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J Radich

Publications and source records attributed to J Radich.

At least 19 recordsLinked to original sources
PubMed1998

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS: Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS: The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS: Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.

Adolescent↗
PubMed1998

Isolation of CD34+ cells from blood stem cell components using the Baxter Isolex system.

The CD34 antigen is expressed by human hematopoietic progenitor and stem cells. These cells are capable of reconstituting marrow function after marrow-ablative chemo-radiotherapy. Several different technologies have been developed for the separation of CD34+ cells from bone marrow or peripheral blood stem cell (PBSC) components. We used an immunomagnetic separation technique to enrich CD34+ cells from PBSC components in anticipation of autologous transplantation for patients with B lymphoid malignancies. Twenty-nine patients enrolled on this study and received mobilization chemotherapy followed by G-CSF. Of these, 21 achieved a peripheral blood CD34+ cell level of at least 2.0 x 10(4)/l required by protocol for separation of the stem cell components. A median of three components per patient was collected for processing. The average CD34+ cell concentration in the components after apheresis was 1.0 +/- 1.2%. After the CD34+ cell selection, the enriched components contained 0.6 +/- 0.6% of the starting nucleated cells. The recovery of CD34+ cells, however, averaged 58.4 +/- 19.2% of the starting cell number, with a purity of 90.8 +/- 6.5%. Overall depletion of CD34- cells was 99.96 +/- 0.06%. Nineteen patients were treated with marrow-ablative conditioning regimens and received an average of 6.2 +/- 2.0 x 10(6) CD34+ cells/kg body weight. These patients recovered to an ANC >0.5 x 10(9)/l at a median of 11 days (range 8-14), and platelet transfusion independence at a median of 9 days (range 5-13). Four patients died of transplant-related complications or relapse before 100 days after transplantation. No patient required infusion of unseparated cells because of failure of sustained bone marrow function. These data demonstrate that peripheral blood-derived CD34+ cells enriched by use of an immunomagnetic separation technique are capable of rapid engraftment after autologous transplantation.

Adult↗
PubMed1998

The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults.

Chromosomal translocations are commonly found in de novo acute myeloid leukemia (AML) cells, and the fusion proteins produced from these genetic abnormalities are assumed to contribute directly to leukemogenesis and/or progression. The AML1/ETO fusion protein, created by translocations between chromosomes 8 and 21 [t(8;21); G. Nucifora and J. D. Rowley, Leuk. Lymphoma, 14: 353-362, 1994; K. L. Rhoades et al., Proc. Natl. Acad. Sci. USA, 93: 11895-11900, 1996] can induce anti-apoptotic Bcl-2 expression in vitro and was proposed to thereby promote the survival of t(8;21)-bearing AML cells (L. Klampfer et al., Proc. Natl. Acad. Sci. USA, 93: 14059-14064, 1996). We confirm that cells of the t(8;21)-bearing Kasumi cell line do express high levels of Bcl-2 protein, as reported previously. However, we show that primary AML cells with (8;21) chromosomal translocations generally express low levels of Bcl-2 protein relative to normal bone marrow-derived myeloid cells and to AML samples with other simple karyotypic abnormalities. We note that p53 mutations are present in the myeloid cell lines expressing AML-ETO protein from chromosomal translocations (Kasumi and SKNO) or from transfected fusion genes (U937) but were undetected in our analyses of 28 primary t(8;21)-bearing AML cell samples from de novo AMLs. Because wild-type p53 can transcriptionally down-regulate bcl-2, we speculate that p53 mutations may contribute to the association of t(8;21) chromosomal abnormalities with higher Bcl-2 expression levels in leukemia cell lines. We also note that some t(8;21)-bearing samples from pediatric and older adult patients do express somewhat higher levels of Bcl-2 than t(8;21)-bearing samples from young adult patients. This suggests that Bcl-2 overexpression could occur in these AML cells by an as yet undefined, p53-independent mechanism and could contribute to the reported association of t(8;21) karyotypes with poor clinical outcomes in childhood AML patients and/or to typically poor clinical outcomes in elderly AML patients.

Acute Disease↗
PubMed1997

Use of alpha-2a-interferon to treat cytogenetic relapse of chronic myeloid leukemia after marrow transplantation.

Fourteen patients with cytogenetic relapse of chronic myeloid leukemia (CML) after transplantation with unmanipulated bone marrow were treated with alpha-2a-interferon. There were eight men and six women, median age, 33 years. Twelve patients received marrow from a related allogeneic donor and two received marrow from a syngeneic donor. The median percentage of Ph-positive metaphases at the time of starting interferon was 55% (10% to 87%). Daily interferon was started at a dose of 1 to 3 x 10(6) U/M2/d, depending on initial blood counts and was adjusted as tolerated to maintain the white blood count in the range of 2,000 to 3,000/microL and the platelet count greater than 60,000/microL. After a stable cytogenetic remission was achieved, the interferon dose was decreased to a maintenance level. Twelve patients achieved a complete cytogenetic remission on at least one occasion. Median time to achieve a complete cytogenetic remission was 7.5 months (range, 1.5 to 12). Eight patients remain in cytogenetic remission for 10+ to 54+ months from the time of first documented remission. After complete cytogenetic remission was established, nine patients were tested for the presence of the mRNA transcript of the bcr/abl fusion gene by polymerase chain reaction (PCR) testing. Four patients were PCR-negative on at least one occasion: two patients were PCR-negative on a single occasion; one patient had serial tests, which were PCR-negative; and one patient had serial PCR-negative peripheral blood tests with a single PCR-positive bone marrow obtained concurrently with a negative peripheral blood test. Median follow-up time for all patients is 44 months (range, 20 to 64). Interferon was generally well tolerated; only one responding patient was unable to continue interferon because of toxicity. Interferon induces durable cytogenetic remissions in a significant proportion (57%) of patients with cytogenetic relapse following bone marrow transplantation (BMT) without causing life-threatening toxicities.

Adolescent↗
PubMed1997

Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Transplantation of marrow from unrelated donors was investigated in patients with Philadelphia chromosome-positive (Ph1+) acute lymphoblastic leukemia (ALL) who lacked a suitable family donor. Eighteen patients underwent transplantation at our center between 1988 and 1995. The median patient age was 25 years (range, 1.7 to 51 years). Seven patients were in first complete remission, 1 in second remission, 3 in first relapse, and the remaining 7 had more advanced or chemotherapy refractory leukemia at transplant. All patients were conditioned with cyclophosphamide and total body irradiation followed by marrow transplants from closely HLA-matched, unrelated volunteers. Posttransplant graft-versus-host disease (GVHD) prophylaxis included methotrexate with either cyclosporine or FK506. Graft failure was not observed. Severe (grades III-IV) GVHD appeared in 6 of 17 evaluable patients and chronic extensive GVHD in 7 of 13 patients at risk. Five patients had recurrent ALL after transplantation and another 4 died from causes other than leukemia. Six patients transplanted in first remission, 2 in first relapse, and 1 in second remission remain alive and leukemia-free at a median follow-up of 17 months (range, 9 to 73 months). The probability of leukemia-free survival at 2 years is 49% +/- 12%. These data indicate that unrelated donor marrow transplantation is an effective treatment option for patients with early stage Ph1+ ALL without a family match and suggest that in such patients an unrelated donor search should be initiated as soon as possible after diagnosis.

Adolescent↗
PubMed1997

Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (C(SS)BU) during the dosing interval were measured for each patient. The mean C(SS)BU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with C(SS)BU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with C(SS)BU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). C(SS)BU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with C(SS)BU above and below the median (P = .33). There was no statistically significant association of C(SS)BU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly C(SS)BU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Adult↗
PubMed1997

Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation.

Thirty-six patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) were studied for the presence of the bcr-abl fusion mRNA transcript after an allogeneic matched related (N = 12), partially matched related (N = 4), matched unrelated (N = 14), autologous (N = 5), or syngeneic (N = 1) bone marrow transplant (BMT). Seventeen were transplanted in relapse, and 19 were transplanted in remission. Twenty-three patients had at least one positive bcr-abl polymerase chain reaction (PCR) assay after BMT either before a relapse or without subsequent relapse. Ten of these 23 relapsed after a positive assay at a median time from first positive PCR assay of 94 days (range, 28 to 416 days). By comparison, only 2 relapses occurred in the 13 patients with no prior positive PCR assays; both patients had missed at least one scheduled follow-up assay and were not tested 2 months and 26 months before their relapse. The unadjusted relative risk (RR) of relapse associated with a positive PCR assay compared with a negative assay was 5.7 (95% confidence interval 1.2 to 26.0, P = .025). In addition, the data suggest that the type of bcr-abl chimeric mRNA detected posttransplant was associated with the risk of relapse: 7 of 10 patients expressing the p190 bcr-abl relapsed, compared with 1 of 8 who expressed only the p210 bcr-abl mRNA (P = .02, log-rank test). The RR of p190 bcr-abl positivity compared to PCR-negative patients was 11.2 (confidence interval 2.3-54.8, P = 0.003), whereas a positive test for p210 bcr-abl was apparently not associated with an increased relative risk. In separate multivariable models, PCR positivity remained a statistically significant risk factor for relapse after separately adjusting for donor (unrelated and partially matched v matched, autologous, and syngeneic), remission status at the time of transplant, the presence of acute graft-versus-host disease (GVHD), and type of conditioning regimen (total body irradiation dose of < or = 1,200 cGy v > 1,200 cGy). The PCR assay appears to be a useful test for predicting patients at high risk of relapse after BMT and may identify patients who might benefit from therapeutic interventions. The finding that the expression of p190 bcr-abl may portend an especially high risk of relapse suggests a different clinical and biologic behavior between p190 and p210 bcr-abl.

Acute Disease↗
PubMed1997

Advances in the detection of minimal residual disease.

The study of minimal residual disease (MRD) is an attempt to detect and define the significance of leukemia invisible to normal morphologic examination. In many circumstances the clinical significance of MRD detection is unclear, because the technical ability to detect and quantify it has outpaced studies demonstrating its clinical significance. The detection of minimal residual disease most consistently has been associated with relapse in acute lymphoblastic leukemia, t(15;17) acute myeloid leukemia, and chronic myeloid leukemia post-transplant, especially after T-cell depletion. But, in many types of leukemia, including acute myeloid leukemia and acute lymphoblastic leukemia, MRD can be detected in long-term remission patients without subsequent relapse. The study of MRD is evolving from detecting residual disease and predicting relapse to the study of the mechanisms that explain how minimum residual disease can coexist in a "cured" patient.

Hematologic Neoplasms↗
PubMed1996

Unusual expression of mRNA typical of Philadelphia positive acute lymphoblastic leukemia detected in chronic myeloid leukemia.

The Philadelphia chromosome (Ph) is found in both chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The Ph translocation, t(9;22)(q34;q11), can disrupt the BCR gene on chromosome 22 in one to two areas called the major (Mbcr1) and minor (mbcr1) breakpoint cluster regions. In CML the breakpoint has been mapped almost exclusively to Mbcr1, whereas in Ph positive ALL both Mbcr1 and the upstream mbcr1 breakpoints have been described. In this communication we describe an unusual patient with typical chronic phase Ph positive CML and evidence of the uncharacteristic mbcr1 breakpoint, predicting expression of the ALL-type p190 fusion protein. Fluorescence in situ hybridization demonstrated BCR gene rearrangement, the reverse transcription polymerase chain reaction detected the BCR-ABL fusion mRNA characteristic of the mbcr1 breakpoint, and failed to detect BCR-ABL mRNA characteristic of the Mbcr1 breakpoint. Southern blot analysis revealed no rearrangement in Mbcr1, and direct sequencing of the PCR product confirmed it to be the ALL-type mbcr1 fusion mRNA with the first exon of the BCR gene fused to ABL exon a2. This case differs from the previously reported cases of "p190" CML in that the patient presented without abnormal hematopoietic features other than those found in typical CML and provides further evidence that the p190 mRNA is not sufficient to cause an acute rather than chronic leukemia.

Base Sequence↗
PubMed1996

A family inheriting different subtypes of acute myelogenous leukemia.

Rare inherited cancer syndromes have proven invaluable for the identification of genes involved in the more frequent corresponding noninherited cases. We report on a family with an adult onset, incompletely penetrant, autosomal dominant syndrome of myelodysplasia and acute myelogenous leukemia, affecting at least eight, and probably ten, individuals from three generations. The patients have developed leukemias differing in morphologic subtype, tumor cytogenetics, and abruptness of presentation. Some have presented with acute onset and others with protracted myelodysplasia. This family does not have an unusual incidence of other malignancies; however, one person at 50% risk of inheriting this gene developed atypical mycobacterium infection in the absence of leukemia, but also without appreciable risk factors for acquired deficiencies in cellular immunity. Features common to affected family members, including the individual with mycobacterium infection, are the early presence in the bone marrow of red cell and platelet maturation defects. A search for mutations in diseased marrows fails to detect abnormalities of p53 or N-ras. Two of the affected family members, third degree relatives, have co-inherited a constitutional chromosomal banding variation of 9p21-22, potentially suggesting linkage to this locus. The variable penetrance and expressivity of this syndrome support a multistep model of leukemia evolution, in which the gene defined by this family's syndrome is the signal step.

Adolescent↗
PubMed1996

Detection of minimal residual disease in acute and chronic leukemias.

The study of minimal residual disease is an attempt to redefine the concept of remission. Opinion as to the clinical utility of minimal residual disease is still in evolution. It has become clear that the ability to merely detect minimal residual disease by the polymerase chain reaction amplification of the molecular "fingerprint" of a leukemia does not always foretell relapse. Rather, careful consideration must be taken of the context of the type of disease, the molecular lesion itself, and the type of therapy employed. Thus although the detection of minimal residual disease in acute lymphoblastic leukemia or acute promyelocytic leukemia has a high correlation with relapse, detection of minimal residual disease in t(8;21) acute myelogenous leukemia has little correlation with relapse. In some diseases (eg. chronic myeloid leukemia) the clinical relevance of minimal residual disease detection may be strengthened by quantification, although this in itself introduces another level of complexity and potential pitfalls. Nevertheless, we are moving toward the day when the molecular definition of disease status will guide therapy.

Acute Disease↗
PubMed1995

Benign marrow progenitors are enriched in the CD34+/HLA-DRlo population but not in the CD34+/CD38lo population in chronic myeloid leukemia: an analysis using interphase fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) was used to discriminate between benign and malignant cells in sorted populations of chronic myelogenous leukemia (CML) marrow. FISH has the advantage of allowing for a cell by cell analysis of the breakpoint cluster region (BCR) gene rearrangement immediately after flow sorting in nondividing G0/G1 cells that are potentially transcriptionally inactive. We initially selected CD34+ cells with very low expression of the activation antigen CD38 as a candidate phenotype for an immature and hypothetically more benign cell population, but found no enrichment for Ph negativity in that subtype. In five CML samples, 55% +/- 3.3% (mean +/- SE) of CD34+/CD38hi cells had the BCR gene rearrangement, similar to 57% +/- 3.7% seen in the CD34+/CD38lo population. In contrast, subsequent experiments (n = 4) determined that the CD34+/HLA-DRlo population in CML marrow does contain an increased proportion of benign cells: 15% +/- 1% of the CD34+/DRlo cells were BCR rearranged, compared with 52% +/- 5.8% of the CD34+/DRhi cells (P = .001). Our results indicate that benign progenitors in CML are enriched within the CD34+ cells with low DR antigen expression, but not low CD38 expression. One possible interpretation of these observations is that low CD38 antigen expression is not as useful as low HLA-DR expression for isolating immature cells.

ADP-ribosyl Cyclase↗
PubMed1995

Minimal residual disease.

The study of minimal residual disease has been fueled by the technologic advent of the polymerase chain reaction and basic developments identifying the genetic lesions involved in human malignancies. Thus far advances in identifying, cloning, and the subsequent polymerase chain reaction amplification of relevant genes have outpaced clinical studies designed to tell us the significance of minimal residual disease. It has become clear that the mere detection of minimal residual disease does not foretell relapse; thus, although the presence of minimal residual disease in acute lymphoblastic leukemia and acute prolymphocytic leukemia appears to be associated with a high risk of relapse, the presence of minimal residual disease in t(8;21) acute myeloid leukemia, chronic myeloid leukemia, and t(14;18) non-Hodgkin's lymphoma is not clearly associated with impending relapse. In most situations there is clearly a need for carefully controlled studies to evaluate the predictive value of minimal residual disease.

Acute Disease↗
PubMed1995

Multiplex PCR of bcr-abl fusion transcripts in Philadelphia positive acute lymphoblastic leukemia.

We describe a multiplex PCR assay for the detection of bcr-abl fusion mRNA in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). The assay provides a quick method for screening p190 (e1:a2) and p210 (b2:a2 or b3:a2) bcr-abl mRNAs simultaneously. The assay proves to be highly sensitive with detection of as little as one positive bcr-abl-expressing cell in a background of 10(5) negative bcr-abl cells. Bone marrow and peripheral blood specimens from six patients were in total accordance when run by multiplex PCR and by the single primer PCR approach. The multiplex bcr-abl assay may prove to be highly useful for screening newly diagnosed patients with ALL for the bcr-abl fusion transcript and in following the course of disease during therapy.

Base Sequence↗
PubMed1995

Bone marrow transplantation for chronic myelogenous leukemia.

Based on our understanding of CML, we recommend that patients age 65 or less with newly diagnosed CML should be evaluated to determine the stage of their disease and should be human lymphocyte antigen-typed along with their siblings. Patients age 55 years and younger who have matched or single antigen mismatched siblings should be advised to undergo BMT as soon as possible and patients up to age 65 should be considered for BMT early in their disease course if in good health. Patients age 55 years or younger without appropriately matched family member donors should have a search for an unrelated donor initiated and should be offered BMT if an appropriate donor is found. Patients for whom no donor is found and older patients without family matches can be considered for entry onto clinical trials evaluating autologous BMT or other experimental approaches.

Aged↗
PubMed1995

Polymerase chain reaction-based detection of minimal residual disease in acute lymphoblastic leukemia predicts relapse after allogeneic BMT.

We studied 20 patients who had received allogeneic bone marrow transplants for acute lymphoblastic leukemia. Using the polymerase chain reaction (PCR), we examined them for the presence of immunoglobulin heavy chain variable-diversity-junctional (IgH V-D-J) gene rearrangements as a marker of minimal residual disease (MRD). Seventeen of the patients were transplanted in relapse or for primary refractory disease, and three were transplanted in "high risk" remission. Thirteen patients had at least one positive PCR assay for MRD in the first 100 days after transplant; two died of nonleukemic causes, while all the remaining 11 relapsed. Seven patients had all negative PCR assays; two died of nonleukemic causes, four remain alive and well, and one patient with consistently negative PCR assays relapsed 47 days after his last negative test. Considering PCR status as a time-dependent covariate, the relative risk of relapse for PCR-positive patients compared to PCR-negative patients is 6.4 (p = 0.0067; 95% CI, 1.6-24.4), and the relative risk of relapse or death is 4.8 (p = 0.0052; 95% CI, 1.6-14.2). The Kaplan-Meier estimate of relapse at 1 year for PCR-positive patients is 100% compared to 33% for PCR-negative patients. The estimate for disease-free survival at 1 year for PCR-positive patients is 0% compared to 44% at 3 years for the PCR-negative group. The PCR assay for MRD appears to be a sensitive and specific test, identifying patients at high risk of relapse following allogeneic BMT who might benefit from further therapeutic interventions.

Adolescent↗