Prognostic impact of early-versus-late responses to different induction regimens in patients with myeloma undergoing autologous hematopoietic cell transplantation: results from the CALM study by the CMWP of the EBMT
European journal of haematology. 2021
BACKGROUND In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. METHOD We analysed 1,222 ASCT patients who were classified based on (1) the interval between induction and stem cell collection, (2) the type of induction regimen: BID (Bortezomib, IMiDs and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide and Dexamethasone), and (3) the time to best response (Early i.e. best response within 4 or 5 months, depending on the regimen vs Late; Good i.e. VGPR or better vs Poor) RESULTS The length of induction treatment required to achieve a Good response did not affect PFS (p=0.65) or OS (p=0.61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (p=0.31), and median OS 81.7, 92.7, and 77.4 months, respectively (p=0.83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, p value = 0.02). However, achieving a Good response at induction was associated with a better response (= VGPR) post-transplant CONCLUSION The kinetics of response did not affect outcomes.
Risk stratification using FLT3 and NPM1 in acute myeloid leukemia patients autografted in first complete remission
Bone marrow transplantation. 2020
FLT3-ITD and NPM1 mutation refine prognostic stratification in acute myeloid leukemia (AML) with intermediate-risk cytogenetics. However, data on their role in patients undergoing autologous stem cell transplantation (Auto-SCT) as post-remission therapy (PRT) are limited. We therefore sought to retrospectively evaluate the role of FLT3-ITD and NPM1 in a cohort of AML patients (n = 405) with intermediate-risk cytogenetics, autografted in first complete remission (CR1). Patients were transplanted between 2000 and 2014 and reported to the European Society for Blood and Marrow Transplantation (EBMT) registry. Leukemia-free survival (LFS) was the primary outcome. Median follow-up was 5.5 years. FLT3-ITD(neg)/NPM1(WT) was the leading molecular subtype (50%), followed by FLT3-ITD(neg)/NPM1(mut) (30%). In the univariate analysis, molecular subtype was associated with LFS, overall survival (OS), and relapse incidence (RI) (p < 0.001); 5-year LFS: FLT3-ITD(neg)/NPM1(mut) 62%, FLT3-ITD(pos)/NPM1(mut) 38%, FLT3-ITD(neg)/NPM1(WT) 32%, and FLT3-ITD(pos)/NPM1(WT) 21%. At 5 years, OS and RI in the FLT3-ITD(neg)/NPM1(mut) subtype were 74% and 35%, respectively. The corresponding OS and RI in other subtypes were below 48% and over 57%. In a Cox multivariable model, molecular subtype was the strongest predictor of LFS, OS, and relapse. In conclusion, AML patients with intermediate-risk cytogenetics and FLT3-ITD(neg)/NPM1(mut) experience favorable outcomes when autografted in CR1, suggesting that Auto-SCT is a valid PRT option.
[Epidemiology of early infections after autologous hematopoietic stem cell transplantation. Analysis of data from 699 patients treated in a Hungarian centre]
Orvosi hetilap. 2020;161(3):103-109
Introduction: Autologous hemopoietic stem cell transplantation remains a promising therapy in certain malignant and non-malignant conditions. The procedure, however, will increase the risk of complications, most notably early and late infections. Aim: To analyze the frequency and spectrum of pathogens in early (<+100 days) post-transplant infections and to evaluate risk factors for mortality. Method: Prospectively collected data from 699 patients undergoing autologous hemopoietic stem cell transplantation between 2007 and 2014 at our center were retrospectively reviewed and analyzed. Results: The median age of 699 patients was 56 (interquartile range: 43-62) years, 54% (376) were male. 25 patients have been transferred to other centers and 19 patients were lost to follow up. Neutropenic fever occurred in 69.8% (488) of patients. In addition, 102 infectious episodes in 96 patients were identified. Most commonly bacteremia occurred (49 episodes) with a median onset of 7 (5-11) days. The majority (33/49) of bacteremias have been observed during the pre-engraftment period. Their incidence proved to be higher in patients with malignant lymphoma compared to individuals with plasma cell disorders (p = 0.0005, OR: 2.41, 95% CI: 1.49-3.99). 12 episodes of viral infections and 8 cases of proven or probable invasive mycoses have been identified. Among the 655 patients with complete follow up, 16 in-hospital deaths (2.4%) occurred, 8 of them were associated with infections. Survival was adversely affected by early infections (p = 0.0001). Conclusion: In autologous stem cell transplantation, microbiologically unconfirmed neutropenic fever is common. Documented early bacteremia, however, is infrequent. Lymphoma patients have a significantly higher chance to develop bloodstream infections compared to individuals with plasma cell disorders. Early infections decrease the chance of survival; thus, an effective prophylaxis and therapy remains of paramount importance. Orv Hetil. 2020; 161(3): 103-109.
The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT
Annals of hematology. 2019
It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.
EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL)
Bone marrow transplantation. 2019
Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.
Allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL.
With a median follow-up of 50 months, the 4-year non-relapse mortality was 32%, relapse incidence 38%, progression-free (PFS) 30% and overall survival 42%. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM.
Donor KIR2DS1 reduces the risk of transplant related mortality in HLA-C2 positive young recipients with hematological malignancies treated by myeloablative conditioning
PloS one. 2019;14(6):e0218945
BACKGROUND Recognition of HLA-C2 group alleles on recipient cells by activating killer immunoglobulin like receptors, KIR2DS1 on donor natural killer cells may lead to increased graft-versus-leukemia effect or immunomodulation in patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) influencing disease free and overall survival (OS). OBJECTIVE In the present study, 314 consecutive, allo-HSCT recipient and donor pairs were included with retrospective donor KIR-genotyping and clinical parameters analyzes. RESULTS After a median follow-up of 23.6 months, recipients with HLA-C2 group allele (rC2) showed improved (p = 0.046) OS if transplanted with KIR2DS1 positive donors (d2DS1) compared to those without one or both of this genetic attribute. Within the myeloablative conditioning (MAC) subgroup (n = 227), rC2 homozygous+d2DS1 patients (n = 14) showed a 5 years OS of 93% followed by rC2 heterozygous+d2DS1 patients (n = 48, 65%) compared to rC2 and/or d2DS1 negatives (47%, p = 0.018). Multivariate analyses indicated rC2+d2DS1 positivity as an independent predictor of OS (HR:0.47, 0.26-0.86, p = 0.014) besides donor type, presence of CMV-reactivation or chemoresistant disease. Among MAC-treated patients, the combined rC2+d2DS1 presence was associated with a markedly decreased cumulative incidence of transplant related mortality (p = 0.0045). CONCLUSION The combination of rC2+d2DS1 may be a favorable genetic constellation in allo-HSCT with MAC potentially reducing transplant related mortality.
Impact of antithymocyte globulin on outcomes of allogeneic hematopoietic cell transplantation with TBI
Blood advances. 2019;3(13):1950-1960
The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.
Investigation of TGFB1 -1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation
Bone marrow transplantation. 2019
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor beta1 (TGFbeta1) play a pivotal role in immune reconstruction, and the development of graft versus host disease (GvHD) or infections. The aim of this study was to investigate the role of TGFB1 gene -1347C>T variant in the outcome of HSCT in a cohort of 409 adult recipient-donor pairs. TGFB1 variant was analysed from genomic DNA with LightCycler hybridisation probe method. In case of myeloablative conditioning, donor TGFB1 genotype correlated with overall survival (60-month OS for CC: 62.1 +/- 4.8%; CT: 46.8 +/- 4.8%; TT: 35.6 +/- 9.3%; p = 0.032), which was independent of age, donor type and GvHD prophylaxis in multivariate analysis (HR:2.35, 95%CI:1.35-4.10, p = 0.003). The cumulative incidence of acute GvHD grade III-IV [CC:10%; CT:17%; TT:24%], and non-relapse mortality was higher in TT-carriers (24-month NRM: CC:24%; CT:26%; TT:46%, p = 0.035). We did not find any association between recipient TGFB1 -1347C>T polymorphism and HSCT outcome. Our results suggest that donor TGFB1 -1347C>T may exert an adverse influence on the outcome of myeloablative conditioning transplantation.
Tandem autologous stem cell transplantation improves outcome in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the Chronic Malignancies Working Party of EBMT
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Although high-dose therapy and autologous stem cell transplantation combined with novel agents is still the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease and high-risk cytogenetics is not defined yet. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with extramedullary disease undergoing single autologous (n=373), tandem autologous (n=84), or autologous-allogeneic transplantation (n=31) between 2003 and 2015. At least one high-risk abnormality was present in 41% (n=202), with del(17p) (40%) and t(4;14) (45%) being the most frequent. More than one high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival and progression-free survival of 54% and 29% vs. 78% and 49% for standard-risk (p<0.001, respectively). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, overall and progression-free survival were 70% and 43% for single autologous vs. 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (p=0.06 and p=0.30). In multivariate analysis, high-risk cytogenetics were associated with worse survival (HR, 2.00; p=0.003) while tandem autologous significantly improved outcome vs. single autologous transplant (hazard ratios, 0.46 and 0.64; p=0.02 and p=0.03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival while results were limited due to small population (hazard ratio, 0.31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with extramedullary disease and significantly worsens outcome after single autologous while tandem autologous transplant strategy may overcome onset poor prognosis.
Adult myeloma patients with extramedullary disease (n=488).
Tandem autologous transplantation (n=84) or autologous-allogeneic transplantation (n=31)
Single autologous transplantation (n=373)
Overall and progression-free survival were 70% and 43% for single autologous vs. 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic. In multivariate analysis, high-risk cytogenetics were associated with worse survival, while tandem autologous significantly improved outcome vs. single autologous transplant. Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival while results were limited due to small population.
Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT
Journal of hematology & oncology. 2019;12(1):108
BACKGROUND Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. METHODS In this retrospective registry study, we explored whether measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated donors. RESULTS In 1816 of patients, no disease was detectable, and in 964 patients, MRD was positive. Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), and 1.51 (1.26-1.8). TBI was associated with a higher OS, LFS, and lower RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82), and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS and LFS and higher RI in the TBI group, and with higher RI in the chemotherapy group. TBI-based conditioning was associated with improved outcomes in both MRD-negative and MRD-positive patients. CONCLUSIONS In this large study, we confirmed that patients who are MRD-negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI-based conditioning in the myeloablative setting.