melphalan and Chromosome-Deletion

Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S+VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P = .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade ≥3 adverse-event incidence was 92% on S+VMP and 81% on VMP (P = .09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.gov as #NCT00911859.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chromosome Deletion; Chromosomes, Human, Pair 17; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunoglobulin A; Interleukin-6; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pyrazines; Survival Rate

The prognostic value of chromosomal abnormalities was studied in untreated multiple myeloma patients who were registered into a prospective randomised multicentre phase 3 study for intensified treatment (HOVON24). A total of 453 patients aged less than 66 years with stage II and III A/B disease were registered in the clinical study. Cytogenetic analysis was introduced as a standard diagnostic assay in 1998. It was performed at diagnosis in 160 patients and was successful in 137/160 patients (86%). An abnormal karyotype was observed in 53/137 (39%) of the patients. Abnormalities of chromosome 1p and 1q were found in 19 (36% of patients with an abnormal karyotype) and 21 patients (40%). There was a strong association between chromosome 1p and/or 1q abnormalities and deletion of chromosome 13 or 13q (n = 27, P < 0.001). Patients with karyotypic abnormalities had a significantly shorter overall survival (OS) than patients with normal karyotypes. Complex abnormalities, hypodiploidy, chromosome 1p abnormalities, chromosome 1q abnormalities, and chromosome 13 abnormalities were associated with inferior OS on univariate analysis, as well as after adjustment for other prognostic factors. In conclusion, chromosome 13 abnormalities and chromosome 1p and/or 1q abnormalities were highly associated, and are risk factors for poor outcome after intensive therapy in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 13; Cyclophosphamide; Dexamethasone; Doxorubicin; Epidemiologic Methods; Female; Humans; Karyotyping; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prognosis; Treatment Outcome; Vincristine

The combination of high levels of beta2-microglobulin (beta2-m) and chromosome 13 deletion allows identification of a high-risk subgroup of patients with de novo multiple myeloma (MM). In this population of patients, we have evaluated the impact of a murine anti-interleukin 6 (anti-IL-6) monoclonal antibody (BE-8) as part of the second conditioning regimen in a multicenter prospective randomized trial of tandem autologous stem cell transplantation (ASCT). Conditioning for the first ASCT was accomplished with melphalan 200 mg/m2 and for the second one with melphalan 220 mg/m2 plus dexamethasone with or without BE-8 infusion. This trial included 219 patients, of whom 166 were randomized, 85 without BE-8 (arm A) and 81 with BE-8 (arm B). The median overall survival (OS) and event-free survival (EFS) times of the whole group of patients were 41 and 30 months, respectively. Response rates, OS, and EFS were not different between the 2 arms of the trial. OS at 54 months was 46% in arm A and 51% in arm B (P = .90); median EFS was 35 months in arm A and 31 in arm B (P = .39). In high-risk patients the dose intensity of melphalan at 420 mg/m2 led to encouraging results, but the addition of anti-IL-6 monoclonal antibody to the second conditioning regimen did not improve either OS nor EFS.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Chromosome Deletion; Chromosomes, Human, Pair 13; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-6; Male; Melphalan; Middle Aged; Multiple Myeloma; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

High-dose therapy (HDT) has increased complete remission (CR) rates and survival in multiple myeloma (MM). We now report on continuous CR (CCR) and associated prognostic factors in 1000 consecutive patients receiving melphalan-based tandem HDT. Five-year CCR was 52% among 112 CR patients without chromosome 13 (triangle up13) abnormalities and with beta-2-microglobulin

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 13; Disease-Free Survival; Humans; Melphalan; Middle Aged; Multiple Myeloma; Survival Rate; Time Factors

Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters.. A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p).. We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients.. Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chemotherapy, Adjuvant; Chromosome Deletion; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 4; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; France; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization, Fluorescence; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Neoadjuvant Therapy; Prospective Studies; Protease Inhibitors; Pyrazines; Time Factors; Translocation, Genetic; Treatment Outcome; Vincristine

A 45-year-old woman was referred to our hospital with acute renal failure and pyrexia. In August 2005, the patient was diagnosed with IgA-λ type multiple myeloma with chromosome 13 deletion, and received three cycles of vinclistine, adriamycin and dexamethasone followed by high-dose melphalan-based autologous peripheral stem cell transplantation: this resulted in remission 2 months before admission to our hospital. Serum IgA concentration was within the normal limit, but an excess of myeloma cells in bone marrow was confirmed. Immunoelectrophoresis revealed BJP-λ production with no IgA-λ. The patient received several courses of chemotherapy with mechanical ventilation and regular hemodialysis. The progression of the illness was rapid: multiple organ failure promptly developed and the patient died 2 months after admission. Autopsy revealed deposition of light chain λ protein in multiple organs. We report this unusual case of aggressive myeloma recognized shortly after successful autologous transplantation.

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 13; Dexamethasone; Doxorubicin; Female; Fever; Humans; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Remission Induction; Transplantation, Autologous; Vincristine

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common treatment for patients under 65 years of age with multiple myeloma (MM). In this study, we present a retrospective analysis of the prognostic impact of different factors in patients who have received this treatment as first line therapy in our centre. Abnormalities in chromosome 13 were identified by fluorescence in situ hybridization at the time of diagnosis. The median overall survival (OS) and progression-free survival (PFS) from transplantation time in the whole group of 193 patients were 90 and 48 months respectively. The median follow-up was 65 months (range: 6-186 months). The complete remission (CR) rate in patients with and without del(13) was 31 and 40% respectively whereas the median OS in patients with del(13) was 58 months but not reached in patients without del(13) (p=0.006). The PFS was 26 months in patients with del(13) and 84 months in those without del(13) (p=0.001). The transplantation related mortality was 2.5% both in the absence and presence of del(13). Patients who achieved CR following ASCT had longer OS and PFS when compared to those who only achieved partial remission. Thus, this study confirms the role of del(13) as a marker of poor prognosis. Multivariate analysis showed that the existence of del(13) was the only single independent factor effecting survival (p=0.001). In patients without del(13), the prognostic impact was even stronger when combined with the plasma cell load in the bone marrow (p=0.020), whereas the plasma cell load had no effect on survival of patients with del(13). Overall, the absence of del(13) in combination with low plasma cell infiltration at diagnosis predicts the best survival.

Topics: Adult; Aged; Chromosome Deletion; Chromosomes, Human, Pair 13; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Patient Selection; Plasma Cells; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Stem Cell Transplantation; Survivors; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

In this report, the authors describe their collective experience with melphalan-based autotransplants since the inception of their program at the University of Arkansas for Medical Sciences in 1989.. The authors evaluated the clinical outcomes of 3077 successive patients with multiple myeloma (MM) who underwent at least 1 melphalan-based autotransplantation at the University of Arkansas. Of these, 1078 patients were enrolled on front-line Total Therapy (TT) protocols (TT-P) TT1, TT2, and TT3; 1104 patients were entered on protocols for newly diagnosed or previously treated patients (non-TT-P); and 895 patients were treated off protocol (non-P).. The 10-year overall survival (OS) rates after first transplantation were 41%, 19%, and 11% (P< .001) for the TT-P, non-TT-P, and non-P groups, respectively. In the TT-P group, the median OS was 72 months on TT1, was not reached at >or= 7 years on TT2, and was 88% at 2 years on TT3. Among 2683 patients with complete baseline data, absence of hypodiploidy/chromosome 13 deletion, beta-(2)-microglobulin <3.0 mg/L, C-reactive protein <6 mg/L, albumin >or= 3.0 g/dL, and platelet count >or= 100,000/microL all were associated independently with superior OS (P< .001), event-free survival (P< .001), and duration of complete remission (P< .001).. The results from this large, single-institution experience demonstrated that >10-year OS was accomplished in >40% of all patients enrolled on TT-P, whereas such success was observed in only 15% of the remaining patients (including 25% in the presence of all 5 good-risk features). Superior outcomes with protocol-based, primary transplant regimens such as TT-P draw attention to the importance of applying the best available therapies upfront.

Topics: Aged; Antineoplastic Agents, Alkylating; Arkansas; beta 2-Microglobulin; C-Reactive Protein; Chromosome Deletion; Chromosomes, Human, Pair 13; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Myeloablative Agonists; Platelet Count; Ploidies; Remission Induction; Serum Albumin; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 17; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization, Fluorescence; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Prognosis; Remission Induction; Risk Factors; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse impact on the outcome in myeloma patients. A wide spectrum of abnormalities involving chromosomes 1, 13, 14, and 17 has been described. We analyzed the outcome of 83 patients with clonal cytogenetic abnormalities, who underwent high-dose therapy and autologous stem cell transplantation for multiple myeloma at our institution. Clonal abnormalities were detected at diagnosis by conventional cytogenetic analysis in 83 patients. Patients underwent a single autologous transplant between April 2000 and May 2005. Preparative regimen was high-dose melphalan alone (73), or a combination of topotecan, melphalan, and cyclophosphamide (TMC=10). The most commonly observed chromosomal abnormalities were deletion of chromosome 13 (32%), hyperdiploidy (21%), deletion of chromosome 1p (18%), and t (11; 14) in 7% patients. Median follow-up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range: 2.5-52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with deletion 1p (P=.001 and <.0001, respectively). Thirty-two patients whose cytogenetic abnormalities returned to normal prior to autotransplant had longer PFS and OS than patients with persistent abnormalities (P=.02 and .08, respectively). Deletion 1p is associated with a significantly shorter remission and survival in patients undergoing high-dose therapy and a single autologous transplant for myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 1; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Predictive Value of Tests; Prognosis; Transplantation, Autologous

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. It is well known that alkylating agents are capable of inducing myelodysplastic syndromes (MDS) and acute myelocytic leukemias (AML). This risk of both diseases in patients with multiple myeloma has been estimated to be 10-20% after 10 years. We aimed to evaluate the time course and the type of genetic abnormalities in melphalan-treated patients in the chronic stage of the disease. We applied fluorescence in situ hybridization methods with probes to 5q31 and 7q31 to mononuclear peripheral blood leukocytes of 18 melphalan-treated patients and compared the results to those of 8 untreated myeloma patients. We found three patients (17%) with a 5q31 deletion in their peripheral white blood cells, but no 7q31 deletion. These findings suggest that 5q- occurs before the overt development of MDS/AML and raise important concerns regarding long-term treatment of myeloma patients with alkylating agents. Also, the performance of cytogenetic evaluation should be considered before autologous transplantation. The clinical and biological implications of these findings should be evaluated in larger clinical and laboratory studies.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chromosome Deletion; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Female; Humans; In Situ Hybridization, Fluorescence; Male; Melphalan; Middle Aged; Multiple Myeloma; Time Factors

The risk of myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) in patients with multiple myeloma has been estimated to be 10-20% after 10 years. Most myeloma patients develop MDS/AML after 3-4 years of treatment with alkylating agents, mainly melphalan; chromosomes 5 and 7 are most frequently involved. We studied 14 patients with myeloma by fluorescence in situ hybridization (FISH) with a probe to 5q31 (the critical area of deletion on chromosome 5) to verify whether deletion of 5q31 occurs during the course of stable, uncomplicated myeloma, and to assess the clinical importance of this abnormality. We found 2 patients (14%) with deletion of 5q31 in 30-40% of their peripheral white blood cells. One patient with this deletion received a high cumulative amount of melphalan, and the other patient was treated with multiple alkylating agents, including melphalan. In these patients, no clinical or laboratory evidence of transformation occurred 14 and 12 months after the finding of the aberration. These findings suggest that 5q-may occur months prior to the overt development of (t)-MDS/AML, and raise important concerns regarding the management of patients with this and similar aberrations, including modification of treatment and performance of cytogenetic evaluation prior to autologous or PSC transplantation. The clinical and biological implications of these findings should be evaluated in larger clinical and laboratory studies.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinogens; Chromosome Deletion; Chromosomes, Human, Pair 5; Female; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Time Factors

A multiple myeloma patient presented for cytogenetic analysis at diagnosis of secondary MDS, which followed cytotoxic treatment including melphalan. Two abnormal unrelated clones were detected, one of them had 5q-, 7q- with clonal evolution of an additional aberration, t(12;13); in the second clone there was a translocation between the two homologues of chromosome 1 as the only aberration. We suggest that the clone with 5q- and 7q- represented the secondary MDS cells, whereas the abnormal clone with t(1;1) represented the plasmablasts of the multiple myeloma.

Topics: Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Humans; Karyotyping; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Translocation, Genetic

The chromosomes of 111 ovarian cancer patients were studied in G- and C-banded slides from peripheral blood lymphocyte (PBL) cultures for chromosome damage caused by chemotherapy and radiotherapy and for asymmetry of the constitutive heterochromatin of chromosomes 1, 9, and 16. We also monitored the survival of these patients to determine whether any secondary neoplasia induced by the therapy and report the findings of our investigations. Melphalan (MEL) was the only drug used in single-drug chemotherapy. The incidence of chromosome abnormalities in melphalan-treated cells (25%) was higher than in the control group (17%). The incidence of structural changes was also higher (10.5%) in the MEL-treated group than in controls (6%). After treatments with combinations of drugs, the incidence of structural changes remained at the same level (11%). In the patients receiving combined treatment with MEL and radiation, the rate of structural changes increased dramatically (24%). The overall rate of chromosome aberrations in this group was also higher (50%). Combination of two or more drugs and radiation produced only 14% structural chromosome changes. The overall rate of chromosome aberrations was also low (20%) in this group. Of 111 patients studied, only 33 were alive 6 years after initiation of the study. Of the surviving patients, eight had rearranged chromosomes in the first analysis. After 5 years, new blood samples were collected from these patients and chromosome analyses showed abnormal karyotypes in all eight patients. All chromosome abnormalities in the second analysis were completely unrelated to those in the first analysis, however. Whether the chromosome changes in the second analysis were due to therapy or to other unknown factors could not be determined. Data on C-banding and the distribution of inversions indicated that 91% of the patients had C-band heteromorphisms of chromosomes 1, 91% had heteromorphisms of chromosome 9, and 69% had heteromorphisms of chromosome 16. Furthermore, inversions were observed in chromosome 1 (41% of patients), chromosome 9 (28% of patients), and chromosome 16 (5% of patients).

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Chromosome Aberrations; Chromosome Deletion; Chromosome Inversion; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 9; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Heterochromatin; Humans; Karyotyping; Melphalan; Methotrexate; Middle Aged; Mitomycins; Neoplasms, Second Primary; Ovarian Neoplasms; Radiotherapy; Translocation, Genetic; Vincristine

Specific-locus experiments have previously shown melphalan to be mutagenic in all male germ-cell stages tested and particularly so in early spermatids. All but 2 of 24 specific-locus mutations recovered were tested genetically, cytogenetically, and/or molecularly. At least 12 of 15 tested mutations recovered from postspermatogonial stages but only 1 of 7 mutations recovered from stem-cell or differentiating spermatogonia gave evidence of being deletions or other rearrangements. Melphalan-induced mutations, thus, confirm the pattern of dependence of mutation structure on germ-cell stage that had been shown earlier for other chemicals. Results of the present investigation illustrate the capabilities of combined genetic, cytogenetic, and molecular analyses for characterizing the nature of specific-locus mutations. Fine-structure molecular mapping of long regions surrounding specific loci has been greatly facilitated by the availability of genetic reagents (particularly, deletion complexes) generated in specific-locus experiments over the course of decades. Reciprocally, this mapping permits increasingly detailed characterization of the nature of lesions induced by mutagenic exposures of germ cells, adding great powers for qualitative analysis of mutations to the specific-locus test. Cytogenetic and genetic investigations also provide evidence on lesion type, especially for loci at which mutations cannot yet be analyzed molecularly. Melphalan, like chlorambucil, can generate many mutations, a high proportion of which are deletions and other rearrangements, making this chemical valuable for generating mutations (at any locus) amenable to molecular access.

Topics: Animals; Chromosome Banding; Chromosome Deletion; Gene Rearrangement; Male; Melphalan; Mice; Mutagenesis; Mutagens; Polymorphism, Restriction Fragment Length; Spermatogenesis; Spermatogonia

The unusual behaviour of the 9q1 human chromosome region is studied in various conditions. In controls with normal chromosomes 9, del(9q1) is the most frequent spontaneously occurring deletion. This deletion is highly inducible by melphalan, an S phase-dependent alkylating agent. This may correspond to the uncovering of pre-existing DNA breaks in this region. In a 46,XX,9qh+ control, melphalan does not induce deletions any more efficiently than in donors with normal chromosomes 9. In a 46,XY,inv(9) (p11q1205) donor, all deletions of inv(9) affect the short, but not the long, arm. This indicates that the sensitive segment is not the whole heterochromatic region, but rather a limited structure. The high rate of rearrangements affecting this structure may be responsible for somatic crossing over, leading to loss of heterozygosity for 9q, and to the frequent occurrence of inv(9) in human populations.

Topics: Cells, Cultured; Chromosome Deletion; Chromosome Fragility; Chromosomes, Human, Pair 9; DNA Damage; Female; Gene Rearrangement; Heterochromatin; Humans; Karyotyping; Lymphocytes; Male; Melphalan

Alkalating chemotherapeutic agents are frequently implicated in the development of acute non-lymphocytic leukemia. A case report illustrates the danger of administering a prolonged course of adjuvant chemotherapy with Melphalan following mastectomy for breast cancer.

Topics: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Chromosome Deletion; Chromosomes, Human, Pair 7; Female; Humans; Leukemia, Myelomonocytic, Acute; Melphalan; Middle Aged; Risk Factors; Time Factors

Chromosome lesions detected in lymphocytes from 14 patients previously treated with melphalan, a bifunctional alkylating agent, have been analyzed on R-banded preparations. In comparison to controls, there was no significant increase of chromatid-type lesions, but chromosome-type lesions were quite frequent, affecting 21.5% of metaphases, on the average. Reciprocal translocations represent 54%, unbalanced translocations 15%, deletions 19% and inversions 6% of all rearrangements. Most of these would not have been detected without the use of chromosome banding. The distributions of affected chromosomes and chromosome bands were not random. Almost all imbalances resulting from rearrangements lead to losses but not to gains. The distribution of the abnormal chromosomes has been compared to that observed in controls and in in vitro experiments, and to the characteristic pattern of malignant cells from patients affected by secondary acute leukemia (ANLL).

Topics: Breast Neoplasms; Chromosome Aberrations; Chromosome Banding; Chromosome Deletion; Chromosome Inversion; Humans; Lymphocytes; Lymphoma; Melphalan; Translocation, Genetic

Topics: Aged; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 7; Female; Humans; Male; Melphalan; Middle Aged; Monosomy; Multiple Myeloma; Myelodysplastic Syndromes; Uterine Cervical Neoplasms

Among 20 patients with acute nonlymphocytic leukemia or dysmyelopoietic preleukemia secondary to Alkeran therapy for another tumor, four had a del(12)(p11-p12) and four had a translocation to 19q13 among multiple karyotypic alterations in their neoplastic hematopoetic clones. It is suggested that these two cytogenetic abnormalities may occur nonrandomly in such hemic disorders and may play a limited role in their pathogenesis.

Topics: Chromosome Deletion; Chromosomes, Human, 19-20; Chromosomes, Human, 6-12 and X; Humans; Leukemia; Melphalan; Preleukemia; Translocation, Genetic

A variant of the MPC 11 cell line, M 311, produces a short immunoglobulin heavy chain. When compared with the parental gamma 2b heavy chain, M 311 was found to have a carboxyl terminal deletion comprising the CH3 domain. The COOH-terminal cyanogen bromide (CNBr) cleavage fragment of M 311 is identical to a corresponding segment ofa parental heavy chain CNBr fragment, with the exception of a substitution of asparagine for lysine at the COOH-terminal residue. This observation enabled prediction of both the parental DNA sequence in this region and the genetic mechanism which generated the variant, a frameshift followed by premature termination. This hypothesis is supported by studies of the DNA sequence of the MPC 11 gamma 2b constant region gene.

Topics: Animals; Cell Line; Chromosome Deletion; Genes; Immunoglobulin G; Immunoglobulin gamma-Chains; Macromolecular Substances; Melphalan; Mice; Mutation; Myeloma Proteins; Neoplasms, Experimental; Peptide Chain Termination, Translational; Plasmacytoma