Hematology Commons^™

Lessons Learned From The Validation Of A Machine Learning-Based Colorectal Carcinoma Screening Pipeline In Sub-Saharan Africa, Alfred Githuka, Ulysses Balis, Ye Chan Kim, Eileen Weinheimer-Haus, Christopher Williams, Jerome Cheng, Kelou Yao, John Blau, Shahin Sayed, Mansoor Saleh

Haematology and Oncology, East Africa

Background Artificial intelligence for digital pathology may improve cancer detection and workflow efficiency in low- and middle-income countries, but most models are trained and validated in high-income settings, creating uncertainty about generalizability and real-world deployability under differing pre-analytic and infrastructure conditions.

Objective To validate a locally optimized colorectal carcinoma screening pipeline, retrained on data from a local Kenyan cohort, and to assess its feasibility as a sensitivity-forward assistive pre-screening workflow.

Methods Formalin-fixed, paraffin-embedded hematoxylin and eosin-stained slides from 136 biopsy-proven colonic adenocarcinoma cases and 20 normal controls from 2 Kenyan institutions were digitized at 40× using a Grundium Ocus scanner. …

Two Years Of Ocrelizumab Treatment In Black And Hispanic People With Multiple Sclerosis In Chimes: A Single-Arm Clinical Trial, Lilyana Amezcua, Anthony Reder, Evanthia Bernitsas, Nancy Monson, Timothy Vartanian, Gregory Wu, Mansoor Saleh, Annette Okai, Ahmed Obeidat, Dilraj Sokhi

Haematology and Oncology, East Africa

Objective To evaluate the effectiveness and safety of ocrelizumab in self-identified black and Hispanic people with relapsing multiple sclerosis.

Methods The Characterization of Ocrelizumab in Minorities with Multiple Sclerosis (CHIMES) trial, a prospective, open-label, single-arm, phase 4 study, intentionally recruited underrepresented populations in the US, Puerto Rico, and Kenya. Black and Hispanic people with relapsing multiple sclerosis aged 18–65 years with Expanded Disability Status Scale score 0–5.5 received ocrelizumab for 2 years. The primary endpoint was the proportion of participants with no evidence of disease activity in 3 components at week 48: protocol-defined relapse, 24-week confirmed disability progression, and disease …

Estimation Of The Optimal Radiotherapy Utilization Rate For Childhood Neuroblastoma, Azumi Fukushima, Varsha Hande, Katherine Wakeham, Michael Barton, Mohamed Zaghloul, Daniel Moreira, Nickhill Bhakta, Kathy Pritchard-Jones, Bilal Mazhar Qureshi, Michael Sullivan

Haematology and Oncology, East Africa

Background and purpose: The optimal utilization rate of radiotherapy (oRUR) serves as a benchmark for assessing service demand and improving access to cancer care. While it is estimated that approximately 50 % of adult cancer patients require external beam radiotherapy during their treatment, there is a scarcity of data regarding the optimal use of radiotherapy in pediatric cancer. In this study, we adopted an established method and developed a model to estimate the oRUR in childhood neuroblastoma.

Materials and methods: We developed a decision tree model to calculate the oRUR using indications for radiotherapy and corresponding epidemiological data collected through …

Open-Label, Dose-Escalation Fight-101 Study Of Pemigatinib Combined With Targeted Therapy, Chemotherapy, Or Immunotherapy In Patients With Advanced Malignancies, Mansoor Saleh, Minal Barve, Vivek Subbiah, Kyriakos Papadopoulos, Daniel Morgensztern, Niharika Mettu, Sameek Roychowdhury, Iben Spanggaard, Maria Luisa Veronese, Chenwei Tian

Haematology and Oncology, East Africa

Background Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here.

Patients and methods Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. …

Regulatory Approval Of Clinical Trials: Is It Time To Reinvent The Wheel?, Mansoor Saleh, Karishma Sharma, Aisleen Shamshudin, Innocent Abayo, Stacey Gondi, Noureen Karimi

Haematology and Oncology, East Africa

Less than 1% of all clinical trials are conducted in Africa. In 2019, only six of 26 oncology clinical trials conducted in Africa were conducted in countries with subjects of African ancestry. There are multiple barriers that hinder the conduct of cancer clinical trials in Africa. Time to trial activation (TTA) is the administrative and regulatory process required before a study can be activated—an important metric and often a major barrier for site selection. In Kenya, TTA involves review by Institutional Review Board (IRB), Pharmacy and Poisons Board, National Commission for Science, Technology and Innovation and Ministry of Health, all …

A Phase Ib/Ii Study Of Galunisertib In Combination With Nivolumab In Solid Tumors And Non-Small Cell Lung Cancer, Ernest Nadal, Mansoor Saleh, Santiago Aix, Maria Ochoa-De-Olza, Sandip Patel, Scott Antonia, Yumin Zhao, Ivelina Gueorguieva, Michael Man, Shawn Estrem

Haematology and Oncology, East Africa

Background In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab.

Methods Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor β receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab …

Phase I Study Of Bosutinib, A Src/Abl Tyrosine Kinase Inhibitor, Administered To Patients With Advanced Solid Tumors, Adil Daud, Smitha Krishnamurthi, Mansoor Saleh, Barbara Gitlitz, Mitesh Borad, Philip Gold, Elena Chiorean, Gregory Springett, Richat Abbas, Shefali Agarwal

Haematology and Oncology, East Africa

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies.

Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non–small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non–small cell lung) and median overall survival (pancreas).

Results: In …

Phase Iii Study Of Doxorubicin/Cyclophosphamide With Concomitant Versus Sequential Docetaxel As Adjuvant Treatment In Patients With Human Epidermal Growth Factor Receptor 2–Normal, Node-Positive Breast Cancer: Bcirg-005 Trial, Wolfgang Eiermann, Tadeusz Pienkowski, John Crown, Saeed Sadeghi, Miguel Martin, Arlene Chan, Mansoor Saleh, Sandeep Sehdev, Louise Provencher, Vladimir Semiglazov

Haematology and Oncology, East Africa

Purpose: Anthracyclines, taxanes, and alkylating agents are among the most active agents in treatment of adjuvant breast cancer (BC), but the optimal schedule for their administration is unknown. We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide (AC) followed by docetaxel (ie, AC>T) with the combination regimen of TAC.

Patients and Methods: Women with node-positive, human epidermal growth factor receptor 2–nonamplified, operable BC were stratified by number of axillary nodes and hormone receptor status and were randomly assigned to adjuvant chemotherapy with six cycles of TAC (75/50/500 mg/m2 every 3 weeks) or four cycles …

Randomized Phase Iii Trial Of Paclitaxel/Carboplatin With Or Without Pf-3512676 (Toll-Like Receptor 9 Agonist) As First-Line Treatment For Advanced Non–Small-Cell Lung Cancer, Vera Hirsh, Luis Paz-Ares, Michael Boyer, Rafael Rosell, Gary Middleton, Wilfried Eberhardt, Aleksandra Szczesna, Pavel Reiterer, Mansoor Saleh, Oscar Arrieta

Haematology and Oncology, East Africa

Purpose: This phase III study examined efficacy of the synthetic Toll-like receptor 9–activating oligodeoxynucleotide PF-3512676 in combination with standard paclitaxel/carboplatin chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods: Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomly assigned (1:1) to receive up to six courses of paclitaxel/carboplatin (intravenous paclitaxel 200 mg/m2 and carboplatin at area under the [concentration-time] curve 6 on day 1 of a 3-week cycle) alone (control arm) or in combination with 0.2 mg/kg subcutaneous PF-3512676 on days 8 and 15 (investigational arm). Primary end point was overall survival (OS).

Results: Baseline demographics …

Sunitinib Plus Paclitaxel Versus Bevacizumab Plus Paclitaxel For First-Line Treatment Of Patients With Advanced Breast Cancer: A Phase Iii, Randomized, Open-Label Trial, Nicholas Robert, Mansoor Saleh, Devchand Paul, Daniele Generali, Laurent Gressot, Mehmet Copur, Adam Brufsky, Susan Minton, Jeffrey Giguere, John W. Smith Ii

Haematology and Oncology, East Africa

Introduction: A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2− advanced breast cancer.

Patients and Methods: Patients with HER2− advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m2 every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks.

Results: The trial was terminated early …

Eltrombopag For Management Of Chronic Immune Thrombocytopenia (Raise): A 6-Month, Randomised, Phase 3 Study, Gregory Cheng, Mansoor Saleh, Claus Marcher, Sandra Vasey, Bhabita Mayer, Manuel Aivado, Michael Arning, Nicole Stone, James Bussel

Haematology and Oncology, East Africa

Background: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period.

Methods: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months’ duration who had baseline platelet counts lower than 30 000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a …

Pemetrexed With Or Without Matuzumab As Second-Line Treatment For Patients With Stage Iiib/Iv Non-Small Cell Lung Cancer, Joan Schiller, Joachim Von Pawel, Philipp Schütt, Rafat Ansari, Michael Bijoy Thomas, Mansoor Saleh, Robert D. Mccroskey, Wolfgang Pfeife, Thomas Marsland, Goetz Kloecker

Haematology and Oncology, East Africa

Introduction: This randomized phase II study investigated pemetrexed in combination with the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer.

Methods: Patients received pemetrexed 500 mg/m2 every 3 weeks either alone (n = 50) or in combination with matuzumab at either 800 mg weekly (n = 51) or 1600 mg every 3 weeks (n = 47). The primary end point was objective response, as assessed by an independent review committee.

Results: Tumor EGFR expression was detected in 87% of randomized patients. The objective response rate …

Results Of Bone Marrow Examinations In Patients With Chronic Immune Thrombocytopenic Purpura Treated With Eltrombopag, Mansoor Saleh, James Bussel, Oliver Meyer, Henrik Frederiksen, Diane Johnni, Manuel Aivado, Andres Brainsky

Haematology and Oncology, East Africa

Background: Bone marrow (BM) reticulin fibers can be increased in conditions such as neoplasms and autoimmune diseases (Frisch Haematol [Budap] 1982; Aharon Lupus 1997) and can lead to a clinical situation similar to osteomyelofibrosis. In healthy individuals, grade 1 and 2 reticulin have been reported in 27–70% and 4–20% of BM biopsies, respectively (Hultdin Med Onc 2007; Beckman Arch Path Int Med 1990; Bauermeister Am J Clin Path 1971). The presence of grade 1/2 reticulin was reported in the BM of up to 67% of patients with immune thrombocytopenic purpura (ITP) (Mufti J Supp Onc 2007). Theoretically, prolonged stimulation of …

Multicenter Randomized Phase Ii Study Of Weekly Or Twice-Weekly Bortezomib Plus Rituximab In Patients With Relapsed Or Refractory Follicular Or Marginal-Zone B-Cell Lymphoma, Sven De Vos, André Goy, Shaker R. Dakhil, Mansoor Saleh, Peter Mclaughlin, Robert Belt, Christopher R. Flowers, Mark Knapp, Lowell Hart, Dipti Patel-Donnelly

Haematology and Oncology, East Africa

Purpose: To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20+ follicular lymphoma (FL) or marginal-zone lymphoma.

Patients and Methods: Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m2 weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m2 weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using …

High-Dose Imatinib In Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: High Rates Of Rapid Cytogenetic And Molecular Responses, Jorge E. Cortes, Hagop M. Kantarjian, Hagop M. Kantarjian, Stuart L. Goldberg, Bayard L. Powell, Francis J. Giles, Meir Wetzler, Luke Akard, John M. Burke, Mansoor Saleh

Haematology and Oncology, East Africa

Purpose: Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML).

Patients and Methods: The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial is a multicenter study of imatinib 400 mg twice a day as initial therapy in 115 patients (70% Sokal low risk) with newly diagnosed CML in chronic phase who were observed for both molecular and cytogenetic responses for up to 18 months. Eighty-three patients (72%) completed the study, 10 patients (9%) discontinued the study because of adverse events, and six patients (5%) discontinued because …

A Randomized, Phase Ii Trial Of Two Dose Schedules Of Carboplatin/Paclitaxel/Cetuximab In Stage Iiib/Iv Non-Small-Cell Lung Cancer (Nsclc), M.A. Socinski, Mansoor Saleh, D.F. Trent, T.W. Dobbs, L.M. Zehngebot, M.A. Levine, R. Bordoni, P.J. Stella

Haematology and Oncology, East Africa

Background: This trial investigated the efficacy and safety of weekly cetuximab combined with two different schedules of paclitaxel/carboplatin for stage IIIB/IV non-small-cell lung cancer (NSCLC).

Methods: A total of 168 patients with previously untreated stage IIIB/IV NSCLC were randomized to arm A, cetuximab (400 mg/m² day 1 followed by weekly 250 mg/m²) + paclitaxel (Taxol) (225 mg/m²)/carboplatin (AUC6) day 1 every 3 weeks or arm B, same cetuximab regimen plus paclitaxel (100 mg/m²) days 1, 8, and 15 every 3 weeks and carboplatin (AUC6) day 1 every 4 weeks. Treatment continued for a …

Eltrombopag For The Treatment Of Chronic Idiopathic Thrombocytopenic Purpura, James Bussel, Bhabita Mayer, Nicole Stone, Michael Arning, Drew Provan, Mansoor Saleh

Haematology and Oncology, East Africa

Background: The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder.

Methods: We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per …

Phase Ia/Ib Trial Of Anti-Gd2 Chimeric Monoclonal Antibody 14.18 (Ch L4.18) And Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (Rhgm-Csf) In Metastatic Melanoma, James Murray, Eugenie Kleinerman, Shu-Fang Jia, Michael Rosenblum, Omar Eton, Antonio Buzaid, Sewa Legha, Merrick Ross, Lora Thompson, Mansoor Saleh

Haematology and Oncology, East Africa

We performed a phase Ia/Ib trial of chimeric anti-GD2 monoclonal antibody 14.18 (ch14.18) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the maximum tolerated dose as well as immunologic and biologic responses to the regimen. Sixteen patients with metastatic malignant melanoma received escalating doses of ch14.18 (15-60 mg/m2) administered intravenously for 4 h on day 1. Twenty-four hours later, subcutaneous injections of rhGM-CSF were administered daily for a total of 14 days. Significant side effects were related to ch14.18 infusion and consisted of moderate to severe abdominal and/or extremity pain, blood pressure changes, headache, nausea, diarrhea, peripheral …

Effect Of Alcohol On The Postnatal Development Of Cerebellar Cortex In Rat Ii: Ultrastructural Study, Mansoor Saleh, Saadia Sayed, Entesar Saber

Haematology and Oncology, East Africa

In The present work, it was found that alcohol produced distinct changes in both Purkinje and granule cells during postnatal development. On the fifth day, the apical cones of the Purkinje cells were less developed and the cells showed an occasional somnatic spines but no somatic processes. At 21 days and adult stage these cells including their dendrites showed marked degenerative changes. The nuinber of basket cell axon synapses on Purkinje cell soma was reduced. There was also a reduction in the amount of basket fibers contributing to the pinceau around the intial seginent of the Purkinje cell axons. The …

Phase Ii Trial Of Murine Monoclonal Antibody D612 Combined With Recombinant Human Monocyte Colony-Stimulating Factor (Rhm-Csf) In Patients With Metastatic Gastrointestinal Cancer, Mansoor Saleh, Michael Khazaeli, Richard Wheeler, Pat Bucy, Tiepe Liu, Michael Everson, David Mun, Jeff Schlom

Haematology and Oncology, East Africa

In a Phase II study, 14 patients with metastatic gastrointestinal cancer received the mAb D612 (40 mg/m2, days 4, 7, and 11) in combination with recombinant human monocyte colony-stimulating factor [(rhM-CSF) 80 ug/kg/days 1-14]. The combined treatment was well tolerated and resulted in characteristic biological activity associated with each of the agents. Thus, 10 of 14 patients experienced D612-associated secretory diarrhea, which responded to the prostaglandin inhibitor Indomethacin in 5 of 7 patients. rhM-CSF therapy was associated with peripheral mono- cytosis (peak absolute monocyte count, 1444 ±394/mm3) and thrombocytopenia (nadir count, 78 ±10/nim '). Monocyte surface marker analysis revealed a …

Cd16+ Monocytes In Patients With Cancer: Spontaneous Elevation And Pharmacologic Induction By Recombinant Human Macrophage Colony- Stimulating Factor, Mansoor Saleh, Goldman Samuel, Lobuglio Albert, Beall Arthur, Sabio Hernan, Mccord Melissa, Minasian Lori, Alpaugh Katherine, Weiner Louis, Munn David

Haematology and Oncology, East Africa

The small subset of circulating monocytes that express the maturation- associated CD16 antigen has recently been reported to be elevated in patients with bacterial sepsis. We now show that this novel CD16+ monocyte population is also spontaneously expanded in patients with cancer. We studied 14 patients with metastatic gastrointestinal carcinoma enrolled in a clinical trial of recombinant human macrophage colony-stimulating factor (rhMCSF) plus monoclonal antibody D612. We found that before any cytokine treatment, 12 of 14 patients constitutively displayed significant elevations in both the percentage and the absolute number of CD16+ monocytes, as compared with both normal subjects and ill …