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Biomedical subjects

J D Shepherd

Publications and source records attributed to J D Shepherd.

At least 55 records · Page 3Linked to original sources
PubMed1993

Chemotherapy with high-dose cytosine arabinoside and mitoxantrone for poor-prognosis myeloid leukemias.

Forty-seven patients with poor-prognosis myeloid leukemias received induction therapy with high-dose cytosine arabinoside (HDara-C), 1.5-3.0g/m2 for 8-10 doses, and mitoxantrone (DHAD), 12-15 mg/m2 for 3 doses. Complete remissions were achieved in 21 [45%, 95% confidence interval (CI) 30.2-59.9%] of the patients, including 11 of 14 with acute myelogenous leukemia (AML) in first relapse (79%, 95% CI 49.2-95.3%), 4 of 8 with refractory anemia with excess blasts in transformation (RAEBiT) (50%, 95% CI 15.4-84.6%), and 4 of 6 (67%, 95% CI 22.3-95.7%) previously untreated elderly AML patients. Patients with secondary AML and advanced chronic myelogenous leukemia had a very low response rate. The incidence of reversible toxicity was low and only 3 treatment-related deaths occurred. After reinduction, 8 of 9 AML patients < or = 60 years of age were ultimately able to undergo intensive therapy and either autologous 4-hydroperoxycyclophosphamide-purged bone marrow (7 patients) or peripheral blood stem cell (1 patient) transplantation with satisfactory hematological recovery. We conclude that HDara-C and DHAD is an effective antileukemic regimen in selected AML and RAEBiT patients, and that its use may allow subsequent successful autologous BMT in appropriate patients.

Adult↗
PubMed1993

Induction therapy for acute myelogenous leukemia in patients over 60 years with intermediate-dose cytosine arabinoside, mitoxantrone and etoposide.

Twenty-three patients greater than age 60 years with acute myelogenous leukemia (AML) received induction therapy with continuous infusion cytosine arabinoside (1.5 g/m2/day, day 1-3), mitoxantrone (10 mg/m2/day, day 1-3) and etoposide (800 mg/m2, day 4). Patients entering complete remission (CR) were eligible to receive an identical consolidation cycle. Eighteen of the 23 patients (78%; 95% confidence interval 56% to 93%) entered CR. Twelve of these received consolidation therapy and 4 of these remain in remission at 3 to 20 months. Hematologic toxicity of the regimen was acceptable; only 1 patient died following therapy (having attained a CR). Non-hematologic toxicity was mostly mild (grade 2 or less) with one episode of grade 3 cerebellar toxicity. While this regimen induces a high CR rate in patients > age 60 years, relapses remain common and overall survival is too early to assess.

Aged↗
PubMed1993

Combination of t(14;18) and a Burkitt's type translocation in B-cell malignancies.

The combination of chromosomal translocations associated with bcl-2 rearrangement [t(14;18)] and c-myc rearrangement [t(8;14), t(8;22), or t(2;8)] has infrequently been detected in lymphoproliferative disorders. We have recently identified four cases of a B-cell malignancy exhibiting this dual translocation. In addition to t(14;18), one case had t(8;14) and three had the t(8;22). One case presented as de novo acute lymphoblastic leukemia (ALL-L2), two as de novo high grade lymphomas and the fourth evolved to a "blastic" phase from a previously documented follicular lymphoma. Immunophenotyping and molecular analysis was performed on three of the cases: all were negative for terminal deoxynucleotidyl transferase (TdT) but were CD10 positive. Two of the three cases with t(8;22) were negative for surface immunoglobulin (SIg) and positive for HLA-DR. Rearrangement of the oncogene bcl-2 was identified in a single case by polymerase chain reaction (PCR) only. Similar to cases reported in the literature, all patients had a poor clinical outcome despite aggressive therapy. Dual translocation lymphoid malignancy has a relatively characteristic morphology and the diagnosis should be considered when there is a history of an antecedent low grade lymphoma or when there is discordance between the "blastic" morphology and the immunophenotype (TdT- and/or SIg+). Confirmation requires demonstration of the characteristic translocations. Recognition of this entity has significant clinical implications that may require consideration of alternate treatment strategies.

Adult↗
PubMed1993

Allogeneic bone marrow transplantation for poor-prognosis non-Hodgkin's lymphoma.

Twenty-one patients with non-Hodgkin's lymphoma (NHL) felt to be incurable with conventional chemotherapy underwent high-dose chemo +/- radiotherapy and allogeneic sibling donor transplant. The median patient age was 27 years (range 6-47 years); 13 were male and 8 female. By the working formulation, 6 patients at diagnosis had low-grade NHL, 8 intermediate-grade, and 7 high-grade disease. Three patients were in first remission at transplant, 3 in an advanced remission, 5 had failed to respond to initial therapy while 4 had a partial response to initial therapy, and 6 were in relapse (first or beyond). Sixteen patients were conditioned with cyclophosphamide, etoposide and total body irradiation (TBI), 4 with cyclophosphamide and TBI, and one with a combination of busulfan, melphalan and cyclophosphamide. GVHD prophylaxis was variable. At last follow-up, 8 of 21 patients remain alive and progression-free at a median of 37.5 months (range 6-58 months); actuarial event-free survival is 38% (95% confidence interval 17-58%). Thirteen patients died at a median of 2 (range 0.5-8) months post-BMT, 5 from regimen-related toxicity, 3 from acute GVHD, 2 from infections related to chronic GVHD and 3 from disease progression. Factors which were adverse predictors of progression-free survival included low-grade disease, presence of B symptoms at BMT, Karnofsky performance status at BMT and female sex. We concur with previous workers in concluding that allogeneic BMT may offer effective therapy for selected patients with incurable NHL. Major issues to be considered include timing of BMT and disease status at BMT.

Adolescent↗
PubMed1993

Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4-hydroperoxycyclophosphamide.

In August 1988 we began a program in which multiple myeloma patients achieving < or = 10% marrow plasma cells and > or = 50% reduction in paraprotein levels after the VAD (vincristine, doxorubicin, dexamethasone) regimen underwent bone marrow harvest, ex vivo marrow purging with 4-hydroperoxycyclophosphamide (4-HC) and marrow cryopreservation. Conditioning with a regimen of high-dose busulfan (total dose 16 mg/kg), cyclophosphamide (120 mg/kg) and melphalan (90 mg/m2) (BU + CY + MEL) followed by autologous BMT was then carried out. Seventeen of the 24 patients who received VAD (71%, 95% confidence interval [CI] 49 to 87%) were eligible for bone marrow harvest. One patient was not harvested because of non-medical reasons; two patients who underwent marrow harvest had gross plasmacytosis present in biopsies performed intraoperatively and did not undergo BMT. Fourteen patients (58%, 95% CI 37 to 78%) received BU + CY + MEL and 4-HC-purged autologous BMT. The median time to recovery of 0.5 x 10(9)/l neutrophils was 19 days (range 14 to 26) while the last platelet transfusion was given on a median of day 32 (range 10 to 46) post-BMT in the evaluable patients. The major non-hematologic toxicity was hepatic; two patients in complete remission died of hepatic veno-occlusive disease. Another patient succumbed to fungal infection despite neutrophil recovery. The remaining 11 patients achieved responses (complete in six and partial in five) associated with a normal performance status.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Spontaneous remission of multilobated non-Hodgkin lymphoma.

A 67-year-old previously well man was admitted with hypercalcemia after a 7-day history of fever, night sweats, and back pain. The blood showed 5% multilobated lymphoid cells. A multilobated non-Hodgkin lymphoma associated with marked reticulin fibrosis was diagnosed on a bone marrow biopsy. During the next 7 days, in the absence of specific therapy, his symptoms disappeared. Three weeks after admission his biochemical abnormalities had resolved and after 9 weeks his bone marrow examination was normal. He remains in clinical and laboratory remission 16 months after presentation.

Aged↗
PubMed1992

Treatment of myelodysplastic syndrome with busulfan-cyclophosphamide conditioning followed by allogeneic BMT.

Twenty-three consecutive patients undergoing related-donor BMT for myelodysplastic syndrome (MDS) were conditioned with a combination of busulfan (BU) and cyclophosphamide (CY). GVHD prophylaxis was with cyclosporine (CSP)/methotrexate (MTX) in 15 patients, CSP/methylprednisolone (MP) in six patients, and CSP/MP/MTX in two patients. The most frequent regimen-related toxicities were oral mucosal (87% of patients, 61% > or = grade II) and hepatic (82% of patients, 43% > or = grade II). The overall incidence of grade II-IV acute GVHD was 48% with eight patients dying of acute or chronic GVHD. There have been five relapses, with the cumulative risk of relapse being 35% (95% confidence interval [CI], 16%-66%). Eight patients remain alive and well (median follow-up 27 months, range 15-70 months), with an estimated 3-year event-free survival (EFS) of 35% (95% CI, 17%-54%). Univariate analysis of EFS by pretransplant variables indicated that only age < or = 35 years correlated with a favorable outcome (p = 0.04). BUCY is an effective, well-tolerated alternative conditioning regimen for MDS patients undergoing allogeneic BMT.

Acute Disease↗
PubMed1992

Anti-interleukin-2 receptor monoclonal antibody (BT 563) in the treatment of severe acute GVHD refractory to systemic corticosteroid therapy.

Fourteen patients with corticosteroid-resistant acute GVHD were treated with a murine monoclonal antibody to the pp55 interleukin-2 (IL-2) receptor (MoAb BT 563). Nine of the 14 patients had also failed Xoma-Zyme-H65 as GVHD prophylaxis and/or treatment. Seven patients had received HLA-matched sibling donor bone marrow transplants, five had received HLA-matched transplants from unrelated volunteer donors, and two had received one-antigen mismatched transplants from unrelated volunteer donors. At the time of MoAb BT 563 therapy, the overall clinical grading of acute GVHD (Seattle grading system) was as follows: grade II--one patient, grade III--four patients, and grade IV--nine patients. MoAb BT 563 was administered as a short iv infusion of 5 mg daily for 10 doses, followed by 5 mg on alternate days for a further five doses. A complete response (CR) was observed in four patients (28%), and a partial response (PR) in four patients (28%). All four complete responders were treated within 28 days of first onset of grade > or = II acute GVHD. Four patients (three CR, one PR) remain alive. One complete responder subsequently died from chronic GVHD. MoAb BT 563 administration was well tolerated in all 14 patients; no significant toxicity was observed. We conclude that MoAb BT 563 directed against the IL-2 receptor on activated T lymphocytes may be useful in treating corticosteroid-resistant acute GVHD if given early, but that it is of limited value in attempting to rescue patients with far-advanced refractory acute GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1992

Influence of post-methotrexate folinic acid rescue on regimen-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation.

Thirty-two patients undergoing related-donor bone marrow transplantation (BMT) received cyclosporine (CSP) and methotrexate (MTX) with folinic acid rescue (FAR) as graft-versus-host disease (GVHD) prophylaxis. Fifty consecutive related-donor BMT patients given the CSP/MTX combination without FAR were utilized as historical controls. Patients receiving FAR experienced earlier engraftment, with absolute neutrophil count greater than 0.5 x 10(9)/l at a median of 17 days (vs 21 days in controls, p = 0.002). The day of last platelet transfusion was earlier in the FAR group (median of 14 days vs 17 days in controls, p = 0.01). Compared with the control group, patients receiving FAR had a lower incidence of grade II-IV stomatic (53% vs 78%, p = 0.04) and hepatic (25% vs 56%, p = 0.01) regimen-related toxicity. In the FAR group, 70% required total parenteral nutrition vs 92% of controls (p = 0.02). Broad-spectrum antibiotics were given to FAR patients for a median of 21 days (vs 23 days in controls, p = 0.09). The incidence of grade II-IV acute GVHD was similar in the FAR and control populations (45% and 35%, respectively, p = NS) as was the incidence of chronic GVHD (62% vs 55%, respectively, p = NS). Estimated event-free survival is 59% for FAR patients (median follow-up 64 weeks) and 58% for controls (median follow-up 109 weeks, p = NS). FAR reduces regimen-related toxicity in patients receiving CSP/MTX acute GVHD prophylaxis without significantly influencing GVHD incidence or event-free survival.

Adolescent↗
PubMed1991

Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected].

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.

Adolescent↗
PubMed1991

High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults.

Seventy consecutive adult patients with acute myelogenous leukemia (AML), median age 44 years, received high-dose cytarabine (3 g/m2 every 12 hours for 12 doses) followed by daunorubicin (45 mg/m2 daily for three doses) for remission induction. A single, identical course was planned for postremission therapy. Complete remission (CR) was achieved in 63 patients (90%, 95% confidence interval [CI] 83% to 97%), 60 after a single course. Eight patients were selected to undergo elective bone marrow transplantation (BMT) during first CR. Of the remaining 55 patients, 40 (73%) underwent planned post-CR therapy; 15 patients did not, owing to early relapse, excessive toxicity from the induction chemotherapy, or refusal. Nineteen patients, including 13 who received planned post-CR therapy, remain in continuous CR at a median follow-up of 5.2 years (range 3.0 to 7.1 years). The 5-year actuarial leukemia-free survival was 30% (95% Cl, 19% to 42%) for all patients achieving CR and 32% (95% Cl, 19% to 47%) for the 40 patients who received the planned post-CR chemotherapy. Analysis of various putative prognostic factors for CR and overall and leukemia-free survival showed significance for a previous history of myelodysplasia, higher initial leukocyte counts, certain French-American-British (FAB) types, and certain abnormal karyotypes. None of these factors was consistently significant regarding the above parameters, although small patient numbers in certain analyses may have obscured significant associations. Myelosuppression was occasionally prolonged after remission induction and especially post-CR therapy. Severe cerebellar toxicity was observed in 13 patients; in 11 cases, this toxicity was fully reversible. Other serious complications were infrequent. Intensive chemotherapy with high-dose cytarabine and daunorubicin has substantial antileukemic activity in adult AML, and may represent an improvement over conventional therapy. Relapses were common, however, even in patients who received planned therapy, and substantial toxicity was observed. The optimum use of this regimen in AML remains to be determined.

Adult↗
PubMed1991

Intrathoracic complications following allogeneic bone marrow transplantation: CT findings.

The authors retrospectively reviewed computed tomographic (CT) scans of 18 patients who developed 21 episodes of intrathoracic complications after allogeneic bone marrow transplantation (BMT). Pathologic and/or microbiologic diagnoses were available for all patients. All patients were immunocompromised due to either graft-versus-host disease (GVHD), neutropenia, or recurrent malignancy after BMT. CT demonstrated diagnostically relevant findings that were not apparent at radiography in 12 of the 21 cases (57%). These included a ground-glass pattern in early pneumonia (n = 5); a peripheral distribution in GVHD, bronchiolitis obliterans organizing pneumonia, and eosinophilic drug reaction (n = 4); cavitating lesions in Pneumocystis carinii pneumonia (n = 1); hemorrhagic infarcts in aspergillosis (n = 1); and mediastinal adenopathy in recurrent Hodgkin disease (n = 1). The authors conclude that chest CT is superior to radiography in demonstrating the presence, distribution, and extent of intrathoracic complications developing in patients after allogeneic BMT. CT is useful in guiding procedures for tissue diagnosis.

Adult↗
PubMed1991

Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy.

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.

Actuarial Analysis↗
PubMed1991

Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation.

Hemorrhagic cystitis is a major complication of high-dose cyclophosphamide therapy used in preparation for allogeneic or autologous bone marrow transplantation. Although previous reports had suggested that the sulfhydryl-containing compound mesna might be superior to forced diuresis in preventing hemorrhagic cystitis, there were concerns about the effect of mesna on engraftment in these studies. To address these concerns, 100 patients were randomized to receive mesna or forced saline diuresis while undergoing bone marrow transplant conditioning with regimens that included high-dose cyclophosphamide. To try to minimize the likelihood of graft rejection, patients who were being transplanted with cyclophosphamide as a sole agent were excluded from the study. After randomization and administration of therapy, patients were monitored by microscopic and dip-stick urinalyses; they were also followed for effects of therapy on engraftment. The incidence of consistent or severe hematuria was 33% in the mesna arm and 20% in the hyperhydration arm (P = .31). Severe bleeding occurred in 12.5% of mesna patients and 7.5% of hyperhydration patients (P = .71). No unexpected toxicities were encountered, and engraftment times did not differ. Based on this randomized trial of 100 patients, we conclude that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation patients.

Adolescent↗
PubMed1991

Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation.

The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac, bladder, renal, pulmonary, hepatic, CNS, stomatic, and gastrointestinal) according to a recently developed RRT scale. A set of patient, disease, and treatment parameters (age, sex, diagnosis, Eastern Cooperative Oncology Group [ECOG] score, preconditioning liver function tests [LFT], prior chemotherapy exposure, disease status, graft-versus-host disease [GVHD] prophylaxis, antimicrobial agent use, hematologic recovery, and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%, respectively) but were rarely serious (9% and 1% grades II to IV, respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven), pulmonary (two), bladder (two), and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis, only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%, with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.

Adolescent↗