Haifa K. Al-Ali

Treatment for Acute Myelogenous Leukemia by Low-Dose, Total-Body, Irradiation-Based Conditioning and Hematopoietic Cell Transplantation From Related and Unrelated Donors

Purpose The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors. Patients and Methods The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m2/d from days −4 to −2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day −3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Results Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after relate...

Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study

Abstract The safety and efficacy of azacitidine (5-day schedule) were assessed in a multicenter study in 40 patients (median age 72 years) with acute myeloid leukemia (AML) medically unfit for (n = 20) or resistant to chemotherapy (n = 20) from April to October 2008. Median marrow blasts were 42%. After a median follow-up of 13 months, response (complete remission [CR]/partial remission [PR]/hematologic improvement [HI]) was 50% and 10% in newly diagnosed and relapsed/refractory patients, respectively (p = 0.008). Median time-to-response was 2.5 months with a median duration of 5.9 months. Median survival was not reached for responders versus 3.8 months for 15 (38%) patients with stable disease (p < 0.045). High-risk cytogenetics was associated with inferior survival (p = 0.05). Lower marrow blasts on day 15 of cycle 1, irrespective of pretreatment count, predicted subsequent response (p = 0.01). Azacitidine is active and well tolerated in elderly patients with newly diagnosed AML.

Mesenchymal stem cells remain host-derived independent of the source of the stem-cell graft and conditioning regimen used.

Background. Human bone marrow contains hematopoietic stem cells and stroma cells known as mesenchymal stem cells (MSC). MSC are cells with the morphological features of fibroblasts, which, in addition to their nursing function for hematopoietic stem cells, retain the ability to differentiate into cartilage, bone, fat, muscle, and tendon and have an important immunmodulatory function. To understand in more detail hematopoietic engraftment and immune modulation after hematopoietic cell transplantation, we investigated the ability of donor MSC to engraft after hematopoietic cell transplantation in dependency to the conditioning regimen (myeloablative vs. reduced intensity) and source of the graft (bone marrow vs. peripheral blood). Methods. Bone marrow MSC of 12 patients were analyzed, a median of 23.4 (range 0.9–137.8) months after human leukocyte antigen matched but gender mismatched bone marrow transplantation after myeloablative conditioning (n=4) or peripheral blood cell transplantation after myeloablative (n=4) or reduced intensity conditioning (n=4). MSC were characterized by morphology, positivity for CD 105+, CD73+, CD 44+, and CD 90+, and by their capacity to differentiate into adipocytic and osteogenic cells. Recipient and donor origins were determined by fluorescent in situ hybridization for sex chromosomes. Results. While overall blood and bone marrow chimerism was 100% donor type, MSC remained in all patients of recipient origin (>96%). There was no difference between patients receiving bone marrow and peripheral blood grafts, nor was any difference observed between patients receiving full intensity in comparison with reduced intensity conditioning. Conclusions. We conclude that MSC remain of host type irrespective of the conditioning regimen and graft source.

Transmission of donor illness by stem cell transplantation: should screening be different in older donors?

Summary:With increasing donor age, the potential of transmitting diseases from donor to recipient reaches new dimensions. Potentially transmittable diseases from donors include infections, congenital disorders, and acquired illnesses like autoimmune diseases or malignancies of hematological or nonhematological origin. While established nonmalignant or malignant diseases might be easy to discover, early-stage hematological diseases like CML, light-chain multiple myelomas, aleukemic leukemias, occult myelodysplastic syndromes and other malignant and nonmalignant diseases might not be detectable by routine screening but only by invasive, new and/or expensive diagnostic tests. In the following article, we propose recommendations for donor work-up, taking into consideration the age of the donors. In contrast to blood transfusions, stem cells from donors with abnormal findings might still be acceptable for HCT, when no other options are available and life expectancy is limited. This issue is discussed in detail in relation to the available donor and stem cell source. Finally, the recommendations presented here aim at harmonized worldwide work-up for donors to insure high standard quality.

Matched unrelated donor stem cell transplant in 131 patients with follicular lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

Matched unrelated donor stem cell transplantation (MUD‐SCT) provides the only curative option for patients with follicular lymphoma (FL) who fail conventional therapies and do not have a sibling donor. The purpose of this study was to analyse the outcome of patients with FL treated with MUD‐SCT included in the European Group for Blood and Marrow Transplantation registry. 131 patients treated with reduced‐intensity conditioning (RIC, n = 87) or conventional myeloablative (CONV, n = 44) MUD‐SCT between 2000 and 2005 were included. Median time from diagnosis to MUD‐SCT was 47 months and the median number of previous therapeutic regimens was 4 (previous autograft: 47%). RIC recipients were significantly older, with a longer interval from diagnosis to MUD‐SCT and had failed a previous autograft more frequently than CONV recipients. Non‐relapse mortality (NRM) was 24% and 30% at 100‐d and 1‐year, respectively. After a median follow‐up of 36 months, 17% of the patients developed disease progression, the 3‐year progression‐free survival (PFS) being 47%. Three‐year overall survival (OS) for the whole series was 51%. On multivariate analysis, RIC regimens were associated with at lower NRM and a significantly longer PFS and OS. This retrospective study demonstrated that MUD‐SCT results, even in heavily pre‐treated populations, in a meaningful PFS and OS.

Lenalidomide, bendamustine and prednisolone exhibits a favourable safety and efficacy profile in relapsed or refractory multiple myeloma: final results of a phase 1 clinical trial OSHO – #077

This phase 1 dose finding study tested a combination of lenalidomide, bendamustine and prednisolone (RBP) in 21 patients in five cohorts with advanced multiple relasped/refractory myeloma (MM) to determine the maximum tolerable dose (MTD) of the combination. The first cohort received a starting dose of lenalidomide 10 mg/d, days 1–21, bendamustine 60 mg/m2/d, days 1–2, and prednisolone 100 mg/d, days 1–4. Dose escalation was done in cohorts of three to six patients with lenalidomide dose increasing to 15, 20 and 25 mg, and after reaching 25 mg/d, bendamustine was increased to 75 mg/m2. A total of 21 patients were enrolled and all completed at least two cycles. Two patients developed dose‐limiting haemotoxicity: one patient on lenalidomide 25 mg/d and bendamustine 60 mg/m2 and another patient at the highest dose level (lenalidomide 25 mg/d and bendamustine 75 mg/m2). The MTD was not reached. Sixteen patients (76%) responded after at least two cycles of RBP with one stringent complete response (CR), one near CR, five very good partial response and nine partial response. After a median observation time of 16 months, progression‐free survival at 18 months was 48% and overall survival was 64%. In conclusion, RBP with lenalidomide 25 mg/d, days 1–21 and bendamustine 75 mg/m2 days 1–2 is well tolerated in patients with relapsed/refractory MM.

Does the Expression of c-kit (CD117) in Neuroendocrine Tumors Represent a Target for Therapy?

Abstract:  Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so‐called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5‐cm‐large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.

Low-dose total body irradiation-based regimens as a preparative regimen for allogeneic haematopoietic cell transplantation in acute myelogenous leukaemia.

Although much progress has been made in understanding the molecular basis of acute myeloid leukaemia (AML), this has not yet led to major improvements in the overall survival of patients. In particular, the treatment of elderly patients with AML remains one of the major challenges in haematology. Despite increases in complete remission rates, relapse remains a major obstacle and the major determinant of overall survival. Allogeneic stem cell transplantation (SCT) is the most efficient antileukaemic treatment for patients with AML, but eligibility for the treatment was confined for a long time to younger patients. More than 10 years ago, SCT protocols were initiated with reduced-intensity conditioning (RIC) rather than ablative chemoradiotherapy, with the intention of inducing a graft-versus-leukaemia effect also in elderly patients and patients with concomitant diseases. Operationally, all protocols below the conventional preparative regimens are referred to as RIC. Low-dose total body irradiation-based protocols result in minimal myelosuppression and are among the most popular. After extensive phase I and phase II studies, associated problems of graft rejection have been largely resolved and transplant-related mortality (TRM) evaluated in more than 3000 patients. TRM does not currently exceed 10–12% in related and 20% in unrelated SCT even in patients up to the age of 75 years, so that relapse after transplantation remains the major problem. A number of strategies for decreasing relapse rates has been developed. The most promising approach consists of monitoring CD34+ donor cell chimerism after transplantation. This has led to decreases in the relapse rate over the past few years. Randomized studies are now being initiated to define the role of SCT in the treatment of elderly patients with AML.

Rapid Progression of Myelodysplastic Syndrome to Acute Myeloid Leukemia on Sequential Azathioprine, IFN-β and Copolymer-1 in a Patient with Multiple Sclerosis

A woman with relapsing-remitting multiple sclerosis (MS) was treated with oral azathioprine (AZA) for 4 years and subsequently switched to interferon-β1a. Five years later, leukopenia developed and resolved after interferon was discontinued; MS treatment was changed to copolymer-1. Recurrent pancytopenia subsequently led to diagnosis of myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 (MDS 5q–). Within several months, unusually rapid for this subtype, MDS progressed to secondary acute myeloid leukemia. While AZA is the probable cause for the chromosomal deletion and MDS, combined or sequential immunomodulatory therapies may permit clonal expansion of malignant hematopoietic progenitors.

Delayed processing of bone marrow samples reveals a prognostic pattern of NME mRNA expression in cytogenetically normal acute myeloid leukemia

Abstract Improvements in the therapy of cytogenetically normal acute myeloid leukemia (CN-AML) will depend largely on the characterization of functional subtypes identified by prognostic markers. Exposing leukemic cells to stress ex vivo may reveal relevant phenotypic markers not apparent in freshly explanted cells. Here, we assess the prognostic relevance of expression of the nucleoside diphosphate kinase genes NME1 and NME2 in a cohort of 78 patients with CN-AML aged < 60 years using archived mononuclear cell samples originally prepared from bone marrow either directly (n = 25) or following 2–3 days of transport (n = 53). The stress conditions arising during transport resulted in the development of a prognostic pattern of NME mRNA with maintenance of high NME2 mRNA being a strong indicator of increased event-free survival independent of FLT3-internal tandem duplication. Prospective analysis of CN-AML bone marrow (n = 7) confirmed that NME1 mRNA is always decreased during storage, while NME2 mRNA is either decreased or maintained. We conclude that ex vivo stress can reveal novel prognostic markers.