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Biomedical subjects

H A Messner

Publications and source records attributed to H A Messner.

At least 19 recordsLinked to original sources
PubMed2005

Treatment of elderly patients with acute lymphoblastic leukemia--evidence for a benefit of imatinib in BCR-ABL positive patients.

All patients with acute lymphoblastic leukemia (ALL) over age 60 years seen at Princess Margaret Hospital over an 11-year period were analysed retrospectively. Of 53 patients, 45 received multiagent induction chemotherapy using a variety of regimens. There were 13 BCR-ABL positive patients, 9 of who received imatinib mesylate, either during induction or post-remission therapy. The overall complete remission (CR) rate of all 45-induction patients was 56%, with a 27% induction-related mortality rate. The CR rate was not influenced by induction regimen, age, initial WBC, LDH or BCR-ABL status. The median overall survival of the induction patients was 9 months, while the median progression-free survival (PFS) of the patients achieving CR was 10 months. The estimated overall survival (OS) at 3 years was 18.4% (95% CI: 9.8-34.3%). Age and initial WBC did not significantly predict for OS when evaluating the entire group of induction patients. However, there was a strong trend for BCR-ABL status to favorably predict for PFS, and for OS when only patients treated after July 2000 (when imatinib became available) were evaluated. The results indicate that ALL remains a poor prognosis disease in elderly patients, and that aggressive induction regimens designed for younger patients are very toxic for these patients. These data suggest that BCR-ABL+ ALL is becoming a relatively more favorable prognosis disease in the elderly, likely due to the influence of imatinib therapy. Further regimens should explore the use of less aggressive regimens in elderly patients and should evaluate the optimal way of combining imatinib with conventional agents in BCR-ABL+ patients.

Aged↗
PubMed2005

Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation.

The purpose of this study was to evaluate the estimated incidence of secondary malignancies post-allogeneic bone marrow transplantation (BMT) in a cohort of adult patients previously reported now with an additional 8.5 years of follow-up. A cohort of 557 patients older than age 16 years underwent allogeneic BMT between June 1970 and November 1993. Histologic reports confirmed the diagnosis of a secondary malignancy. Multivariate Cox proportional hazards method was utilized to investigate predictors for the development of secondary malignancies. In all, 31 patients in this cohort developed a secondary malignancy a median of 6.79 years after their transplant. The estimated cumulative incidence rate of secondary malignancy was 4.2% at 10 years post transplant. When compared to the general population, the estimated observed/expected ratio of new cancer diagnoses was 5.13. On multivariate analysis, older age at the time of transplant was the only significant predictor for development of secondary cancer (P=0.01). The most common malignancies observed were nonmelanomatous skin cancers and squamous cell cancers of the buccal cavity. The risk of developing a secondary malignancy after allogeneic BMT is significant, particularly in older patients. Long-term survivors of transplant require regular monitoring for early signs of cancer, particularly of the skin and oral cavity.

Adult↗
PubMed2005

Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease.

In all, 30 patients with CLL proceeded to myeloablative allogeneic BMT using related (n=20, 67%) or unrelated (n=10) donors, at the Princess Margaret Hospital (Toronto) (n=20) or the Leukemia/BMT Program of BC (Vancouver) (n=10), from 1989 to 2001. Median (range) interval from diagnosis to BMT was 4.8 (0.3-13) years, median number of prior therapies was three and median age 48 years. The preparative regimen included total body irradiation in 15 (50%). In all, 14 of 30 patients (47%) are alive, with median (range) follow up of 4.3 (2.4-10.5) years. All are in complete remission, two following therapy for post-BMT progression. Actuarial overall (OS) and event-free survival (EFS) at 5 years is 39% (OS 48% for related donor and 20% for unrelated donor BMT); cumulative incidence of nonrelapse mortality (NRM) and relapse is 47 and 19%, respectively. Both acute (RR=0.008, P=0.01) and chronic (RR=0.006, P=0.02) Graft-versus-host disease (GVHD) were associated with markedly decreased risk of relapse. Patients receiving grafts from unrelated donors had increased NRM (RR=3.6, P=0.02) and decreased OS (RR of death=3.4, P=0.002). Allogeneic BMT has resulted in long-term EFS in approximately 40% of patients with CLL. There is evidence for a strong graft-versus-leukemia effect associated with acute and chronic GVHD, resulting in near complete protection from relapse.

Adult↗
PubMed2004

The role of allogeneic bone marrow transplantation in adult patients below the age of 55 years with acute lymphoblastic leukemia in first complete remission: a donor vs no donor comparison.

The role of allogeneic bone marrow transplantation (alloBMT) in adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) remains controversial. At our institution, the policy is to offer alloBMT to ALL patients in CR1 up to the age of 55 years if a related donor is available. In addition, unrelated donor transplants are offered to patients with Philadelphia (Ph+) ALL. We report the results on 92 patients with ALL treated according to this policy from September 1992 to October 2001. Of the 87 patients achieving CR1, the comparison of patients with (n=48) or without donors (n=39) was done using an intention-to-treat approach. Of the 48 patients with donors (39 related and nine unrelated), 35 (73%) received alloBMT in CR1. No significant difference in 3-year event-free survival (EFS) (40 vs 39%, P=0.74) or overall survival (OS) (46 vs 58%, P=0.41) was seen in 'donor' vs 'no-donor' groups. For Ph+ patients, 3-year EFS and OS in 'donor' group were 46 and 57%, respectively, none of the patients in 'no-donor' group survived beyond 3 years. With our treatment strategy, 3-year OS of Ph+ patients was equivalent to Ph-negative (Ph-) patients (51 vs 52%, P=0.77). In conclusion, our data show that the policy of performing alloBMT if a sibling donor is available has not resulted in better outcome in Ph- patients.

Adolescent↗
PubMed2004

Long-term pulmonary function abnormalities and survival after allogeneic marrow transplantation.

We studied long-term pulmonary function testing (PFT) in a retrospective cohort of 6-month survivors of allogeneic marrow transplant (BMT) between 1980 and 1997. Of 593 patients, 73, 71 and 65% had adequate data to assess for obstruction, restriction and diffusion impairments respectively. Over 5 years, mean declines in 1-s forced expiratory volume/forced vital capacity (FEV1/FVC), total lung capacity (TLC) and diffusion were 4, 7 and 17%, respectively. TLC and diffusion tended to subsequently increase. In all, 6, 12 and 35% of patients met criteria for obstruction, restriction and impaired diffusion, respectively. Obstruction was less common in recent transplants (5 vs 15%, P=0.004), while restriction and diffusion impairment rates remained stable. There was significantly greater mortality with obstruction (HR 2.0 (1.04-3.95)), and a nonstatistically significant higher mortality rate with restriction (HR 1.6 (0.95-2.75)), but not with impaired diffusion (HR=0.99 (0.65-1.50)). cGVHD (OR 16.7 (2.2-129.8)) and busulfan (OR 2.9 (1.01-8.24)) were associated with obstruction. Marrow from nonsibling or mismatched donors (OR 4.9 (2.2-10.7)) was associated with restriction. In summary, after BMT, decreased diffusion capacity is common and benign; obstruction has decreased in frequency, is rare without cGVHD, and is associated with mortality; nonsibling and mismatched donor are risk factors for restriction.

Acute Disease↗
PubMed2004

Bone marrow aspirates as part of routine donor assessment for allogeneic blood and marrow transplantation can reveal presence of occult hematological malignancies in otherwise asymptomatic individuals.

Pre transplant screening work-up of donors for allogeneic blood and marrow transplantation is essential in an effort to minimize risks to the recipient and protect the donor. At Princess Margaret Hospital, every potential donor is screened with a bone marrow aspirate. The case histories of three asymptomatic potential donors who presented within 1 year with normal complete blood counts, history and physical examination are presented. A 65-year-old male patient was diagnosed with smouldering multiple myeloma, a 72-year-old male patient with chronic lymphocytic leukemia and a 42-year-old male patient with myelodysplastic syndrome. Bone marrow examination led to the diagnosis in each one of these cases. Of note is that each of the potential donors was discovered to have the same disease as the transplant recipient. In vitro clonogenic hemopoietic progenitor assays were compared to those of 20 normal volunteers. Inferior growth of hemopoietic progenitor colonies in all three was noted. In conclusion, particularly in older donors and donors with potential for familial malignancies, more screening investigations including bone marrow aspiration may be reasonable to investigate for occult hematological malignancies prior to stem cell donation. Clonogenic assays can contribute to detect hemopoietic abnormalities pre transplant.

Adult↗
PubMed2004

Rescue of interferon induced bone marrow aplasia in a patient with chronic myeloid leukemia by allogeneic bone marrow transplant.

A patient with chronic phase Philadelphia chromosome positive CML, developed severe protracted bone marrow hypoplasia after interferon therapy. This complication did not respond to two courses of immunosuppressive therapy with anti-thymocyte globulin, cyclosporin A and prednisone. The patient continued to be transfusion dependent with persistence of Philadelphia chromosome. Allogeneic BMT restored normal hematopoeisis.

Adult↗
PubMed2004

Subdural hematomas during CML therapy with imatinib mesylate.

Seven of one hundred twenty-one patients with chronic myeloid leukemia (CML) treated with imatinib mesylate developed subdural hematomas. All had advanced disease and were treated initially at a dose of 600 mg per day. Three patients had thrombocytopenia (platelet < 10 x 10(9)/l), one had leukocytosis (white blood cell count > 150 x 10(9)/l) and three had neither around the time of diagnosis of the subdural hematomas. Four patients required surgical evacuation. One patient, in blast crisis, died as a consequence of the subdural hematoma. Three patients survived but died of progressive CML. The remaining three patients having recommenced imatinib, are alive and well, and one has achieved a major cytogenetic response. Subdural hematomas must be considered even in mildly symptomatic patients receiving imatinib regardless of their peripheral blood counts. Patients who survive can be cautiously restarted on imatinib. Further studies are required to study the potential relationship between imatinib mesylate and subdural hematomas.

Aged↗
PubMed2003

Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin's lymphoma.

This study reports on overall and recurrence-free survival (OS and RFS) of 37 consecutive patients with low- and intermediate-grade NHL receiving a related donor allogeneic BMT using a nonradiation-containing preparative regimen. In addition, transplant-related toxicity and factors influencing outcome are discussed. The preparative regimen consisted of busulfan and cyclophosphamide. Median patient age was 44 years (range 20-55). In all, 18 were female. Median follow-up of surviving patients from BMT was 4.2 years. A total of 25 patients had low-grade, and 12 intermediate grade NHL. Most patients (89%) were treated with at least two different chemotherapy regimens prior to BMT. In all, 22 patients (59%) were transplanted in partial remission, 15 (41%) in complete remission. OS at 12 months was 89% (95% confidence interval (CI) of 79-99%) and 79% (64-93%) at 60 months. RFS at 12 months was 86% (75-97%) and at 5 years 70% (54-86%). Four patients (11%) relapsed. Seven patients (19%) died, six because of treatment-related toxicity and one with relapse. Univariate analysis showed improved OS for younger patients and patients of female gender, suggesting that allogeneic BMT using busulfan-cyclophosphamide as a preparative regimen can achieve disease control and possibly cure patients with NHL particularly younger ones.

Adult↗
PubMed2003

Imatinib Mesylate (Gleevec) is a useful agent in the salvage treatment of adults with relapsed/refractory Philadelphia positive acute leukemias.

Philadelphia chromosome-positive (Ph+) acute leukemias have a markedly poor prognosis when treated with conventional chemotherapy alone. Even with intensive treatment such as allogeneic transplant, a large proportion of patients relapse. We describe here four cases of relapsed/refractory Ph+ acute leukemias who were treated with Imatinib Mesylate (Gleevec) as monotherapy. Significant clinical and molecular responses were observed in these patients, which allowed us to deliver highly intensive treatments such as second allogeneic stem cell transplant and matched unrelated transplant in these patients. Gleevec may prove to be a useful agent in the salvage therapy of such patients.

Adult↗
PubMed2003

Vascular events associated with alpha interferon therapy.

Alpha Interferon (IFN) is a biological agent used for the therapy of an increasing number of diseases, either as an established effective therapeutic tool or in the context of clinical trials. The use of IFN may be complicated by serious adverse reactions. We describe here the clinical course of a variety of vasculopathic complications in association with IFN-therapy in 12 patients with the diagnosis of chronic myeloid leukemia and 1 patient with malignant melanoma treated at our institute. Vascular manifestations in these patients include Raynaud's phenomena, digital ulcerations and gangrene, pulmonary vasculitis, pulmonary hypertension and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). These reactions occurred after 3 months to 3 years of 3-10 million units (MU) daily IFN therapy. Concomitant administration of hydroxyurea (HU) was noted in 5 patients. Discontinuation of IFN and initiation of immunosuppressive therapy brought about a complete resolution or arrested progression of these reactions. IFN-therapy may be complicated by severe vasculopathic/vasospastic complications that usually improve after its discontinuation. Possible underlying mechanisms for these complications are discussed. The early diagnosis of these complications may be vital and IFN should be immediately discontinued when early signs of these complications become evident.

Adult↗
PubMed2002

Long-term medical outcomes and quality-of-life assessment of patients with chronic myeloid leukemia followed at least 10 years after allogeneic bone marrow transplantation.

PURPOSE: Benchmark analysis of patients with chronic myeloid leukemia (CML) alive for more than 10 years after allogeneic bone marrow transplantation (BMT) including data on disease status, bone marrow reserve, long-term complications, and quality of life (QOL). PATIENTS AND METHODS: Eighty-nine patients (46 in first chronic phase, 43 in advanced phase) received an allogeneic BMT for CML during the study period. Medical outcomes and QOL of patients were analyzed retrospectively. RESULTS: Twenty-eight (31.5%) of 89 patients were alive at 10 years and included in this analysis. Thirteen (46.4%) of 28 long-term survivors never relapsed. Fifteen patients relapsed between 0.5 and 16 years after transplantation. Ten patients showed a hematologic relapse and received salvage treatment. Five patients showed transient low levels of BCR-ABL-positive cells by Southern blot with no subsequent hematologic relapse. One of the 28 patients died in blast crisis at 12 years. The most frequent long-term complications were chronic graft-versus-host disease, osteoporosis, and cataracts. Frequency of clonogenic progenitors remained persistently decreased. QOL assessment yielded lower scores in physical performance as compared with an age-matched normative population, whereas social functioning was equivalent. A high degree of satisfaction was noted with interpersonal relationships. CONCLUSION: Patients with CML surviving their BMT long term do well in terms of medical outcomes. A constant rate of relapse was noted, with a high salvage rate of affected patients, suggesting the need for lifelong monitoring. QOL is perceived as good, particularly as related to social functioning; however, it is inferior to a normative population with regard to physical performance.

Adult↗
PubMed2002

Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation.

Pneumocystis carinii pneumonia (PCP) poses a serious risk to allogeneic bone marrow transplant (BMT) patients, who are often intolerant of trimethoprim-sulfamethoxazole (TMP-SMX), the traditional first-line prophylactic agents. There are limited published data supporting the use of aerosolized pentamidine (AP) prophylaxis in the BMT population. We assessed the effectiveness of AP in BMT recipients by reviewing the experience at our center. We divided our review into four time periods from January 1990 to March 2000, during which approximately 700 BMTs were performed. The first period includes patients receiving AP treatments from January 1990 to July 1997 (baseline), the second from August 1997 to July 1998 (pre-outbreak), the third from August 1998 to October 1999 (outbreak), and the fourth from November 1999 to March 2000 (post-outbreak). At our center, TMP-SMX is the first-line agent for PCP prophylaxis, which is routinely continued for at least one year, or for the duration of enhanced immunosuppression. During the baseline period, 505 BMTs were performed and 192 patients (38%) received AP for part of their time at risk. Six patients (3%) experienced toxicities requiring discontinuation of AP. Three cases of PCP were diagnosed over 1114 patient-months of treatment in the baseline period. During the last 42 months of the baseline period, 2/154 patients receiving AP and 2 of an estimated 293 patients receiving exclusively oral prophylaxis developed breakthrough PCP (p = 0.61). During the outbreak period, 9 of 180 patients receiving AP developed PCP compared to none in the group receiving exclusively oral prophylaxis. Either changes in our AP protocol during the pre-outbreak period or pentamidine resistance may have led to this failure of prophylaxis. There were no further cases during the 5-month post-outbreak period. Our observed overall breakthrough rate was 12 cases out of 439 patients (2.7%). Our study shows that AP is an effective and well-tolerated second-line agent in preventing PCP post BMT and we recommend its continued use in this regard. However, it should be administered using a well-studied protocol, and only when TMP-SMX is not tolerated.

Administration, Inhalation↗
PubMed2002

Pulmonary function abnormalities after allogeneic marrow transplantation: a systematic review and assessment of an existing predictive instrument.

Pulmonary function testing (PFT) is used to characterize non-infectious pulmonary complications after allogeneic BMT. Identifying high-risk patients could facilitate preventive or early therapeutic measures. The objectives of the study were first, to review available data on PFT changes after BMT and second, to validate a previously published predictive index for PFT obstruction in patients transplanted at one center. For the systematic review, frequency, severity and time course of PFT changes after BMT and for the validation study, retrospective cohort comparing predicted with observed PFT, and calculation of indices of predictive accuracy were summarized. The validation study involved 434 patients from Princess Margaret Hospital, Toronto, Canada, who received their first BMT between 1980 and 1997, survived for at least 6 months and had adequate PFT follow-up. The systematic review included 20 studies. After BMT, decreased diffusion and total lung capacity were common and partially reversible. Obstruction was less common. The validation study of a previously published index, performed in 434 patients, found a sensitivity and specificity of 48% and 68% for identifying patients who develop obstruction. We concluded that PFT changes after BMT are common. A published predictive index is not sufficiently accurate to identify high-risk patients for potential preventive or early therapeutic strategies.

Bone Marrow Transplantation↗
PubMed2001

Illness intrusiveness among survivors of autologous blood and marrow transplantation.

BACKGROUND: Illness-induced disruptions to lifestyles, activities, and interests (i.e., illness intrusiveness) compromise subjective well-being. The authors measured illness intrusiveness in autologous blood and bone marrow transplantation (ABMT) survivors and compared the results with survivors of solid organ transplants. METHODS: Forty-four of 64 consecutive ABMT survivors referred to the University of Toronto ABMT long-term follow-up clinic completed the Illness Intrusiveness Ratings Scale (IIRS), the Affect Balance Scale (ABS), the Atkinson Life Happiness Rating (ATKLH), the Beck Hopelessness Scale (BHS), and the Center for Epidemiologic Studies Depression (CES-D) Scale. Mean time from ABMT to evaluation was 4.6 +/- 2.8 years. All patients were in remission or had stable disease at the time of evaluation. Autologous blood and bone marrow transplantation patients' IIRS scores were compared with scores reported by recipients of kidney (n = 357), liver (n = 150), lung (n = 77), and heart (n = 60) transplants. RESULTS: Mean IIRS score for the 44 ABMT patients was 37.2 +/- 17 (maximum possible score, 91; minimum possible score, 13). Higher IIRS scores correlated with lower scores on the ABS (r = -0.54; P < 0.0001), and ATKLH (r = -0.44; P = 0.004), and with higher scores on the BHS (r = 0.58; P < 0.0001) and CES-D (r = 0.48; P < 0.0001). The authors compared IIRS scores from the ABMT survivors with scores from recipients of solid organ transplants. Scores were corrected for age, gender, and time from transplant to evaluation. Corrected mean IIRS scores for the marrow (37.5), kidney (38.9), heart (40.0), lung (30.1), and liver (32.3) transplant recipients differed significantly (P < 0.0001 by analysis of covariance). Higher scores among marrow, kidney, and heart transplant survivors were caused by increased scores in the instrumental domain of the IIRS that measures disruptions in health, work, financial situation, and active recreation. CONCLUSIONS: Despite achieving a remission after ABMT, patients continue to experience illness intrusiveness compromising subjective well-being.

Activities of Daily Living↗
PubMed2001

Replicative stress after allogeneic bone marrow transplantation: changes in cycling of CD34+CD90+ and CD34+CD90- hematopoietic progenitors.

To further characterize hematopoietic "replicative stress" induced by bone marrow transplantation (BMT), the cell-cycle status of CD90+/- subsets of marrow CD34+ cells obtained 2 to 6 months after transplantation from 11 fully chimeric recipients was examined. Cycling profiles, derived by flow cytometry after staining with Hoechst 33342 and pyronin Y, were compared with those of 14 healthy marrow donors. Primitive CD34+CD90+ cells represented a smaller proportion of CD34+ cells in recipients (10% +/- 4% versus 19.6% +/- 5.3% in donors; P <.0001) and were more mitotically active, with the proportion of cells in S/G2/M nearly 4-fold higher than in donors (15.6% +/- 3% and 4.4% +/- 1.6%, respectively; P <.0001). By comparison, there was a modest increase in the proportion of CD34+CD90- progenitors in S/G2/M after BMT (10.9% +/- 1% vs 9.6% +/- 2% in donors; P =.04). Replicative stress after BMT is borne predominantly by cells in a diminished CD34+CD90+ population.

Adult↗