimal treatment on initial diagnosis was not provided to 45% patients. DISCUSSION: Advanced stage, poor socio-economic status, illiteracy were common. Associated co-morbid conditions were a major cause in delay in treatment. Optimal treatment was not provided to majority of patients. All these factors are contributing to poor cure rates seen in Pakistan.