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Background: Renal impairment occurs in up to 30% of patients who present with multiple myeloma and in up tp 50% of patients at some stage of the illness. It is known that renal impairment can be reversed in a significant number of such patients by correction of precipitating factors and rehydration but that 3–12% patients will require dialysis or other major intervention. These patient have a worse prognosis largely due to an excess of early deaths, renal failure being the major cause of death in 14% of myeloma patients and contributing factor in a further 14%. (Drayson et al UK MRC MM trials 1980–2002) We have conducted a study to look into the clinical course and outcome of all patients with renal impairment sufficiently severe to be referred to the regional renal unit in South East England between 2000 and 2007 with either newly diagnosed multiple myeloma (MM) or relapsed disease to try to identify features which predict for better outcomes. Methods: 62 patients with MM and renal failure received treatment in our hospital over the last 8 years. Patients have been assessed for recovery of renal function and dialysis independence in two groups - newly diagnosed (n=47) and relapsed patients (n=15). They were analysed separately as the disease tends to be biologically different at presentation and relapse, and therapeutic options may be different. In addition relatively little data on relapsed myeloma with renal failure is available. Results: 14 patients in the newly diagnosed group and 4 in the relapsed group were deemed unsuitable for an active treatment approach and have been excluded from statistical analysis in this paper but will be analysed separately to try to identify factors which could improve the outcome for this group. The patients with newly diagnosed MM and actively treated had a mean age of 65.3±1.7 years (range 41.9–83.3), male to female ratio of 1.7:1 and a mean peak creatinine at presentation of 684.5±60.9 mmol/l (range 107–1820). Light chain myeloma was overrepresented and was seen in 57.5% of patients (n=19). 12 (36.3%) of 33 the new patients avoided dialysis. 21 required dialysis, of whom 8 patients (38.1%) recovered function to dialysis independence at 6 months. There were only 3 deaths at 6 months follow-up. The mean age of the relapsed patients was 61.8±3.5 years (range 34.9–80.7), male to female ratio of 2.6:1 and a mean peak creatinine at presentation of 824±118.4 mmol/l (range 231–1591). Majority of myeloma was IgA in 36.3% (n = 4). Among the 11 relapsed, 82% (n=9) required dialysis but a significant proportion, 88% (n=8), were dialysis independent at 6 months There was only one death within 6 months of a relapse. Treatments in the 2 groups varied but involved the use of regimes containing high dose steroids in most patients. Conclusions: Our data suggest that renal failure and dialysis dependence can be avoided or is reversible in a large number of newly diagnosed and relapsed myeloma patients. This study of an unselected group of patients receiving current therapy provides an important baseline against which to compare the effect of approaches involving the newer biological agents.

The management of refractory advanced chronic lymphocytic leukaemia (CLL) continues to pose a considerable challenge to the clinician. CLL patients who are refractory or become resistant to fludarabine containing regimens currently have a poor prognosis. High dose methylprednisolone (HDMP) has been shown to be an effective therapeutic option in patients who are resistant to fludarabine particularly those with bulky lymphadenopathy or refractory cytopenias who are unsuitable for alemtuzumab therapy. We have used HDMP in combination with the anti-CD20 monoclonal antibody, Rituximab, to treat 14 patients with advanced refractory CLL. Eight of fourteen patients were male. The median age was 62.5 years (range 30–71). Twelve patients had bulky lymphadenopathy with nodal masses greater than 5 centimetres in diameter. Nine patients had Binet stage C and the remainder were stage B. Autoimmune manifestations were present in five of the patients, and in one of them fludarabine therapy was contraindicated due to active autoimmune haemolysis. FISH analysis was performed to detect 17p, 11q and 13q deletions and showed 11q23 deletions in five patients. The overall response rate was 93% with a median progression free survival (PFS) of seven months. Two patients achieved a CR, another a nodular PR and 10 patients had a PR. Responses were seen in all 4 patients who had not responded to alemtuzumab as a single agent. Only one patient failed to respond. The median survival was 20 months. All five patients with 11q23 deletions responded, and the mean progression free survival in this subgroup was 10.5 months. These results compare extremely favourably with our own previous study (Thornton et al, 1998) that used HDMP alone in the management of advanced/refractory CLL where only 43% of patients responded and no patients achieved a CR. We have demonstrated that the combination of HDMP with rituximab is more effective than HDMP alone (p<0.01) in advanced refractory CLL. Although HDMP in combination with rituximab causes little or no myelosuppression, 6/14 patients (43%) developed opportunistic fungal or viral infections and this included fungal mould infections, fungal yeast infections and opportunistic viral infections. Three patients died of pulmonary fungal infections, although 2 of these patients had been retreated with alternative regimens. While the immunosuppressive effects of high dose steroids are well recognised, it appears that the addition of rituximab has made these patients more prone to opportunistic infections. In summary, HDMP in combination with rituximab is an effective rescue regime in purine analogue refractory CLL particularly in patients with bulky lymphadenopathy who are unsuitable for alemtuzumab, and in patients with 11q23 deletions.

Background: Renal impairment occurs in up to 30% of patients who present with multiple myeloma and in up tp 50% of patients at some stage of the illness. It is known that renal impairment can be reversed in a significant number of such patients by correction of precipitating factors and rehydration but that 3–12% patients will require dialysis or other major intervention. These patient have a worse prognosis largely due to an excess of early deaths, renal failure being the major cause of death in 14% of myeloma patients and contributing factor in a further 14%. (Drayson et al UK MRC MM trials 1980–2002) We have conducted a study to look into the clinical course and outcome of all patients with renal impairment sufficiently severe to be referred to the regional renal unit in South East England between 2000 and 2007 with either newly diagnosed multiple myeloma (MM) or relapsed disease to try to identify features which predict for better outcomes.

The management of refractory advanced chronic lymphocytic leukaemia (CLL) continues to pose a considerable challenge to the clinician. CLL patients who are refractory or become resistant to fludarabine containing regimens currently have a poor prognosis. High dose methylprednisolone (HDMP) has been shown to be an effective therapeutic option in patients who are resistant to fludarabine particularly those with bulky lymphadenopathy or refractory cytopenias who are unsuitable for alemtuzumab therapy. We have used HDMP in combination with the anti-CD20 monoclonal antibody, Rituximab, to treat 14 patients with advanced refractory CLL. Eight of fourteen patients were male. The median age was 62.5 years (range 30–71). Twelve patients had bulky lymphadenopathy with nodal masses greater than 5 centimetres in diameter. Nine patients had Binet stage C and the remainder were stage B. Autoimmune manifestations were present in five of the patients, and in one of them fludarabine therapy was contraindicated due to active autoimmune haemolysis. FISH analysis was performed to detect 17p, 11q and 13q deletions and showed 11q23 deletions in five patients. The overall response rate was 93% with a median progression free survival (PFS) of seven months. Two patients achieved a CR, another a nodular PR and 10 patients had a PR. Responses were seen in all 4 patients who had not responded to alemtuzumab as a single agent. Only one patient failed to respond. The median survival was 20 months. All five patients with 11q23 deletions responded, and the mean progression free survival in this subgroup was 10.5 months. These results compare extremely favourably with our own previous study (Thornton et al, 1998) that used HDMP alone in the management of advanced/refractory CLL where only 43% of patients responded and no patients achieved a CR. We have demonstrated that the combination of HDMP with rituximab is more effective than HDMP alone (p<0.01) in advanced refractory CLL. Although HDMP in combination with rituximab causes little or no myelosuppression, 6/14 patients (43%) developed opportunistic fungal or viral infections and this included fungal mould infections, fungal yeast infections and opportunistic viral infections. Three patients died of pulmonary fungal infections, although 2 of these patients had been retreated with alternative regimens. While the immunosuppressive effects of high dose steroids are well recognised, it appears that the addition of rituximab has made these patients more prone to opportunistic infections. In summary, HDMP in combination with rituximab is an effective rescue regime in purine analogue refractory CLL particularly in patients with bulky lymphadenopathy who are unsuitable for alemtuzumab, and in patients with 11q23 deletions.

From August 1973 to December 2003, 1651 patients (median age: 28yr., range: 1–74 yr.; M: 982, F: 669) received stem cell transplants for haematological malignancies (Ac. Leuk: 1246, Chr. Leuk: 182, other: 223). Donor was allogeneic (n=1088), autologous (n=537) or syngeneic (n=26) and conditioning was with (n=1243) or without TBI (n=408). Primary disease was classed as high risk in 714 and low risk in 937 patients. Dose of TBI was =9.5 Gy (n=342), 10.5 Gy (n=613) or = 10.5 Gy (n=282) delivered in single fraction (n=1015) or multiple fractions (n=222). Donor was sibling (n=900), matched unrelated (n=135) or mismatched family member (n=53). Cranial top-up radiation was used in 357 patients. Source of stem cell was marrow (n=1312), PBSC (n=320) or both (n=19). GVH prophylaxis was CyA alone (n=527), CyA with other agent (n=516) or other measures (n=45). Of all the patients 1515 received single transplant but 136 received more than one transplant. Data was analysed as of 01/07/2006. Of all the patients 897 (54.3%) survived for at least 1 yr. post transplant and the median follow-up in this group was 27yr. Second cancers developed in 50 cases with the incidence of 2.6% at 5yr (95% CI: 1.3–3.9), 7.5% at 10 yr (95% CI: 4.9–10.1) and 11.5% at 15yr (95%CI: 7.6–15.4). Site of second malignancy was brain (n=10), breast (n=6), cervix (n=3), GIT (n=2), lung (n=1), skin (n=9), sarcoma (n=3), thyroid (n=1), oral cavity (n=4), MDS (n=6), CML (n=1), ovary (n=1) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SMN was significantly higher with chronic GVHD (5% vs. 10%, p=0.008, high risk disease (5% vs. 11%, p=0.0007), cranial RT (4% vs. 18%, p=0.015) and ALL as primary diagnosis (4% vs. 10%, p=0.06). In multi-variate analysis advanced stage disease (RR: 2.4, 95% CI: 1.3–4.2, p=0.004), Chr. GVHD (RR: 2.5, 95% CI: 1.4–4.4, p=0.003) and cranial RT (RR: 2.3, 95% CI: 1.2–4.4, p=0.01) were independently associated with increased risk of SMN. There was strong interdependence between cranial RT and ALL as primary diagnosis. It was noted that the multi-variate risk factors were different for site specific SMNs. For brain tumours cranial RT (RR: 12.8, 95% CI:2–75.5, p=0.006) and age <16 yr at the time of transplant (RR:15.7, 95% CI:1.9–130.6, p=0.011) were associated with increased risk. For epithelial malignancies Chr. GVHD (RR: 5.8, 95% CI: 2.2–15.5, p=0.0005), female sex (RR: 3.0, 95% CI:1.1–8.3, p=0.033) and advanced stage disease (RR: 3.6, 95% CI: 1.4–9.4, p=0.01) were associated with increased risk. No independent risk factors could be identified for development of skin or haematological malignancies. 25 patients have died due to SMN (49%) at a median of 31 months. Survival was significantly better in skin SMNs (85%) as compared to haematological SMNs (20%), brain tumours (30%) and epithelial SMNs (56%)(p=0.02). This single centre analysis shows that the risk of developing SMN does not relate to the type of conditioning and increases with longer follow-up. The risk factors vary for the different sites of SMNs. These patients need long term cancer screening.

Between March 1973 and August 2003, 747 patients (M: 430, F:317; median age: 29yr, range:1–65) who survived for at least 1 yr. post stem cell transplant and were 15 to 65 years of age (median: 38, range:15–71) at the time of last follow-up (LFU) were analysed to study the incidence and outcome of pregnancies. At the time of transplantation, 138 patients were pre-pubertal (M: 79, F: 59, p=0.8). Transplants were allogeneic (n=429, median age: 28yr), autologous (n=304, median age: 32) or syngeneic (n=14, median age: 37) and were performed for Ac. Leukaemia (n=583), Chr. Leukaemia (n=82) or other diseases (n=82). Patients with Myeloma who received Autograft were not included. Conditioning included TBI in 561 patients using either single fraction (n=478) or a fractionated schedule (n=83) and 168 patients also received cranial radiation. Stem cell source was marrow (n=573), PBSC (n=166) or both (n=8). GVHD prophylaxis was CyA alone (n=188), CyA with another agent (n=227) or other measures (n=14). 79 patients received more than one transplant. The probability of overall survival in this group of patients was 65% at 10yr. Median follow-up was 7 yr. (range: 1–33). Twenty seven patients (10 females and 17 partners of male patients) had 41 pregnancies and sired 45 children, including 4 twin pregnancies. The probability of conception was 4% at 10yr. Pregnancies occurred in 17/429 allografts (3.96%; 6/186 females; 11/243 males), 8/304 autograft patients (2.63%; 4/123 females, 4/181 males) and 2/14 syngeneic transplants (14.3%; 0/8 females, 2/6 males). Amongst 10 female patients 3 had assisted conception and 7 had natural pregnancy. Amongst 17 partners of male patients, 5 had assisted conception, 11 had natural conception and 1 had assisted conception followed by natural pregnancy. In uni-variate analysis chances of becoming pregnant were higher with age> 15yr. at transplant (5% vs. 1% at 10 yr., p<0.001), non-TBI conditioning (9% vs. 2%, p=0.001), age between 20–45 at LFU (5% vs. 2%, p=0.005) and use of PBSC for transplant (8% vs. 5%, p<0.001). The highly significant correlation between use of PBSC and use of non-TBI conditioning probably explains why PBSC had a significant association with pregnancy on univariate analysis. On multi-variate analysis non-TBI conditioning (RR: 3.7, 95% CI: 1.7–8.3, p=0.0014), age at transplant>15 yr. (RR: 11.6, 95% CI: 1.6–86.3, p=0.02) and age of 20–45 at LFU (RR: 5.53, 95% CI: 1.9–16.1, p=0.002) were independently associated with higher chances of conception. Two pregnancies resulted in miscarriages leading to 3 foetal deaths (2/42, 5%; 3/45, 7%). Four babies were born prematurely and required admission to neonatal unit and 2 died after 6 weeks. None had congenital malformations. Currently, 40 children are alive and well; 26 after natural conception and 14 after assisted fertilization. In conclusion, even though the chances of conception are lower in patients undergoing transplant, especially after TBI conditioning, pregnancy outcomes following natural and assisted conception are likely to be similar in terms of chances of successful outcome.

From August 1973 to December 2003, 1651 patients (median age: 28yr., range: 1–74 yr.; M: 982, F: 669) received stem cell transplants for haematological malignancies (Ac. Leuk: 1246, Chr. Leuk: 182, other: 223). Donor was allogeneic (n=1088), autologous (n=537) or syngeneic (n=26) and conditioning was with (n=1243) or without TBI (n=408). Primary disease was classed as high risk in 714 and low risk in 937 patients. Dose of TBI was ≤9.5 Gy (n=342), 10.5 Gy (n=613) or ≥ 10.5 Gy (n=282) delivered in single fraction (n=1015) or multiple fractions (n=222). Donor was sibling (n=900), matched unrelated (n=135) or mismatched family member (n=53). Cranial top-up radiation was used in 357 patients. Source of stem cell was marrow (n=1312), PBSC (n=320) or both (n=19). GVH prophylaxis was CyA alone (n=527), CyA with other agent (n=516) or other measures (n=45). Of all the patients 1515 received single transplant but 136 received more than one transplant. Data was analysed as of 01/07/2006. Of all the patients 897 (54.3%) survived for at least 1 yr. post transplant and the median follow-up in this group was 27yr. Second cancers developed in 50 cases with the incidence of 2.6% at 5yr (95% CI: 1.3–3.9), 7.5% at 10 yr (95% CI: 4.9–10.1) and 11.5% at 15yr (95%CI: 7.6–15.4). Site of second malignancy was brain (n=10), breast (n=6), cervix (n=3), GIT (n=2), lung (n=1), skin (n=9), sarcoma (n=3), thyroid (n=1), oral cavity (n=4), MDS (n=6), CML (n=1), ovary (n=1) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SMN was significantly higher with chronic GVHD (5% vs. 10%, p=0.008, high risk disease (5% vs. 11%, p=0.0007), cranial RT (4% vs. 18%, p=0.015) and ALL as primary diagnosis (4% vs. 10%, p=0.06). In multi-variate analysis advanced stage disease (RR: 2.4, 95% CI: 1.3–4.2, p=0.004), Chr. GVHD (RR: 2.5, 95% CI: 1.4–4.4, p=0.003) and cranial RT (RR: 2.3, 95% CI: 1.2–4.4, p=0.01) were independently associated with increased risk of SMN. There was strong interdependence between cranial RT and ALL as primary diagnosis. It was noted that the multi-variate risk factors were different for site specific SMNs. For brain tumours cranial RT (RR: 12.8, 95% CI:2–75.5, p=0.006) and age <16 yr at the time of transplant (RR:15.7, 95% CI:1.9–130.6, p=0.011) were associated with increased risk. For epithelial malignancies Chr. GVHD (RR: 5.8, 95% CI: 2.2–15.5, p=0.0005), female sex (RR: 3.0, 95% CI:1.1–8.3, p=0.033) and advanced stage disease (RR: 3.6, 95% CI: 1.4–9.4, p=0.01) were associated with increased risk. No independent risk factors could be identified for development of skin or haematological malignancies. 25 patients have died due to SMN (49%) at a median of 31 months. Survival was significantly better in skin SMNs (85%) as compared to haematological SMNs (20%), brain tumours (30%) and epithelial SMNs (56%)(p=0.02). This single centre analysis shows that the risk of developing SMN does not relate to the type of conditioning and increases with longer follow-up. The risk factors vary for the different sites of SMNs. These patients need long term cancer screening.

Between March 1973 and August 2003, 747 patients (M: 430, F:317; median age: 29yr, range:1–65) who survived for at least 1 yr. post stem cell transplant and were 15 to 65 years of age (median: 38, range:15–71) at the time of last follow-up (LFU) were analysed to study the incidence and outcome of pregnancies. At the time of transplantation, 138 patients were pre-pubertal (M: 79, F: 59, p=0.8). Transplants were allogeneic (n=429, median age: 28yr), autologous (n=304, median age: 32) or syngeneic (n=14, median age: 37) and were performed for Ac. Leukaemia (n=583), Chr. Leukaemia (n=82) or other diseases (n=82). Patients with Myeloma who received Autograft were not included. Conditioning included TBI in 561 patients using either single fraction (n=478) or a fractionated schedule (n=83) and 168 patients also received cranial radiation. Stem cell source was marrow (n=573), PBSC (n=166) or both (n=8). GVHD prophylaxis was CyA alone (n=188), CyA with another agent (n=227) or other measures (n=14). 79 patients received more than one transplant. The probability of overall survival in this group of patients was 65% at 10yr. Median follow-up was 7 yr. (range: 1–33). Twenty seven patients (10 females and 17 partners of male patients) had 41 pregnancies and sired 45 children, including 4 twin pregnancies. The probability of conception was 4% at 10yr. Pregnancies occurred in 17/429 allografts (3.96%; 6/186 females; 11/243 males), 8/304 autograft patients (2.63%; 4/123 females, 4/181 males) and 2/14 syngeneic transplants (14.3%; 0/8 females, 2/6 males). Amongst 10 female patients 3 had assisted conception and 7 had natural pregnancy. Amongst 17 partners of male patients, 5 had assisted conception, 11 had natural conception and 1 had assisted conception followed by natural pregnancy. In uni-variate analysis chances of becoming pregnant were higher with age> 15yr. at transplant (5% vs. 1% at 10 yr., p<0.001), non-TBI conditioning (9% vs. 2%, p=0.001), age between 20–45 at LFU (5% vs. 2%, p=0.005) and use of PBSC for transplant (8% vs. 5%, p<0.001). The highly significant correlation between use of PBSC and use of non-TBI conditioning probably explains why PBSC had a significant association with pregnancy on univariate analysis. On multi-variate analysis non-TBI conditioning (RR: 3.7, 95% CI: 1.7–8.3, p=0.0014), age at transplant>15 yr. (RR: 11.6, 95% CI: 1.6–86.3, p=0.02) and age of 20–45 at LFU (RR: 5.53, 95% CI: 1.9–16.1, p=0.002) were independently associated with higher chances of conception. Two pregnancies resulted in miscarriages leading to 3 foetal deaths (2/42, 5%; 3/45, 7%). Four babies were born prematurely and required admission to neonatal unit and 2 died after 6 weeks. None had congenital malformations. Currently, 40 children are alive and well; 26 after natural conception and 14 after assisted fertilization. In conclusion, even though the chances of conception are lower in patients undergoing transplant, especially after TBI conditioning, pregnancy outcomes following natural and assisted conception are likely to be similar in terms of chances of successful outcome.