Leukocyte recovery and early treatment-related mortality after bone marrow transplantation.
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Bone Marrow Transplantation↗
Biomedical subjects
S Singhal
Publications and source records attributed to S Singhal.
Prospective, concurrent comparison of the Cobe Spectra and Haemonetics MCS-3P cell separators for leukapheresis after high-dose filgrastim in patients with hematologic malignancies.
A prospective study was undertaken to compare the mononuclear cell, CD34+ cell, and CFU-GM yields of the Haemonetics MCS-3P and the Cobe Spectra cell separators in ten patients (nine multiple myeloma and one non-Hodgkin lymphoma) on two consecutive days after mobilization with high-dose filgrastim (12-16 micrograms/k) for 4 days. All patients were harvested once on each machine, five starting on each machine. The target duration of the procedure on the Spectra was 160 minutes, and the target blood volume processed on the MCS-3P was 60-70 ml/kg body weight. Both machines were operating on the 1995 software versions supplied by the respective manufacturers. The time taken for the procedure was significantly longer with the Haemonetics machine. The volumes of blood processed and the product collected were significantly higher with the Spectra, as were the absolute mononuclear and CD34+ cell yields, and yields per unit time. Mononuclear and CD34+ cell yields per unit volume of blood processed were comparable for both machines. The differences in CFU-GM yields were not significant, largely because of wide interpatient variations. The extent of platelet depletion as a result of the procedure was greater with the Spectra because of the higher blood volume being processed. We conclude that the Cobe Spectra is a significantly faster machine than the Haemonetics MCS-3P; and consequently, its use is associated with higher mononuclear and CD34+ cell yields.
Antigens, CD34↗
Comparison of marrow vs blood-derived stem cells for autografting in previously untreated multiple myeloma.
Sixty-three new untreated patients with multiple myeloma under the age of 70 years received C-VAMP induction treatment followed by high-dose intravenous melphalan (200 mg m(-2)) and autologous stem cell transplant, either with marrow [autologous bone marrow transplants (ABMT), n = 26] or with granulocyte colony-stimulating factor (G-CSF)-mobilized stem cells from the blood [peripheral blood stem cell transplants (PBSCT), n = 37]. This was a sequential study and the two groups were not significantly different for all known prognostic variables. The complete remission (CR) rate after high-dose treatment was the same for both groups [ABMT 84% and PBSCT 70%; P = not significant (NS)]. Neutrophil recovery to 0.5 x 10(9) l(-1) occurred at a median of 22 days in the ABMT patients compared with 19 days for the PBSCT patients (P = NS). Platelet recovery to 50 x 10(9) l(-1) was significantly faster in PBSCT patients (19 days vs 33 days; P = 0.0015), and the PBSCT patients spent fewer days in hospital (median 20 vs 27 days; P = 0.00001). There was no difference in the two groups with respect to starting interferon (58 days for ABMT vs 55 days for PBSCT), and tolerance to interferon was identical. The median overall survival (OS) and progression-free survival (PFS) for the PBSCT patients has not yet been reached. The OS in the ABMT patients at 3 years was 76.9% (95% CI 60-93%) compared with 85.3% (95% CI 72-99%) in the PBSCT patients (P = NS), and the PFS at 3 years in the ABMT patients was 53.8% (95% CI 34-73%) and in the PBSCT patients was 57.6% (95% CI 34-81%) (P = NS). The probability of relapse at 3 years was 42.3% in the ABMT arm compared with 40% in the PBSCT patients (P = NS). Thus, PBSCT patients had a faster engraftment and a shorter stay in hospital than ABMT; the survival outcome and probability of relapse was the same for both groups.
Adult↗
Early identification of patients at risk of death due to infections, hemorrhage, or graft failure after allogeneic bone marrow transplantation on the basis of the leukocyte counts.
Allograft recipients are often unwell with significant organ dysfunction by the time delayed or failed engraftment is diagnosed. We attempted to identify factors associated with graft failure, or death due to infection, hemorrhage or graft failure in 712 patients undergoing allogeneic BMT. Low leukocyte counts between days 12 and 22 were strongly associated with subsequent graft failure or death. In multivariate analysis, a leukocyte count of < or = 0.2 x 10(9)/l on day 16 was the most powerful predictor of graft failure or death. Transplants from HLA-mismatched and unrelated donors were also associated with increased risk of both, and T cell depletion with increased risk of graft failure. On the basis of these findings, it may be possible to define graft failure in functional terms as early as 2 weeks after BMT rather than at 3 or 4 weeks. The use of growth factors can then be limited to patients most likely to benefit from them, and it may be possible to salvage patients at risk of complications of low counts early before their clinical condition deteriorates. We suggest that patients with leukocyte counts of 0.2 x 10(9)/l or less 14-16 days after BMT should be started on G-CSF or GM-CSF even if they are clinically well, and consideration should be given to a second infusion of cells.
Adolescent↗
Outcome of acute leukemia relapsing after bone marrow transplantation: utility of second transplants and adoptive immunotherapy.
We studied 231 acute leukemia patients relapsing after allogeneic (n = 114) or autologous (n = 117) BMT to assess the outcome of further therapy. In general, all patients in good condition were eligible for second transplants except for post-allograft relapses from 1993-1994 onwards who received cytokine- or cell-mediated immunotherapy. The major reason for patients not progressing to second graft was death from progressive disease or toxicity of salvage chemotherapy. Seventeen of 231 patients (7%) were alive at the last follow-up. Six of 14 post-autograft relapses treated with second transplants were alive and well, compared with five of 103 not undergoing second grafts (P < 0.0001). One of 23 post-allograft recipients treated with second allografts was alive with an extramedullary relapse, compared with five of 13 receiving immunotherapy and none of 78 receiving standard-dose or palliative therapy (P < 0.0001). We conclude that only a small proportion of highly selected acute leukemia patients relapsing after a transplant reach the stage of a conventional second transplant. In our experience, second allografts after myeloablative therapy in patients relapsing after one allograft are associated with very poor results, and immunotherapy may be a better approach in such cases. Selected patients relapsing after an autograft may become long-term survivors following a second autograft or an allograft.
Acute Disease↗
Sensitivity of secondary acute myeloid leukemia relapsing after allogeneic bone marrow transplantation to immunotherapy with interferon-alpha 2b.
A patient with acute myeloid leukemia secondary to therapy of choriocarcinoma underwent T cell non-depleted allogeneic bone marrow transplantation from an unrelated donor in first untreated relapse. Persistent/relapsed leukemia 4 months after transplantation did not respond to cessation of cyclosporine. Due to logistic difficulties in obtaining donor leukocytes, she was treated with interleukin-2 and interferon-alpha 2b. Although the interleukin could be administered for a short period only, the interferon was continued for 4 months. Interferon was stopped when limited chronic graft-versus-host disease developed, but was followed by extramedullary and early marrow relapse. Reinstitution of interferon resulted in the development of scleroderma-like extensive chronic GVHD and remission. Interferon was given for 5 months. GVHD improved slowly with treatment, but scleroderma-like changes still persist. The patient is alive with no evidence of disease and a Karnofsky score of 90% 41 months after relapse and 26 months after stopping cyclosporine. We conclude that cytokines alone may occasionally result in a durable response of acute leukemia relapsing after allografting, and should be considered in patients with a low tumor burden if it is difficult to obtain donor cells.
Adult↗
Amphotericin B lipid complex (ABLC) for the treatment of confirmed or presumed fungal infections in immunocompromised patients with hematologic malignancies.
Sixty-four adult patients (median age 43) with hematologic malignancies who were immunocompromised after allogeneic (n = 23) or autologous (n = 9) blood/marrow transplantation, or chemotherapy (n = 32) received 68 courses of amphotericin B lipid complex (ABLC, Abelcet) at the daily dose of 5 mg/kg for presumed (n = 52) or proven (n = 16) fungal infection. The major indications for ABLC were failure of previous antifungal therapy and/or renal dysfunction. Fifty-three treatment courses in 49 patients comprising 4-58 doses (median 10) were considered evaluable. Fourteen courses administered for confirmed infections resulted in nine complete and one partial responses, and four failures (71% response). Thirty-nine empiric courses resulted in 18 complete and six partial responses, and 14 failures (64% response). The overall response rate was 66%. Five of seven evaluable patients with aspergillus pneumonia responded. Response rates were comparable for chemotherapy, autograft and allograft recipients. The change in serum creatinine from the beginning to the end of therapy was -284 to +277 mumol/l (median +24). The creatinine doubled during seven evaluable courses of therapy, five of which were associated with concomitant nephrotoxic therapy. Nephrotoxicity was comparable for transplant and chemotherapy patients. Renal dysfunction necessitated discontinuation of ABLC in only four patients. These data suggest that ABLC is effective in presumed or confirmed fungal infections in immunocompromised patients after transplantation or chemotherapy.
Adolescent↗
High-dose chemotherapy with carboplatin, cyclophosphamide and etoposide and autologous transplantation for multiple myeloma relapsing after a previous transplant.
Eighteen extensively pre-treated patients (35-73 years, median 46) with relapsed multiple myeloma received salvage chemotherapy with 6 g/m2 cyclophosphamide, 800 mg/m2 carboplatin, and 1800 mg/m2 etoposide (CCV) as a 96-h continuous infusion followed by autologous peripheral blood stem cells. The median number of prior chemotherapy regimens was five (range 4-10), including at least one autograft. Four patients died of toxicity, and one developed dialysis-dependent renal failure, while the others tolerated CCV well. Three of six patients with pre-transplant creatinine of > 1 mg/dl died of toxicity compared with one of 12 with creatinine < or = 1 mg/dl (P = 0.083, Fisher's exact test). Three of four patients treated with four previous regimens showed > 50% reduction in tumor compared with one of 14 treated with > 4 regimens (P = 0.02, Fisher's exact test). At the last follow-up, five patients were alive at 8-24 months (median 13) with stable (n = 1) or progressive (n = 4) disease, and nine had died of progressive disease at 2.5-15 months (median 7). We conclude that CCV chemotherapy with autografting is tolerated well by extensively pre-treated myeloma patients provided the pre-transplant creatinine is normal, but toxicity in patients with abnormal renal function is high. The efficacy in multiply relapsed disease is poor, with response in only 22% of patients. CCV may deserve further evaluation early in the course of myeloma in patients with normal renal function.
Adult↗
Induction of graft-versus-host disease as immunotherapy of leukemia relapsing after allogeneic transplantation: single-center experience of 32 adult patients.
Thirty-two adults (median age 36 years) with leukemia (15 AML, eight CML, six ALL, three CLL) persisting or relapsing 1-40 months (median 4) after allogeneic BMT (20 matched siblings, eight unrelated, four family mismatch) underwent immunotherapy to elicit GVHD. This comprised one or more of: infusion of donor cells (n = 22), stopping cyclosporine (n = 14), and administration of interferon-alpha2b (n = 15) or interleukin-2 (n = 4). Eight acute leukemia patients received chemotherapy as well. The time from relapse to immunotherapy was 0-1344 days (median 4). Acute and/or chronic GVHD developed in 17 patients. Response was not evaluable in three patients due to early toxic death. There was no response in 10 patients, whereas 19 showed objective response. Nine patients died due to toxicity and 10 due to progressive disease. Thirteen patients are alive 4-58 months (median 14) after immunotherapy; 12 in remission (five AML, four chronic phase CML, one ALL, one accelerated phase CML, one CLL) and one with progressive disease (accelerated phase CML). Eleven of 13 patients who are alive had GVHD compared with six of 19 who died (P = 0.005, Fisher's exact test). We conclude that with the exception of CML in myeloid blast crisis, immunotherapy is active in most types of acute and chronic leukemia relapsing after allogeneic BMT. It is associated with considerable toxicity. Clinically obvious GVHD, especially chronic GVHD, results in a higher probability of survival.
Acute Disease↗
Outcome assessment of a population-based group of 195 unselected myeloma patients under 70 years of age offered intensive treatment.
A single centre series of 195 consecutive newly diagnosed untreated myeloma patients under 70 years, seen between September 1986 and March 1994, were analysed to assess the impact of current intensive treatment methods upon remission rate, response rate and subsequent outcome. They were predominantly an unselected population based group of patients (other than by age) that could be used by purchasers of health care as a model for outcome assessment. All patients were scheduled to receive a care plan which included a sequential package of treatment consisting initially of courses of infusional chemotherapy using vincristine, adriamycin and methyl prednisolone (VAMP) and 90 of these also received cyclophosphamide (C-VAMP). Thirty-eight patients received verapamil in addition to C-VAMP(V-C-VAMP). After VAMP all patients were planned to receive high-dose treatment with melphalan and an autograft (marrow or blood) and 112 received this treatment; a further 29 patients received modified high-dose treatment with melphalan alone (23) or busulfan (6) and 54 (28%) did not proceed to high-dose treatment because of refusal, resistant disease, poor performance or treatment-related death. The patients who received melphalan or busulfan alone instead of high-dose melphalan/autografts did so because of increasing age (P = 0.001) and a raised creatinine (P = 0.05). The complete remission rate was 53% for the whole group and 74% for those receiving high-dose melphalan and an autograft. From July 1988, the sequential therapy package included continuous three times weekly interferon (IFN) after high-dose treatment as maintenance therapy, initially as part of a controlled randomised trial and then for all suitable patients. Fifty-seven patients received IFN. The median overall survival (OS) and progression-free survival (PFS) from first treatment for the whole group of 195 patients is 4.5 years and 25 months, respectively. The 112 patients receiving the melphalan autografts fared significantly better than the rest of the patients with OS and PFS (from high-dose treatment) of 6.6 years and 27 months, respectively (P < 0.005), and the 57 patients also receiving IFN have a OS yet to reach a median at 8 years and a PFS of 44 months, significantly better than non IFN high-dose patients (P < 0.0036). However, although we showed benefit for selected patients in studies and trials (particularly with IFN) during the 8-year period of the series, this did not translate into overall PFS benefit in our study for unselected cohorts of patients for 1986-1988 (64 patients) 1989-1992 (100 patients) and 1992-1994 (34 patients) in spite of progressive increases in the proportion of patients receiving IFN (respectively 6, 35 and 58%). This is likely to be due to the dilution of benefit to specific patients by the overall number of patients involved. Outcome data from unselected patients are now expected by purchasers and presented in this way, help qualify the activity impact of advances made from research trials for the treatment of population-based cancer problems.
Adult↗
Cytomegaloviremia after autografting for leukemia: clinical significance and lack of effect on engraftment.
One hundred and fourteen patients with leukemia (66 cytomegalovirus (CMV)-seropositive and 48 CMV-seronegative) were monitored for cytomegaloviremia by early antigen detection or conventional viral culture after autologous stem cell transplantation (ASCT). Twenty-two episodes of viremia were seen at 2-36 weeks (median 11) in 14 seropositive patients. Nineteen resolved without therapy in 11 patients. Three patients with clinical features suggestive of CMV disease were treated with ganciclovir: viremia resolved prior to ganciclovir in one, and with 3 weeks of ganciclovir in the other two. Transient thrombocytopenia (n = 4) and leukopenia (n = 1) were seen in association with five episodes of viremia. The counts recovered in all five patients; with ganciclovir (n = 2) or with spontaneous clearance of viremia (n = 3). One seronegative patient developed viremia which resolved spontaneously in 3 weeks. No symptoms suggestive of CMV disease were seen in any of the other patients. CMV serostatus or development of CMV infection did not affect hematologic recovery. In our experience, cytomegaloviremia is relatively uncommon after autografting for leukemia, and usually does not require treatment. We now do not routinely monitor leukemia patients for CMV infection after autografting, but look for viremia in CMV-seropositive patients with unexplained fever, drop in blood counts, lung infiltrates, or gastrointestinal symptoms.
Adolescent↗
A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma.
In a sequential nonrandomized study, 204 consecutive unselected patients aged < 70 years received induction chemotherapy with infusional vincristine and adriamycin with oral methyl prednisolone (VAMP: n = 75) or with additional cyclophosphamide, C-VAMP (n = 129). 38/129 C-VAMP patients also received verapamil during induction as part of a controlled trial with the aim to overcome drug resistance. A median of five courses (range 1-11) of chemotherapy were required before maximal response was attained and this was similar in both groups. An over-all response rate of 71% was noted at the end of induction. The complete remission (CR) rate with C-VAMP was 24%, which was significantly higher (P = 0.04) than the CR rate with VAMP alone (8%). The addition of verapamil did not alter the response rate of C-VAMP. Compliance to VAMP was overall 83% and not affected by the addition of cyclophosphamide. The proportion of patients going on to receive high-dose chemotherapy and an autograft was the same for VAMP and C-VAMP treated patients (71%). The median overall survival (OS) and progression-free survival (PFS) for the whole group were 4.4 years and 2.0 years and no difference in outcome was observed between the different treatment groups. Therefore the addition of weekly cyclophosphamide to VAMP induction therapy has significantly improved the response rates of previously untreated myeloma patients. C-VAMP was not more toxic and did not compromise the chances of receiving an autograft. Verapamil was without influence on any parameters in this study.
Adult↗
Advances in the treatment of multiple myeloma.
Conventional chemotherapy for multiple myeloma results in low complete response rates, and disease progression usually occurs within a couple of years. High-dose chemotherapy with autotransplantation, which has been shown to result in encouraging complete remission rates over several years in phase II studies, was recently shown in a randomized study to be superior to conventional therapy. Eventual tumor recurrence is a problem after autografting, and the development of novel maintenance chemotherapy or immunotherapy strategies is necessary to eliminate minimal residual disease. Although allogeneic transplantation cures a small proportion of patients, high transplant-related mortality and relapse rates hamper survival. Development of novel conditioning regimens and means to harness the graft-versus-myeloma effect without the associated morbidity of graft-versus-host disease are necessary to improve success rates. Supportive therapy, mainly bisphosphonates to delay progression of bone disease and improve bone density and erythropoietin to improve hemoglobin levels, also plays an important role in the overall management. This article reviews therapeutic advances in multiple myeloma from the 1996 literature.
Humans↗
Coital tear: a rare cause of secondary peritonitis.
A rare cause of secondary peritonitis due to coital tear is presented. The correct diagnosis can be made by a detailed history and gynaecological examination. Prompt surgical management is mandatory to prevent grave prognosis.
Adolescent↗
Nonunion of uterine incision: a rare cause of secondary postpartum haemorrhage: a report of 2 cases.
Secondary postpartum haemorrhage after Caesarean section due to non-union of the uterine incision is an unusual complication. Two women who had had lower segment Caesarean section for placenta praevia presented after 2 and 3 weeks respectively with shock due to massive postpartum haemorrhage. The uterine scars had not healed in both of these women who were managed by emergency subtotal hysterectomy.
Adult↗
Long-term safety of GM-CSF (molgramostim) administration after allogeneic bone marrow transplantation for hematologic malignancies: five-year follow-up of a double-blind randomized placebo-controlled study.
In a double-blind, randomized study performed between 1988 and 1990, 40 patients undergoing allogeneic BMT from HLA-identical siblings for hematologic malignancies received 8 mg/kg/d rHuGM-CSF (molgramostim, n = 20) for 14 days. The median neutrophil count on day 14 was significantly higher in the GM-CSF group (1.90 vs 0.46 yen 10(9)/L, P < .0001). The incidence of acute GVHD and transplant-related mortality were comparable. Only two deaths occurred after 6 months; one due to pulmonary fibrosis in the GM-CSF group on day 1591, and one due to relapse on day 1590 in the placebo group. The Karnofsky score of the 10 survivors, 3 in the placebo group and 7 in the GM-CSF group, is 90-100% (median 100%), and none has chronic GVHD requiring therapy. There was no evidence of increased relapse in the GM-CSF group with only two relapses occurring; both in the placebo group. With a follow-up of 4.5-6.8 years (median 5.5 years), these patients are amongst the longest surviving patients to have received a recombinant growth factor post-allograft. We conclude that the administration of GM-CSF after allogeneic BMT does not appear to be associated with an increased incidence of chronic GVHD or relapse, or of other adverse effects such as the development of myelodysplasia.
Adolescent↗
Autologous transplantation with CD52 monoclonal antibody-purged marrow for acute lymphoblastic leukemia: long-term follow-up.
During 1984-86, 23 patients (5-37 years, median 16) with acute lymphoblastic leukemia (ALL) in first remission (n = 11) or beyond (n = 12) underwent autologous transplantation (ABMT) using marrow purged with the rat anti-CD52 monoclonal antibody Campath-1M after melphalan and total-body irradiation (TBI). Median time to 0.5 x 10(9)/L neutrophils and 50 x 10(9)/L platelets was 38 and 51 days respectively. Myeloid engraftment was significantly slower compared with ALL patients receiving unpurged marrow (P = .01). Eight patients died due to transplant-related causes 53-205 days after the procedure. Six of eight patients receiving 1150 cGy TBI died of toxicity compared with two of 15 receiving less than 1150 cGy (P = .006, Fisher's exact test). Nine patients relapsed at 45-195 days (median 97); eight died and one is alive at nine years in a chemotherapy-induced remission. Six patients are alive and well in continuous remission 9-10 years (median 10) after transplant. The 10-year probabilities of disease-free survival and relapse are 26% (95% CI: 11-45%) and 51% (95% CI: 37-59%) respectively. We conclude that it is feasible to purge marrow for autografting using Campath-1M without killing normal stem cells. Myeloid engraftment is slow but consistent, and long-term survival is seen in a proportion of patients. The role of CD52 monoclonal antibodies for purging in ALL still requires further study.
Adolescent↗
Sequential development of myelodysplasia and acute myeloid leukemia but with no karyotypic evolution after autografting in a patient with Philadelphia positive acute lymphoblastic leukemia.
A woman with Philadelphia chromosome-positive c-ALL with +8 and i17q in addition underwent an unpurged blood stem cell autograft after 200mg/m2 melphalan in first relapse. Maintenance therapy with 6-mercatopurine was started following the autograft. Moderate pancytopenia developed after 4 months, and myelodysplasia (refractory anemia) was diagnosed which rapidly evolved into AML. The cytogenetic findings remained unchanged. She also developed CNS disease, but the blasts in the cerebrospinal fluid were lymphoid in character on immunophenotyping. She then received palliative treatment until death. The remarkable features here are the evolution into myelodysplasia and AML with retention of the original complex karyotype, and subsequent coexistence of lymphoid disease in the CNS and myeloid disease systemically. It is possible that the lineage switch and development of myelodysplasia in this case may have been secondary to treatment, but persistence of the original cytogenetic clone makes this unlikely. This may have been the result of some unusual effect of the treatment on the original clone, or expansion of a small unidentified myeloid clone present originally which gained a proliferative advantage due to the ALL-type treatment. This case confirms the aggressive and polymorphic nature of Ph+ ALL which may be the result of origin from an early progenitor cell (stem cell disease).
Acute Disease↗