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S Singhal

Publications and source records attributed to S Singhal.

At least 37 records · Page 2Linked to original sources
PubMed2004

High-dose melphalan and autotransplantation followed by post transplant maintenance chemotherapy for acute lymphoblastic leukemia in first remission.

A total of 65 adults with acute lymphoblastic leukemia (ALL) received 200 mg/m2 melphalan and an autograft in first remission, with a plan to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years afterwards. There was no transplant-related mortality. In all, 69% of patients received 6MP, 54% received MTX, and 49% received VP. The cumulative incidence of relapse at 5 years was 52%. The 5-year probabilities of disease-free (DFS) and overall (OS) survival were 48 and 55%. Age >30 years, >4 weeks to attain remission, and t(9;22) or t(4;11) karyotypes were adverse prognostic features. Patients with 0 (standard risk), 1 (intermediate risk), and 2-3 (high risk) adverse features had 5-year cumulative incidences of relapse of 19, 59, and 100% (P<0.0001), and 5-year probabilities of DFS of 80, 41, and 0% (P<0.0001). The 5-year probabilities of DFS for patients receiving 0, 1, 2, and 3 maintenance therapy agents were 19, 40, 51, and 70% (P=0.0097). Maintenance therapy intensity was an independent determinant of outcome in Cox analysis. These data show that a high-dose melphalan-based autograft is safe and could be widely applicable in ALL in first remission, and that maintenance chemotherapy very likely contributes to improved outcome of autografted ALL patients.

Adolescent↗
PubMed2003

Cytomegalovirus disease following liver transplantation: an analysis of prophylaxis strategies.

BACKGROUND: Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality following liver transplantation. Though oral ganciclovir may be used as a prophylactic agent, there is some debate as to whether prophylaxis should be given universally or to targeted 'high risk' sub-groups. We, therefore, analysed the cost-effectiveness of both prophylactic strategies. METHODS: We performed a retrospective cross-sectional study of adult liver transplant (LT) recipients who developed CMV disease in 1997 and estimated the morbidity and costs associated with disease in these patients. These costs were compared with the estimated cost (based on a previous multi-centre study) of using oral ganciclovir prophylaxis in order to assess the potential cost-effectiveness of introducing different prophylactic regimes. RESULTS: Universal and targeted prophylaxis would both have prevented all the likely mortality (2 deaths) from CMV disease in that year. The net cost of applying a targeted prophylaxis strategy would have been 206,275 pounds, (i.e. 103,137 pounds per death avoided). The cost per life year saved would have been 15,674 pounds. CONCLUSION: We suggest that LT units should identify patients at high risk for the development of CMV disease and adopt a targeted prophylactic strategy.

Administration, Oral↗
PubMed2003

Ideal or actual body weight to calculate CD34+ cell doses for autologous hematopoietic stem cell transplantation?

The number of CD34+ cells infused influences the speed of hematologic recovery post-transplant. There are limited data on whether ideal (IBW) or actual (ABW) body weight should be used to calculate CD34+ cell dose. We compared the correlation between recovery to 0.5 x 10(9)/l neutrophils and the CD34+ cell dose based upon ABW as well as IBW in 87 patients autografted for cancer. ABW was >or=25% over IBW in 43% of patients. The median number of CD34+ cells administered was 3.6 x 10(6)/kg ABW and 4.2 x 10(6)/kg IBW. The time to neutrophil recovery was 8-15 days (median 10). There was a stronger inverse correlation between CD34+ cell dose/IBW and neutrophil recovery (r(2)=0.308; P<0.0001) than between CD34+ cell dose/ABW and neutrophil recovery (r(2)=0.267; P<0.0001). The median time to neutrophil recovery was comparable for those receiving >or=2 x 10(6)/kg CD34+ cells/kg IBW as well as ABW (10 days) and those receiving >or=2 x 10(6)/kg CD34+ cells/kg IBW but <2/kg ABW (10 days), but was significantly slower for those receiving <2 x 10(6)/kg CD34+ cells/kg IBW (12 days). These data show that the CD34+ cell dose based on IBW is a better predictor of neutrophil recovery after autotransplantation.

Adolescent↗
PubMed2003

Haploidentical vs autologous hematopoietic stem cell transplantation in patients with acute leukemia beyond first remission.

This is a retrospective comparison of partially mismatched related donor transplantation (PMRDT) and autotransplantation (ABMT) in advanced acute leukemia. Patients underwent T-cell-depleted PMRDT (n=164) or ABMT (n=131) for acute myeloid leukemia (n=130) or acute lymphoblastic leukemia (n=165). Fewer PMRDT patients were in remission (29 vs 85%; P<0.0001). The 5-year cumulative incidence of transplant-related mortality (TRM) was 52% after PMRDT and 16% after ABMT (P<0.0001). The 5-year cumulative incidence of relapse was 32% after PMRDT and 54% after ABMT (P=0.006). The actuarial unadjusted 5-year disease-free survival (DFS) was 16% after PMRDT and 30% after ABMT. In Cox's regression analysis, PMRDT (P<0.0001) and age >15 years (P=0.002) were associated with higher TRM, active disease (P=0.0021), ABMT (P=0.0074) and male sex (P=0.011) with higher relapse, and age >15 years (P=0.0007) and PMRDT (P=0.047) with lower DFS. Amongst second remission patients, TRM was higher after PMRDT (P=0.0003), relapse was higher after ABMT (P=0.034), and 5-year DFS was comparable (32% ABMT and 25% PMRDT). ABMT, if feasible, may be preferable to PMRDT in advanced acute leukemia patients since lower relapse after PMRDT is offset by higher TRM. If an autograft is not feasible because of nonavailability of autologous cells or very advanced disease, PMRDT is a potential alternative.

Acute Disease↗
PubMed2003

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease.

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.

Acute Disease↗
PubMed2003

Impact of cytogenetics on the outcome of autotransplantation for acute myeloid leukemia in first remission: is the benefit of intensive pretransplant therapy limited to patients with good karyotypes?

A total of 81 adults with acute myeloid leukemia (AML) (47% favorable karyotypes) were autografted in first remission after melphalan-total body irradiation, having received 0 (n=7), 1 (n=19), 2 (n=51), or 3 (n=4) consolidation chemotherapy cycles before harvest. The cumulative 5-year incidences of relapse and transplant-related mortality were 37 and 17%, respectively. The actuarial 5-year probability of disease-free survival (DFS) was 46%. In Cox analysis, favorable karyotypes, increasing numbers of consolidation cycles (0 vs > or =1 or 1 vs >1), and higher nucleated cell doses were associated with lower relapse rates and higher DFS. Patients with favorable karyotypes benefited from every additional cycle of consolidation therapy (0 vs > or =1 as well as 1 vs >1). Among patients with other karyotypes, while the benefit of one cycle of consolidation was clear (0 vs > or =1), there was no obvious beneficial impact of further consolidation therapy (1 vs >1). Administration of consolidation chemotherapy prior to harvest is essential in AML. While it is possible to enhance the benefit of consolidation with favorable karyotypes by delivering two cycles, its usefulness is limited in others. In them, it may be worthwhile exploring alternatives not normally used in AML (eg high-dose cyclophosphamide) that could have antileukemic effects while permitting mobilization of stem cells.

Acute Disease↗
PubMed2002

Thalidomide in cancer.

Thalidomide has immunomodulatory and anti-angiogenic properties which may underlie its activity in cancer. After its success in myeloma, it has been investigated in other plasma cell dyscrasias, myelodysplastic syndromes, gliomas, Kaposi's sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer. Thalidomide causes responses in 30-50% of myeloma patients as a single agent, and acts synergistically with corticosteroids and chemotherapy. Thalidomide results in the reduction or elimination of transfusion-dependence in some patients with myelodysplastic syndrome. Responses have also been seen in one-third of patients with Kaposi's sarcoma, in a small proportion of patients with renal cell carcinoma and high-grade glioma, and in some patients with colon cancer in combination with irinotecan. The drug is being investigated currently in a number of clinical trials for cancer. Drowsiness, constipation, and fatigue are common side effects, whereas peripheral neuropathy and skin rash are seen in one-third. A minority of patients experience bradycardia. Thrombotic phenomena are especially common when thalidomide is combined with chemotherapy. Adverse effects severe enough to necessitate cessation of therapy are seen in around 20% of patients. A therapeutic trial of thalidomide is essential in all patients with relapsed or refractory myeloma. In other cancers, the best way to use the drug is in the setting of clinical trials. In the absence of access to studies or alternative therapeutic options, thalidomide could be considered singly or in combination with standard therapy.

Angiogenesis Inhibitors↗
PubMed2002

Allogeneic transplantation from HLA-matched sibling or partially HLA-mismatched related donors for primary refractory acute leukemia.

Allogeneic transplantation is successful in a minority of patients with primary refractory acute leukemia (PRAL). An HLA-matched sibling donor (MSD) is available only in 30-40% of the patients, whereas a partially mismatched related donor (PMRD) is available for most. We compared the outcome of 24 MSD (median age 24 years) and 19 PMRD (median age 34 years; P = 0.04) allograft recipients with PRAL. All MSD patients received non-T cell-depleted marrow whereas all PMRD patients received partially T cell-depleted marrow. All evaluable PMRD patients and 90% of the evaluable MSD patients attained CR. Six patients in each group with recurrent/persistent disease died. Ten PMRD (3-year probability 70%) and 14 MSD (3-year probability 63%) patients died of treatment-related causes. At the last follow-up, three PMRD (18-50 months; 3-year probability 14%) and four MSD (20-166 months; 3-year probability 20%) patients were alive and well. We conclude that allogeneic transplantation is a viable therapeutic option for PRAL. PMRD transplantation is a reasonable alternative in patients with no MSD, and results in similar outcome. In terms of identifying a donor and harvesting cells, a PMRD transplant is significantly quicker than an unrelated donor transplant - a point of great practical importance in the setting of failed induction chemotherapy where time is of the essence.

Acute Disease↗
PubMed2002

Cobe Spectra is superior to Fenwal CS 3000 Plus for collection of hematopoietic stem cells.

One hundred and seventy-seven stem cell apheresis procedures performed on 91 patients using the Fenwal CS 3000 Plus cell separator and 61 procedures performed on 37 patients using the Cobe Spectra cell separator were studied to compare the CD34(+) cell collection efficiencies (CE; the proportion of the total CD34(+) cell content in the blood volumes processed that is harvested) of the two machines. The absolute peripheral blood CD34(+) cell count was comparable for the two groups (P = 0.27). A strong correlation was seen between the blood CD34(+) cell count and the total number of CD34(+) cells collected for the Spectra (r(2) = 0.59; P < 10(-6)) and for the CS 3000 Plus (r(2) = 0.60; P < 10(-6)). No significant correlation emerged between the peripheral blood CD34(+) cell count and the CE of either machine. The total number of CD34(+) cells collected per procedure was comparable (P = 0.51): median 113 x 10(6) for CS 3000 Plus and median 218 x 10(6)for Spectra. CE was significantly higher with the Spectra (median 45.7%, range 9.8-98.6%) than the CS 3000 Plus (median 30.3%, range 1.7-89.3%; P < 0.00001). We conclude that the CD34(+) cell CE of the Spectra is superior to that of the CS 3000 Plus. Therefore, under the usual clinical conditions, Cobe Spectra should be used preferentially for peripheral blood progentor cell collection to maximize the number of hematopoietic stem cells collected.

Blood Cell Count↗
PubMed2002

Does donor-recipient ABO incompatibility protect against relapse after allogeneic bone marrow transplantation in first remission acute myeloid leukemia?

It is not known if donor-recipient ABO blood group incompatibility contributes to graft-versus-leukemia after allogeneic BMT. One hundred and nineteen patients with acute myeloid leukemia in first remission underwent non-T cell-depleted marrow allografts from HLA-identical siblings after TBI and cyclophosphamide (n = 72) or melphalan (n = 47). GVHD prophylaxis comprised cyclosporine alone or cyclosporine-methotrexate. Twenty-two patients relapsed at 3-46 months (median 7): 18 of 76 patients with ABO-matched donors and four of 43 patients with ABO-mismatched donors (actuarial 5-year probabilities 33 +/- 6% vs 12 +/- 6%; P = 0.028). The incidence of acute and chronic GVHD was not affected by ABO mismatch. The following factors were studied in Cox analysis for effect on outcome: gender, age, FAB subtype, ABO mismatch, CR-transplant interval, conditioning, TBI dose, nucleated cell dose, lymphocyte recovery, acute GVHD, and chronic GVHD. Donor-recipient ABO match was the only factor independently associated with a higher risk of relapse (RR = 3.7; 95% Cl, 1.1-12.6; P = 0.04). ABO mismatch was also associated with superior overall and disease-free survivals. We conclude that ABO incompatibility may influence relapse rates and survival favorably after allogeneic BMT. It is not known if this holds true for allogeneic blood stem cell transplants.

ABO Blood-Group System↗
PubMed2002

Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.

Adult↗
PubMed2002

Rarity of toxigenic Clostridium difficile infections after hematopoietic stem cell transplantation: implications for symptomatic management of diarrhea.

Diarrhea is a common complication of high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). The frequent and prolonged use of multiple antibiotics in this setting can predispose to infection with toxigenic Clostridium difficile and the development of pseudomembranous colitis. Anti-motility agents are usually not administered in this setting until C. difficile infection has been excluded. The objective of this study was to determine the incidence of C. difficile toxin (CDT) positivity at the time of initial diarrhea in HSCT recipients, and to see if the practice of ensuring negative CDT assays prior to initiating symptomatic management of diarrhea needs modification. One hundred and nineteen patients with malignant diseases undergoing autologous or allogeneic HSCT were studied to determine the incidence of diarrhea and CDT positivity with initial diarrhea. One hundred and nine (91%) had diarrhea. Of these, only seven (6%) were CDT+ at the time of initial diarrhea. The median interval between onset of diarrhea and starting symptomatic anti-diarrheal therapy was 1 day. There were no significant differences between the patients with CDT+ diarrhea and the others in terms of timing or severity of diarrhea, number or duration of antibiotic usage, or leukocyte count. The infection resolved in all patients with metronidazole therapy. Our data suggest that the incidence of CDT+ diarrhea is low in HSCT recipients. Concern about C. difficile infection should not delay symptomatic therapy of initial diarrhea in HSCT recipients.

Adolescent↗
PubMed2002

Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma.

Two hundred and twenty-two myeloma patients autografted after 200 mg/m(2)melphalan were studied to examine the relationship between response to induction chemotherapy and outcome. Induction comprised cyclophosphamide, vincristine, doxorubicin and methylprednisolone (C-VAMP) every 3 weeks for one cycle beyond maximum response. 81% responded to C-VAMP (chemosensitive) with 40 complete (CR) and 139 partial (PR) remissions, and 43 did not respond (NR; <50% reduction in paraprotein; primary refractory). Overall, 130 patients (59%) attained or remained in CR post-transplant; including 40% of NR, 53% of PR, and 97% of CR after C-VAMP (P < 0.0001). Amongst these 130 patients, the 5-year OS was independent of response to C-VAMP (NR 79%, PR 74%, CR 60%; P = 0.69). Similarly, among the 69 patients in PR post-transplant, the 5-year OS was independent of response to C-VAMP. In Cox analysis, lack of response to C-VAMP did not affect outcome significantly. These data show that lack of response to induction therapy does not automatically predict poor long-term outcome in myeloma, since a substantial proportion of these patients attain CR after autograft and enjoy extended survival. Myeloma patients should not be disqualified from an autograft based upon lack of response to induction chemotherapy.

Adult↗
PubMed2002

Reassessing the definition of myeloid engraftment after autotransplantation: it is not necessary to see 0.5 x 10(9)/l neutrophils on 3 consecutive days to define myeloid recovery.

The time to myeloid recovery after autologous hematopoietic stem cell transplantation (HSCT) is usually defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) of >or=0.5 x 10(9)/l (ANC500). Universal documentation of ANC500 for 3 consecutive days, historically required to ensure robust myeloid recovery, has become difficult with a trend towards early discharge and outpatient HSCT. We studied 90 autografted patients to see how frequently ANC declined after having reached >or=0.5 x 10(9)/l. ANC500 was documented on 2 and 3 consecutive days in 14 and 63 patients, respectively. ANC increased by a median of 213% from the 1st to the 2nd day (rise in 75 and unchanged in two), and by a median of 142% from the 2nd day to the 3rd (rise in 60, unchanged in one, and decline in two; higher than the 1st day in the latter three). The increase from the 1st to the 3rd day was 13-3433% (median, 557%). Thus, in all 63 patients, no decline below ANC500 was seen, and the first day with ANC500 was also the first of 3 consecutive days with ANC500. The remaining 13 patients had repeat counts 2-7 days after the 1st day with ANC500 documenting further increase in ANC with no evidence of failed engraftment. These data show that the first day with ANC500 is also consistently the first of 3 consecutive days with ANC500 in autografted patients. Therefore, the traditional definition of myeloid engraftment should be changed to consider the first day with ANC500 as the day of engraftment without necessarily documenting ANC500 on the subsequent 1-2 days. This simple change in definition has significant implications for how data are reported to transplant registries and how peer-review organizations such as the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) define completeness of data.

Adolescent↗
PubMed2002

Neurofibromatosis type 1 and sporadic optic gliomas.

AIMS: To compare the natural history of sporadic optic glioma with those associated with neurofibromatosis type 1 (NF1). METHODS: Optic glioma cases were identified using both the Manchester Children's Tumour Registry (CTR) and the North West Regional NF1 Database (NF1DB), with detailed information on natural history available from the former (in 34 of 36 cases identified). RESULTS: A total of 52 cases over a period of 41 years were identified. From the 34 whose natural history was known, almost all (n = 31) were symptomatic, with mean ages of presentation of 4.5 and 5.1 years for NF1 and sporadic cases respectively. The majority (n = 22) presented with visual impairment, seven of whom were blind in at least one eye. Sporadic cases were over twice as likely as NF1 to have visual impairment. Recurrence occurred in 12 patients. Fewer NF1 patients died as a direct result of their optic glioma, but overall mortality and 5 and 10 year survival rates between the two groups were similar. All five primary (non-metastatic) second central nervous system (CNS) tumours occurred in NF1 cases, two of these following radiotherapy. CONCLUSIONS: Symptomatic sporadic optic gliomas presented with impaired vision more frequently and were more aggressive than NF1 optic gliomas. Only optic glioma cases with NF1 were at risk of developing a second CNS tumour. Aggressive treatment of sporadic optic gliomas and early surveillance of NF1 optic gliomas may be required. The use of radiotherapy in these children requires further clarification.

Adolescent↗
PubMed2001

Glomerular filtration rate prior to high-dose melphalan 200 mg/m(2) as a surrogate marker of outcome in patients with myeloma.

We correlated age and body surface area corrected glomerular filtration rate (GFR) at the time of high-dose melphalan (HDM) administration with treatment-related toxicity (TT), time to disease progression and survival. Between 8/85 and 6/98, 144 newly diagnosed myeloma patients with a median age of 53 years (range, 31-72) received infusional chemotherapy with vincristine, doxorubicin and methylprednisolone, with/without cyclophosphamide or verapamil, followed by HDM 200 mg/m(2)and stem cell rescue. An additional patient received HDM at diagnosis. GFR was below normal in 38 patients (26%). At presentation, patients with low GFR at the time of HDM had higher serum creatinine, beta(2)M, stage III disease, calcium and Bence-Jones proteinuria. Toxic deaths post-HDM were similar in both groups (2/38 (5%) vs. 4/107 (4%)), though patients with low GFR had more oral mucositis (P< 0.0001), diarrhoea (P = 0.005) and infections (P = 0.04). The response and relapse rates of the 2 groups were not substantially different, but the median overall survival (OS) was significantly shorter in patients with low GFR (5.1 vs 7.5 years, P = 0.015). Multivariate analysis showed that a normal GFR and being in CR at the time of HDM were predictive of longer OS. We conclude that in context of high-dose chemotherapy for myeloma, dose of melphalan should not be modified in patients with low GFR and that early intensive treatment at relapse may improve results in patients with abnormal renal function.

Adult↗