John E. Godwin

Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13–14%. This risk has been estimated to be 1–5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993–1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty‐two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon‐α(IFN‐α). Two patients from the phlebotomy‐treated group, one from the HU‐treated group, and 1 from the multiple myelotoxic agent‐treated group developed MDS/AL in the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN‐α, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P = 0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further.

Hypoplastic myelodysplastic syndrome

Over a period of 8 years 11 of 64 patients seen at Loyola University Medical Center with the diagnosis of myelodysplastic syndrome (MDS) also exhibited bone marrow hypoplasia (marrow cellularity of 25% or less) at presentation. The other 53 had normocellular or hypercellular marrow. Clinical features, hemograms, chromosome analysis, incidence of progression to acute leukemia or aplastic anemia, and survival in each group were compared. Using the French‐American‐British (FAB) classification, there were seven patients with refractory anemia (RA), one refractory anemia with ringed sideroblasts (RARS), and three refractory anemia with excess blasts (RAEB) in the hypoplastic MDS group. Those with normocellular or hypercellular marrow included 22 with RA, nine with RARS, 12 with RAEB, three with chronic myelomonocytic leukemia, and four with RAEB in transformation; one had chronic diGuglielmo syndrome and two patients were not classified. Patients with hypoplastic MDS had lower hemoglobin levels (median, 8 g/dl versus 9 g/dl), more severe leucopenia (median 3100/μl versus 4200/μl) and thrombocytopenia (median, 28,000/μl versus 75,000/μl), and marked macrocytosis (mean corpuscular volume (MCV), 107 μ3 versus 97 μ3). Nine patients with hypoplastic MDS had a chromosome analysis of the bone marrow, and all were normal. In those with normocellular or hyperplastic bone marrow, 22 such analyses were done, and seven (23%) were abnormal. One patient (11%) from the hypoplastic group and 11 (23%) from the normocellular or hyperplastic MDS transformed into acute leukemia. None progressed to aplastic anemia. With a mean follow‐up time of 33 months in the hypoplastic MDS, eight patients (72%) are alive. In the group with normal or hyperplastic MDS, the mean follow up was 47 months, and 27 patients (50%) have survived. The two groups differ significantly in leukocyte count (P < 0.0015), platelet count (P < 0.0001), and MCV (P < 0.0023). There may be a possible difference between these groups related to abnormal karyotype, but it is not statistically significant (P = 0.06). Therapy with pyridoxine, folic acid, prednisone, anabolic steroids, retinoids, or low‐dose cytosine arabinoside was not beneficial in hypoplastic MDS. Hypoplastic MDS appears to be a distinct clinicopathologic entity characterized by marrow hypoplasia, macrocytosis, severe leucopenia and thrombocytopenia, low incidence of progression to acute leukemia, and unresponsiveness to conventional therapy.

Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson

Less-intense remission induction regimens for adults with newly diagnosed acute myeloid leukemia (AML) aim to reduce treatment-related mortality (TRM), here defined as death within 4 weeks after starting induction therapy. This assumes that TRM rates are similar to the 15–20% observed 20 years ago. Herein we test this assumption. We examined TRM rates in 1409 patients treated on SWOG (Southwest Oncology Group) trials and 1942 patients treated at MD Anderson (MDA) from 1991 to 2009. Eighty-eight percent of SWOG patients received ‘3+7’ or regimens of similar intensity while 92% of the MDA patients received ara-C at 1.5–2.0 g/m2 daily × 3–5 days+other cytotoxic agents. We examined the relationship between time and TRM rates after accounting for other covariates. TRM rates between 1991 and 2009 decreased from 18–3% in SWOG and 16–4% at MDA. Multivariate analyses showed a significant decrease in TRM over time (P=0.001). The decrease in TRM was not limited to younger patients, those with a better performance status or a lower white blood cell count. Though our observations are limited to patients treated with intensive therapy at SWOG institutions and MDA, the decrease in TRM with time emphasizes the problem with historical controls and could be considered when selecting AML induction therapy.

Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia.

Purpose: Recruitment of histone deacetylases (HDAC) is a mechanism of transcriptional repression implicated in the differentiation block in acute myeloid leukemia (AML). We hypothesized that the HDAC inhibitor romidepsin could cause transcriptional derepression, up-regulation of specific target genes in AML, and differentiation of the leukemic clone. The primary objectives of the study were to evaluate the safety and efficacy of romidepsin in advanced AML. Experimental Design: Twenty patients were stratified into cohort A or B based on the absence or presence of chromosomal abnormalities known to recruit HDACs, including those involving core binding factor (CBF). Romidepsin was administered i.v. at 13 mg/m2/d on days 1, 8, and 15 of a 28-day cycle. Pharmacodynamic endpoints were evaluated at serial time points. Results: Common adverse effects noted were grade 1 to 2 nausea, anorexia, and fatigue. No objective evidence of antileukemic activity was seen in cohort A. In cohort B, although there were no clinical responses by standard criteria, antileukemic activity was observed in 5 of 7 patients. Two patients had clearance of bone marrow blasts and 3 patients had a >50% decrease in bone marrow blasts. Furthermore, in cohort B, at 24 h, there was a significant increase in MDR1 (P = 0.005), p15 (P = 0.01), and p14 (P < 0.0001) expression. In cohort A, although there was a trend toward up-regulation of MDR1, p15, and p14 expression, these changes were not statistically significant. Conclusion: Romidepsin has differential antileukemic and molecular activity in CBF AML. Development of this agent in CBF AML should focus on combinations that target related mechanisms of gene silencing such as DNA methylation.

Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome

Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation.

Legal, financial, and public health consequences of HIV contamination of blood and blood products in the 1980s and 1990s

During the onset of the AIDS epidemic in 1981, persons with hemophilia and blood-transfusion recipients throughout the world became infected with HIV through transfusion of contaminated blood products (1-7) (Table 1). In 1982, 1 year after the first AIDS cases were reported, the U.S. Centers for Disease Control and Prevention suggested that the syndrome was associated with blood and blood products (11, 12). Table 1. Persons with Hemophilia Who Developed HIV Infection from Transfusion of Contaminated Blood Products in Selected Countries Several developed countries have recently completed criminal investigations, civil litigation, and monetary financing programs to deal with the compromised safety of the blood supply during the first decade of the AIDS epidemic. In contrast, developing countries face continued concerns about the safety of their blood supplies. We review the current status of blood-supply considerations in several developed and developing countries. Criminal Investigations In France in 1992, Michel Garretta, former head of the National Blood Transfusion Center, and Jean-Pierre Allain, former head of research at the Center, were sentenced to prison for supplying HIV-infected clotting factors to hemophiliac patients (Table 2). Garretta and Allain were accused of having major roles in the National Blood Transfusion Centers decision not to use heated blood products after 1983an action purportedly taken because of a belief that the French blood supply was safe. From 1983 to 1985, policymakers did not require that blood donors be routinely questioned about drug use and homosexual experiences. Because of a desire to use only domestically obtained blood products, prisoners became a major source of blood products from 1983 to 1985, even though other countries, such as Finland and Canada, had discontinued this practice in the 1970s. Jacques Roux, the former director general of the Health Ministry, received a suspended sentence for his part in these actions. The French scientific community and 30 Nobel Prize winners petitioned for pardons of Garreta, Allain, and Roux (13-15). Controversy also surrounded French approval of the HIV enzyme-linked immunosorbent assay (ELISA). Although the ELISA manufactured by Abbott Laboratories (North Chicago, Illinois) was approved in the United States in March 1985 and was presented for approval in France in February 1985, the French National Public Health Laboratory ruled in favor of the ELISA from the Institut Pasteur in June 1985, reportedly because of economic considerations (16-19). The former Prime Minister, the Secretary of State for Health, and the Minister of Social Affairs were criminally charged with delaying the application. Public unrest, particularly among persons with hemophilia, led to court trials without convictions in 1994 and retrials in 1998 (20-23). Of the three officials charged, only the former Secretary of State for Health was convicted (of manslaughter), but he received no penalty. Table 2. Individuals Criminally Indicted for Blood-Supply Safety Concerns Criminal investigations in Germany led to convictions of five officials of UB Plasma in Koblenz for inflicting bodily harm from 1987 to 1993 by selling thousands of units of viral-infected blood products that were inconsistently tested for HIV (23). In 1993, Germanys health minister recommended HIV testing of persons who had received blood transfusions in the 1980s, fueling speculation of a cover-up. Afterward, Haemoplas, a German blood products company, was charged with having inconsistently tested for HIV in 1986 and 1987. Two officials were charged with murder, and one was sentenced to 6.5 years in prison (24-26). In 1973, the New York Blood Center established a relationship with the Swiss Red Cross, which had a history of innovation and professionalism. As a result, the Center began importing its blood supply from Switzerland (8). In 1985, using ELISA, the Center detected HIV in imported Swiss blood products (27). Alfred Haessig, former director of the Swiss Red Crosss Central Laboratory, was given a suspended sentence in 1998 for delaying introduction of donor screening questionnaires until May 1986, maintaining that HIV could be chemically inactivated, delaying use of imported heat-treated blood products, and testing only exported blood products for HIV (8, 28). In 1996, Dr. Takeshi Abe, the former head of the Japanese AIDS Study Group, was charged with negligence in the death of a patient with hemophilia (29, 30). In 1983, Dr. Abe led a task force that allowed importation of untreated blood products. He was a prominent leader of hemophilia home treatment after government approval of reimbursement for factor VIII concentrate. In 1984, the National Institutes of Health found that 23 of 48 blood samples from Japanese persons with hemophilia were HIV infected (30). Dr. Abe reported this to the Japanese Health and Welfare Ministry but not patients or the public. A high percentage of a second set of blood samples also tested positive for HIV, but Dr. Abe again did not notify the public. As late as 1988, Dr. Abe and other hemophilia specialists did not inform patients that they were HIV positive, reportedly because they believed that since curative therapy for AIDS was lacking, there was no need to inform individuals about their HIV status. In 1989, legislation finally required notifying patients if they had AIDS (31). Factors that had contributed to poor decision making included statements by Japanese hemophilia specialists in 1983 that AIDS was not a Japanese problem and in 1985 that unheated factor VIII products imported from the United States were safe and constantly improving in quality; another factor was delayed adoption of heat-treated products due to concern that this would allow market dominance by Baxter Healthcare Corp. (Deerfield, Illinois). In 2000, Takehiko Kawano, former president of the Green Cross Corp. (Osaka, Japan), and two predecessors were sentenced to 16 to 24 months in prison for having sold non-heat-treated blood products in 1986 and for not recalling these products until 1988 (32-35). Akihito Matsumura, a former official in the Japanese Ministry of Health and Welfare, was indicted in 1996 and ultimately found guilty for perpetuating the spread of HIV through the blood supply (34). From 1983 to 1985, Japan accounted for one third of the worlds annual use of plasma products, 90% of which were imported from the United States (35). In Canada, Justice Horace Krever chaired the Commission of Inquiry on the Blood System, which began hearings in February 1994 and released its final report in March 1997. The report had four major findings: 1) Many blood safety problems resulted from poor coordination among organizations responsible for the blood system; 2) urgency in the provision of heat-treated factor concentrate had been lacking; 3) the 8-month delay between the time that the United States had approved an HIV ELISA in March 1985 and when Canada approved the test in November 1985 had resulted in HIV infection in many recipients of blood and blood products during this period; and 4) physicians and the general population had not been informed about AIDS and hepatitis risks (36, 37). Subsequently, the blood supply responsibilities of the Canadian Red Cross were eliminated and a new agency, the Canadian Blood Services, was charged with these responsibilities (38-42). Monetary Compensation and Civil Litigation More than 20 countries have established compensation programs for persons infected with HIV as a result of HIV-contaminated blood products (43, 44). Funds have often been given to family members who were resultantly infected or to surviving family members of deceased persons who had been infected. To be eligible for monetary compensation, persons usually must renounce their civil rights to any future action against government entities. However, this stipulation has not prevented the filing of lawsuits against private institutions. In Canada, several suits were won against the Canadian Red Cross, which was found to have failed utterly to provide the users of blood and blood products with authoritative, accurate and updated information (45) (Table 3). In April 2001, the Canadian Supreme Court found the Canadian Red Cross guilty of negligence for failing to screen blood donors in the early 1980s, when the nations blood supply became infected with the AIDS virus. The Supreme Court upheld a judgment by the Ontario court of appeal, which had said that the Red Cross failed to exercise a proper standard of care in its collection of blood. The ruling stems from three cases brought by blood recipients who received blood from the Canadian Red Cross Society between 1983 and 1985. Two of the plaintiffs died of AIDS complications, and the third is alive and is HIV positive (46). Armour Pharmaceutical Co., which was a division of Rhne-Poulenc Rorer Pharmaceuticals, Inc. (Paris, France), paid six Canadians with hemophilia

A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: A Southwest Oncology Group study 9617

1.5 million each after discovery of a document indicating that some heat-treated products had not been fully deactivated in the mid-1980s (47). In Italy in 1998, a civil court ruled that the Ministry of Health was responsible for the consequences to patients who had received commercially available contaminated blood products in the 1980s. The Ministry of Health was found to have omitted its duties of prudence, diligence, impartiality, and legality in not recommending viral inactivation treatment for human plasma until 1985, not withdrawing products that were not subjected to this treatment until 1988, and not instituting systematic blood-donor screening until 1994. Overall, 80% of the human plasma products sold in Italy by foreign manufacturers in the 1980s were processed without proper quality control (48). Table 3. Compensation Schemes from Seven Countries for Persons Infected with HIV from Blood or Blood Products The United States was one of the last developed count

Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial.

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia

Elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) have a poor prognosis due to low response rates (26–46%) to standard chemotherapy and high treatment-related mortality (11–31%). In this Phase II study, we used a combination of hydroxyurea (HU), azacitidine and low dose gemtuzumab ozogamicin (GO) to assess its efficacy and toxicity in this group of patients. Twenty patients with non-M3 AML and MDS were treated with this regimen. The treatment was begun with HU 1500 mg orally twice daily to lower white blood cell count below 10,000/μL, followed by azacitidine 75 mg/m2 subcutaneously for 7 days and GO 3 mg/m2 on day 8. Patients who achieved complete remission (CR) received a consolidation course. The median age of patients was 76 years. Eleven patients (55%) were treated in the outpatient setting. Fourteen (70%) achieved a CR, three of which were incomplete (CRi). The median duration of remission was 8 months and median survival was 10 months. Performance status of 0–1 was associated with high complete response rate. Overall toxicity was acceptable with only one (5%) early death due to disease progression. The combination of HU, azacitdine and GO appears to be a safe and effective regimen in the treatment of AML and high risk MDS in the elderly. These results need to be confirmed in a larger cohort of patients.

Dietary fish oil supplementation reduces myocardial infarct size in a canine model of ischemia and reperfusion

This trial tested the safety and efficacy of a regimen consisting of hydroxyurea followed by azacitidine, 75 mg/m(2) for 7 days, and gemtuzumab ozogamicin, 3 mg/m(2) on day 8, in older patients with newly diagnosed acute myeloid leukemia. Those achieving a complete remission received 1 consolidation treatment followed by 4 cycles of azacitidine. The patients were stratified into good-risk (age 60-69 years or performance status 0-1) and poor-risk (age ≥70 years and performance status 2 or 3) groups. Specific efficacy and safety goals were defined as being supportive of further study of the regimen. Eighty-three patients were registered in the good-risk cohort and 59 in poor-risk cohort, with median age of 71 and 75 years, respectively. In the good-risk group, 35 patients (44%) achieved a complete remission. Median relapse-free and overall survivals were 8 and 11 months, respectively. Six patients (8%) died within 30 days of registration. In the poor-risk group, 19 (35%) achieved a complete remission. Median relapse-free and overall survivals were 7 and 11 months, respectively. Seven patients (14%) died early. The results of this trial met predefined goals for efficacy and safety for the poor-risk cohort but not the good-risk group. .