Despite improvements in first-line therapies, published results on the treatment of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still poor. The aim of the present ...retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55) experiencing their first relapse (406 vs 141 shorter or longer than 18 months from diagnosis) were evaluated. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Philadelphia chromosome– and BCR-ABL–negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (n = 224) was 42%. After failure of first salvage (n = 82), the CR rate after second salvage was 33%. In relapse after SCT (n = 48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months and survival was 24% at 3 years. Prognostic factors for survival were relapse localization, response to salvage, performance of SCT, and age. Overall survival appeared superior compared with previously published studies, likely because of the high rate of SCT in the present study (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. The study is registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.
Summary Background Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet ...transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. Methods We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16–80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×109 per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. Findings 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2–43·1; p<0·0001) in all patients (2·44 2·22–2·67 in prophylactic group vs 1·63 1·42–1·83 in therapeutic group), 31·6% (18·6–42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 2·35–3·01 vs 1·83 1·58–2·10), and 34·2% (6·6–53·7; p=0·0193) in those who had had autologous transplantation (1·80 1·45–2·15 vs 1·18 0·82–1·55. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. Interpretation The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. Funding Deutsche Krebshilfe eV (German Cancer Aid).
Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on the health condition of cured adults ...are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (Eastern Cooperative Oncology Group ECOG status) and comorbidity or syndrome occurrence observed after treatment. Five hundred and thirty-eight patients with a median age of 29 (range, 15-64) years at diagnosis were analyzed, median follow-up was 7 (range, 3-24) years. Thirty-one percent had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), graft-versus-host-disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (P<0.0001); comorbidity was observed in 87% and 57% respectively (P<0.0001). Our analysis elucidates the spectrum of comorbidities in cured adult ALL patients, with higher risk for transplanted patients, providing stimulations for the design of adequate aftercare programs. Overall, a large proportion of non-SCT patients achieved unrestricted general condition. The data provide a reference for new patient-centered endpoints in future trials.
Therapy for relapsed and refractory multiple myeloma (RRMM) remains challenging. While monoclonal antibodies against CD38 combined with pomalidomide have demonstrated efficacy in clinical trials, ...real-world data remain sparse. We present real-world data from a compassionate use program (CUP) of isatuximab given in combination with pomalidomide and dexamethasone according to the German Compassionate Use Directive ahead of commercial availability for adult patients with RRMM. Patients had received at least two prior lines of therapy, including lenalidomide and a proteasome inhibitor (PI), and had demonstrated disease progression on the last therapy. Isatuximab was administered as part of the clinical routine. In total, 18 patients were included in the CUP before the official market availability of isatuximab. The data reflect a heterogeneous population in terms of age, risk factors, previous diseases, and treatments. Most of the patients had received two full isatuximab cycles. The analysis showed no new safety signals, supporting the manageable toxicity profile of isatuximab and highlighting its potential in real-world settings.
We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive ...chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m
GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m
GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.
Introduction
Patients (pts) with acute myeloid leukemia (AML) and induction failure or relapse have a dismal prognosis. In 2010 we started to offer an allogeneic transplantation (tx) in aplasia to ...all eligible patients with an HLA-compatible donor as soon as possible after diagnosis of refractory or relapsed AML. Here we report the results of a retrospective analysis.
Patients and treatment
25 pts (median age 51; 24-71) received an allogeneic tx in aplasia. Diagnoses were primary AML in 20 pts, t-AML in 3 and s-AML in 2 patients. 20 pts were transplanted because of primary refractory AML, in 5 pts the indication was relapsed AML. ELN classification was favorable in 3 (all NPM pos), intermediate-1 in 7, intermediate-2 in 4 and adverse in 11 pts. First induction therapy consisted of daunorubicin and Cytarabin (3+7) in all but one pt. A second induction with high-dose Cytarabin was given in 9/20 pts with induction failure. The search for a stem cell donor was started immediately after results of high-risk cytogenetic, no achievement of bone marrow aplasia on day 14 of induction therapy or in case of induction failure. Four patients had a related 10/10 donor, for 11 patients a 10/10 matched unrelated donor was identified and 10 patients received a transplant from a 9/10 unrelated donor. The interval between diagnosis and tx was 3 (1-4) months (mo) for patients with primary refractory AML as well as relapsed AML. In 21 patients melphalan (100-140 mg/m²) was used to induce an aplasia before starting conditioning therapy. The interval between melphalan and conditioning therapy was 13 (9-21) days. 3 pts started the conditioning therapy while in aplasia after previous chemotherapy. The conditioning therapy was of reduced intensity in all pts. and consisted of Treosulfan (30g/m²)/Fludarabin in 18 pts, TBI(8Gy)/Fludarabin in 5 pts and Busulfan(8m/(kg)/Fludarabin in 2 pts, respectively. Most pts (17/25) had a severe neutropenia below 0,5/nl (med 0,2; 0,1-5,2) before starting melphalan because of refractory leukemia.
Results
After a median follow-up of 31 (10-60) mo 6 pts (24%) are alive without relapse. 5 (20%) pts died because of a relapse after a median of 6 (2-18) mo. The non-relapse mortality was 44% (14/25 pts). Most of these pts (9/19, 47%) died because of infectious complications early after transplantation (med 1; 0-11) mo). Two patients developed pulmonary toxicity and died 1, respectively 19 mo after tx. In 3 pts acute gvhd was the main cause of mortality. The results for patients with 10/10 or 9/10 donors were comparable.
Conclusion
In this retrospective "real-life" analysis we showed that an early allogeneic transplantation is feasible for patients with primary refractory and relapsed AML. A reduced intensity conditioning after induction of aplasia with melphalan offers a chance of long-term relapse-free survival for about a quarter of patients with an otherwise dismal prognosis. NRM is high, especially because of infectious complications early after transplantation, probably related to the long period of severe neutropenia. Therefore, the focus has to be set on early recognition and intervention of infectious complications.
No relevant conflicts of interest to declare.
Background: Between 2005 und 2010 we conducted a multicenter randomized study comparing a therapeutic and a prophylactic (morning platelet (ptl) trigger < 10/nl) platelet transfusion strategy in ...patients with hematological disorders. (The Lancet Vol 380, No 9850, pp 1309-16). Briefly, we could show that a therapeutic plt transfusion strategy, where platelets are transfused in clinical stable patients (pts) only if bleeding ≥ WHO grade II occurs is safe in patients after autologous transplantation. In patients with acute myeloid leukemia (AML) we observed significantly more severe bleedings (WHO IV°) with the therapeutic regimen. To proof, if there is a difference in bleeding risk related to the remission status of the patients, we conducted a post-hoc analysis to compare the risk of severe bleeding (WHO III° and IV°) in induction with consolidation therapy.
Patients and Methods: We analyzed 175 pts with 175 cycles of induction therapy, 90 with a prophylactic transfusion regimen and 85 cycles with a therapeutic regimen. 131 pts received 268 cycles of consolidation therapy, 155 with a prophylactic and 113 with a therapeutic transfusion strategy.
Results: Bleedings WHO III° were neither different between the two strategies nor between induction and consolidation therapy. In contrast, there were significantly more bleedings WHO IV° in induction (7,4%) compared to consolidation therapy (1,5%; p=0,01). In addition, there were significantly more bleedings WHO IV° with the therapeutic regimen (11,8%) compared to the prophylactic strategy (3,3%) in induction therapy (p=0,012). This difference was less pronounced in consolidation therapy. But even in the prophylactic arm most WHO IV° bleedings occurred in pts with more than 10/nl ptl, which shows, that the morning platelet count should not be the only trigger for a platelet transfusion.
Conclusions: In consolidation therapy the risk of bleeding is significantly less compared to induction therapy, even with a therapeutic platelet transfusion strategy. During induction therapy the prophylactic strategy should remain the standard of care. The therapeutic transfusion strategy in consolidation therapy will be proven prospectively in an ongoing multicenter study.
No relevant conflicts of interest to declare.
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Detectable MRD during chemotherapy is considered to be the most important prognostic factor in ALL. Pts with molecular failure (MolF) have a poorer overall survival (OS), inferior remission ...duration (RD) and poorer prognosis even after stem cell transplantation (SCT) compared to pts with molecular CR (MolCR) (Gökbuget et al, Blood 2012: 120(9): 1868). Little is known however on the outcome of pts with MRD results not fitting in the above categories e.g. MRD low positive and on the impact of additional treatments in pts with MolF.
We report an expanded cohort of pts treated according to protocol 07/03 (within the trial or in GMALL registry). MRD was tested by real-time PCR of clonal TCR and Ig gene rearrangements in a reference laboratory (Kiel). The analysis refers to molecular response in ‘wk 16‘ after induction/1st consolidation and to molecular relapse (MolR) later than wk 16 (all definitions see table). The GMALL recommended referral of MolF and MolR pts to SCT in CR1.
The median age of 2061 pts with Ph-neg ALL (1484 trial, N=577 registry) was 34 (16-65) yrs. Pts < 18 yrs (3%) were included until 2012 only. 90% (N=1857) achieved a CR, early death and failure rates were 5% respectively (resp). OS and RD were 60% and 64% at 5 yrs resp. 57% of the CR pts (N=1057) had an MRD test in wk 16. The rate of MRD tests increased over the yrs (2003-2009: 53% vs 2010-2016:69%; p<.0001) as prognostic relevance became more evident.
625 (59%)/1857 pts had a MolCR and196 (18%) MolF. In addition 7% were MRDneg and 16% MRDpos - both not fulfilling the criteria of MolCR or MolF (definitions see table). Results for OS at 5 yrs (MolCR vs MolF vs MRDneg vs MRDpos) were 83% vs 43% vs 78% vs 68% resp. and for RD 80% vs 38% vs 76% vs 56% resp. Differences were significant (p<.0001) for comparison of all groups, for MolCR vs MRDpos and MolCR vs MolF, but not for MolCR vs MRDneg.
In 196 MolF pts OS and RD from wk16 onward was 43% and 38% at 5 yrs resp. 121 (62%) MolF pts received SCT in ongoing 1st CR. The SCT rate in MolF pts increased from 54% (2003-2009) to 72% (2010-2016)(p=.008). OS and RD for non-SCT vs SCT pts was 28% vs 53% (p<.0001) and 9% vs 56% (p<.0001) at 5 yrs resp.
Out of 196 MolF pts, 19 relapsed shortly after wk 16, 2 pts were withdrawn, 1 pt died in CR and data were missing in 6 pts. Of the remaining 168 pts, 52 received immediate SCT (31%), whereas 115 pts received consolidation. Data on molecular response after the next 1-3 cycles or after SCT were available for 142 pts. In B-prec ALL (N=95) and T-ALL (N=47) the MolCR rate was 34% and 43% resp. for non-SCT approaches, whereas 75% and 71% resp. achieved a Mol CR after immediate SCT (table). However, the OS with immediate SCT vs later SCT was 34% (N=52) vs 63% (N=69) at 5 yrs resp (p=.002) and the corresp. RD was 42% vs 66% (p=.001) resp. Furthermore, pts with next consolidation leading to molCR had a superior OS (76% at 5yrs) vs those who did not (44% at 5yrs) (p=.02). A similar difference was seen for RD (60% vs 36% resp.; p=.08).
In addition 102 pts with MolR during/after chemo were observed (median time to MolR: 18 mo). OS and RD from MolR onwards were 51% and 35% at 5 yrs. 38 pts were transplanted in ongoing 1st CR. OS w/o and with SCT was 37% vs 71% (p=.001) resp. with corresp. RD of 5% vs 70% (p<.0001). Results of salvage therapies in 41 pts were comparable to those in MolF (table).
Important conclusions for future MRD based therapy can be drawn from this large adult ALL cohort: 1) a similar poor prognostic impact of MolF and MolR is underlined; 2) it is demonstrated that pts with any detectable MRD (MRDpos) have an intermediate prognosis and require regular follow-up MRD testing; 3) SCT offers an advantage in MolF and MolR pts, however 4) evidence was provided that later SCT (i.e. in better molecular status) could be superior to immediate SCT; 5) compliance with MRD testing and SCT in MolF increased over time; 6) many MolF pts relapsed quickly; 7) additional chemotherapy offered limited chances to achieve a MolCR, but 8) promising MolCR rates were observed for targeted therapies.
For future optimisation of MRD based therapy, logistics for decisions have been implemented earlier in the GMALL trial 08 in order to avoid rapid relapses. A first stratification takes place already after induction and targeted therapies are recommended in all MolF pts before SCT.
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Rollig:Janssen: Research Funding; Bayer: Research Funding. Kneba:AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding.
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