Yasser Khaled

Phase II Trial of Combination Therapy With Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone in Patients With Newly Diagnosed Myeloma

PURPOSE This single-center, open-label, phase II trial evaluated the bortezomib, pegylated liposomal doxorubicin (PLD), and dexamethasone combination regimen (VDD) as initial treatment for patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS Enrolled patients (N = 40) received up to six 3-week cycles of treatment with bortezomib 1.3 mg/m(2) intravenously (IV) on days 1, 4, 8, and 11; PLD 30 mg/m(2) IV on day 4; and dexamethasone 20 to 40 mg daily as specified in the study design. The primary end point was the complete/near-complete response (CR/nCR) rate after six cycles. Secondary end points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The impact of VDD on stem-cell mobilization and collection also was evaluated. RESULTS After six cycles, the ORR was 85.0% (CR/nCR, 37.5%; very good partial response [VGPR] or better, 57.5%). Patients who underwent stem-cell transplantation (SCT) after VDD (n = 30) experienced increased rates of VGPR or better (53.3% to 76.6% after SCT). Overall, 1-year PFS and OS rates were 92.5% and 97.5%, respectively. Those who achieved VGPR or better after treatment with VDD showed a significantly greater 1-year PFS versus those who achieved less than VGPR (100% v 82%, respectively; P = .03). Similar results were observed in patients who underwent SCT. Grades 3 or 4 hematologic toxicities occurred in < or = 10% of patients; grade 2 painful neuropathy occurred in 7.5%; and grade 3 palmar-plantar erythrodysesthesia occurred in 2.5%. CONCLUSION VDD is highly effective for initial treatment of MM followed by SCT in appropriate patients, and it has a reasonable safety profile. Achievement of VGPR or better with this initial therapy predicted longer PFS, regardless of the consolidation therapy given.

Acanthamoeba infection in a patient with chronic graft‐versus‐host disease occurring during treatment with voriconazole

Abstract: We report a case of disseminated infection with Acanthamoeba in a patient with graft‐versus‐host disease after hematopoietic stem cell transplant (HSCT) for acute lymphocytic leukemia. The infection involved the brain, skin, and lungs and occurred despite treatment with voriconazole for mold prophylaxis, and did not respond to treatment with multiple other agents reported to have activity against Acanthamoeba. To our knowledge, infection with Acanthamoeba has been reported in 4 other patients after HSCT or bone marrow transplant, and our case is the first to be diagnosed ante‐mortem.

Reduced intensity versus full myeloablative stem cell transplant for advanced CLL

CLL remains incurable with the standard therapy. Allogeneic hematopoietic stem cell transplant may be curative. We examined 50 patients with advanced CLL who underwent allogeneic HCT at the University of Michigan between 1996 and 2006. Twenty-one patients received reduced-intensity conditioning (RIC) and twenty-nine patients received full-intensity conditioning (FIC) consisting of CY, etoposide and BCNU (n=20) or BU and CY (n=9). RIC recipients were older than FIC recipients (median age 54 vs 51, P=0.009). There were no statistically significant differences between groups in terms of the number of earlier therapies or patients with adverse cytogenetics. There were more unrelated donors in the RIC group 62% than in the FIC group 31% (P=0.030). Despite their older age and greater use of URD, the 5-year overall survival (OS) rate was 63% in the RIC group as compared with 18% in the FIC group (P=0.006). The primary cause of inferior survival in the FIC recipients was TRM, which was twice as high at day 100 for the FIC group 27% compared with the RIC group 14% (P=0.005). The relapse rate was 15% regardless with the majority of relapses occurring after day 100. These results suggest a favorable outcome for advanced CLL who undergo a RIC regimen compared with FIC.

Generation of Highly Cytotoxic Natural Killer Cells for Treatment of Acute Myelogenous Leukemia using a Feeder-Free, Particle-Based Approach

Natural killer (NK) cell immunotherapy as a cancer treatment shows promise, but expanding NK cells consistently from a small fraction (∼ 5%) of peripheral blood mononuclear cells (PBMCs) to therapeutic amounts remains challenging. Most current ex vivo expansion methods use co-culture with feeder cells (FC), but their use poses challenges for wide clinical application. We developed a particle-based NK cell expansion technology that uses plasma membrane particles (PM-particles) derived from K562-mbIL15-41BBL FCs. These PM-particles induce selective expansion of NK cells from unsorted PBMCs, with NK cells increasing 250-fold (median, 35; 10 donors; range, 94 to 1492) after 14 days of culture and up to 1265-fold (n = 14; range, 280 to 4426) typically after 17 days. The rate and efficiency of NK cell expansions with PM-particles and live FCs are comparable and far better than stimulation with soluble 41BBL, IL-15, and IL-2. Furthermore, NK cells expand selectively with PM-particles to 86% (median, 35; range, 71% to 99%) of total cells after 14 days. The extent of NK cell expansion and cell content was PM-particle concentration dependent. These NK cells were highly cytotoxic against several leukemic cell lines and also against patient acute myelogenous leukemia blasts. Phenotype analysis of these PM-particle-expanded NK cells was consistent with an activated cytotoxic phenotype. This novel NK cell expansion methodology has promising clinical therapeutic implications.

Cardiac complications in patients undergoing a reduced-intensity conditioning hematopoietic stem cell transplantation.

Reduced-intensity conditioning (RIC) extends hematopoietic stem cell transplants (HSCT) to elderly or debilitated patients who are not candidates for HSCT. The incidence and outcomes of cardiac complications have been reported following myeloablative HSCT. We assessed the incidence and outcomes of cardiac complications in 278 recipients of RIC from July 2000 to July 2006. All patients received conditioning with BU, fludarabine and TBI. Patients were evaluated from conditioning therapy until 100 days after HSCT. Median age was 56 years. Cardiac events were defined as either one or more of the following: arrhythmias, myocardial infarction or congestive heart failure. Twenty-five patients developed arrhythmias at a median of 3 days post transplant, in 19 patients hemodynamic compromise occurred and mechanical ventilation was required in 15 patients. The arrhythmias included atrial fibrillation (n=17), atrial flutter (n=6) and supraventricular tachycardia (n=2). Troponin was elevated in 12 out of 25 patients. The mean brain natriuretic peptide was 679. All patients converted to a normal rhythm by medical therapy at a median of 2 days. Recurrence of arrhythmia occurred in 76% of patients. Day 100 mortality was 40% in this group. A history of high-dose anthracycline treatment and a low ejection fraction were risk factors for the development of cardiac complications.

Mycobacterium chelonae necrotizing pneumonia after allogeneic hematopoietic stem cell transplant: report of clinical response to treatment with tigecycline

Abstract: We present a case of progressive Mycobacterium chelonae ssp. chelonae necrotizing pneumonia after hematopoietic stem cell transplantation (HSCT) in the presence of chronic graft‐versus‐host disease. The patient failed to respond to standard combination therapy with multiple agents and developed resistance to most drugs over the course of treatment. Tigecycline, a new glycylcycline antimicrobial agent with in vitro activity against M. chelonae, was then used with a clinical response to treatment. To our knowledge, this is the first reported case demonstrating tigecycline to have a degree of clinical effectiveness to treat refractory pulmonary infection with M. chelonae in an HSCT recipient.

Systemic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with severe graft-versus-host disease of the gastrointestinal tract

Abstract : Oral vancomycin is often considered the drug of choice for severe Clostridium difficile‐associated disease due to both its efficacy and pharmacokinetics. The potential for absorption is not well described in patients with impaired gastrointestinal (GI) mucosa. We describe a case of significant and potentially toxic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with grade IV graft‐versus‐host disease (GVHD) of the GI tract. In patients with GI GVHD clinicians need to be aware of the potential for oral absorption and, in select cases, monitoring of levels may be appropriate.

Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect.

Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect

Diffuse Osteosclerosis-Associated Acute Myeloid Leukemia

Case Report A 62-year-old woman presented with a 1-month history of progressive fatigue and easy bruisability. Blood counts showed hemoglobin of 8.3 g/dL, WBC count of 5.5 10/L (neutrophils, 0.3 10/L; lymphocytes, 2.9 10/L; monocytes, 0.2 10/L; blasts, 26%), and platelet count of 16 10/L. Review of her medical records revealed normal blood counts with normal differential 10 months earlier. Bone marrow aspiration was dry, and biopsy showed sclerotic bony trabeculae with hypocellular marrow spaces (Fig 1A). Immunohistochemical stains were attempted but noncontributory because of lack of hematopoietic element in the biopsy for evaluation. Flow cytometry of peripheral blood revealed a population of cells in the blast gate (CD45 dim and low side scatter) comprising 29% of the total cells and expressing CD 117 , CD13 , CD 33 , myeloperoxidase positive, and CD34 . Lymphoid markers CD10 and TdT were both negative. Cytogenetics culture was unsuccessful (no dividing cells from peripheral blood). JAK2 v617 point mutation by polymerase chain reaction was not detected. Repeat bone marrow biopsy under computed tomography (CT) guidance revealed severe osteosclerosis of the pelvis with absent marrow space. Alkaline phosphatase was elevated at 1,152 U/L. CT scan of chest, abdomen, and pelvis was unremarkable except for new diffuse osteosclerosis of the osseous structures compared with a prior CT scan of the abdomen and pelvis performed 2 years earlier for lower back pain (Figs 2A, 2B). There was no evidence of hepatosplenomegaly on CT scan; spleen measured 7.6 4.9 5.6 cm. Repeat magnetic resonance imaging of thoracolumbar spine and pelvis confirmed diffuse osteosclerosis of spine and pelvis, with near absence of marrow space. The overall presentation was consistent with acutemyeloidleukemia.Thepatientunderwentinductionchemotherapy with standard seven-plus-three treatment with daunorubicin and cytarabine. After induction, the patient remained neutropenic, with 5% to 10% persistent blasts in peripheral blood consistent with refractory leukemia. Repeat bone marrow aspiration and biopsy were again unsuccessful and revealed only sclerotic bone trabeculae with no marrow elements. The patient underwent myeloablative allogeneicrelated hematopoietic stem-cell transplantation from a human leukocyte antigen–identical sibling with a conditioning regimen of fludarabine (160 mg/M) and busulfan (3.2 mg/kg daily for 4 days). She received immunosuppression with methotrexate, tacrolimus, and thymoglobulin. The patient achieved hematologic remission and granulocytic engraftment by day 15 post transplantation. Peripheral blood chimerisms at day 30 were 100%, 94%, and 100% donor for granulocytes, T lymphocytes, and B lymphocytes, respectively. Although initial attempts to obtain bone marrow aspiration and biopsy were unsuccessful in the first 100 days after transplantation, repeat biopsy at 5 months was successful and revealed recovery of cellularity in bone marrow (70%; Fig 1B). There was radiologic delay of improvement in osteosclerosis as expected on repeat magnetic resonance imaging and CT scans. However, recovery of cellularity of the bone marrow was associated with normalization of alkaline phosphatase level.

Reduced-Intensity Stem Cell Transplantation for Hematological Malignancies: Current Status and the Future

Reduced-intensity stem cell transplantation (RIST) has opened a new era for hematopoietic stem cell transplantation (HSCT). It was developed based on the knowledge that graft-versus-tumor (GVT) effect is the main anti-tumor effect in allogeneic HSCT. Because RIST is associated with less morbidity and mortality, it can be applied to many patients who could not undergo conventional HSCT. Experiences in the last decade clarified many issues related to RIST. For example, graft-versus-host disease (GVHD) in RIST may differ in character compared to conventional HSCT. Also, it is now known that intensity of conditioning is important in disease control, and the optimal regimens may be different for each disease or for each disease status. There are still many unsolved questions, and large prospective randomized trials are necessary to resolve these.