Litzow, Mark R.

e19530 Background: Intensive chemotherapy (IC) regimens are rarely used in patients with myelodysplastic syndromes (MDS) for many reasons including advanced age at diagnosis, the frailty of these patients, the presence of several comorbidities and potentially increased mortality when such regimens are used. Additionally, very little literature exists on its safety and long-term benefit in this population. Aim: To evaluate the safety and effectiveness of IC regimens in patients with MDS. Methods: We searched MEDLINE, Embase, Scopus and Cochrane databases from each database's inception from 1990 to January 27th, 2020. Keywords include: “MDS”, “induction chemotherapy” and “remission induction”. Studies evaluating different IC regimens with MDS were included. IC studies for patients with relapsed/ refractory MDS were excluded. Studies that combined acute myeloid leukemia (AML) and MDS outcomes were excluded. The random-effects model was used to pool relative risks and incidence rates. Main endpoints were overall remission rates (ORR), 30- and 60-days mortality, 1-year, 2-year and 5-year overall survival (OS). Results: Characteristics: From 2001 records, we included 13 studies [1,164 patients, median age 60.1 years (range, 17-88), males 58.9%, 58.4% patients had abnormal cytogenetics, median bone marrow blasts 17.8% (range 4 -29%), 4 studies were randomized]. Induction outcome: IC regimes included “7+3, FLAG, s-HAM, and few other regimens. Response: ORR was 55%, including 52% CR rate. Safety: 30- and 60-days mortality were 7%, 15%, respectively. Survival outcome: median survival was 11.6 months, 1-year, 2-year and 5-year OS were 48%, 21% and 5%, respectively. Randomized studies comparison: adding growth factors to IC did not show statistically significant effects on outcomes regarding induction mortality, ORR and OS (p-value > .05). Conclusions: IC is rarely used in MDS patients and its use is associated with high mortality rates and low long-term survival. Limitations to our studies include the long span of this review over 3 decades and the difficulty of using published studies that combines MDS and AML patients’ outcome. More studies are needed in this population of interest in the future.

7523 Background: tALL is a recently appreciated but poorly defined clinical entity. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and we report a comparative analysis of characteristics, cytogenetics and outcomes for this subset among a modern unselected ALL cohort from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all patients (pts) diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) between 2008-2018. Comparisons of characteristics between tALL and dnALL were made using a Wilcoxon rank sum test (continuous variables) and Fisher’s exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 431 ALL pts were identified during the study period, including n = 69 (16%) classified as tALL. Median follow-up from diagnosis was 2.3 years (range 0-18 years). The most common prior malignancies among tALL pts were Breast (24.6%), Lymphoma (15.9%), Myeloid (15.9%), GU/GYN (14.5%) and Myeloma (11.6%). In comparison to dnALL, pts with tALL were significantly older (63.2 vs 45.2 years, P < 0.001), more often female (65.2% vs 39.8%, P < 0.001), less frequently Hispanic (3.5% vs 13.1%, P = 0.042); more often of B-lineage (92.8% vs 81.8%, P = 0.022). On review of cytogenetics, tALL pts more often had hypodiploidy/near triploidy (Ho/Tr) (21.7% vs 4.1%, P < 0.001), more often had monosomal (MDS-like) (33.3% vs 12.4%, P = 0.0047) and complex karyotype (38% vs 17.3%, P = 0.0069). Importantly, incidence of BCR/ABL-positive (Ph+) ALL was not significantly different. Latency period between exposure to prior cancer therapy and development of tALL was significantly longer for Ph+ compared to Ph-negative ALL (median 9 vs. 4 years, P = 0.007). Patients with tALL had a 3-year OS after diagnosis of 37% [vs 59.7% for dnALL (HR death 1.86, 95% CI 1.31-2.65, P < 0.001)]. However, the two groups did not differ significantly regarding occurrence of AlloHCT (HR = 0.91, 95% CI 0.63-1.31, P = 0.61) or post-AlloHCT survival (HR = 1.29, 95% CI 0.75-2.23, P = 0.35). Conclusions: Therapy-related ALL represents an important & unique clinical entity with poor prognosis & adverse cytogenetic features. Ph+ tALL has a longer latency and similar frequency in both tALL and dnALL. AlloHCT appears to be an appropriate treatment strategy, possibly abrogating the poor prognosis of tALL.

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P &lt; .0001; DIPSS-Int-2 and higher: HR, 0.39, P &lt; .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P &lt; .0001; DIPSS-Int-2 and higher: HR, 2.55, P &lt; .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

Abstract High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460.

Abstract Introduction: The immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor has been crude. There is now a test that reproducibly measures serum levels of FLC. We evaluated the utility of this assay in patients with AL undergoing peripheral blood stem cell transplant (PBSCT). Methods: Between March 1, 1996 and July 31, 2004, 98 patients with AL undergoing PBSCT had serial FLC measurements performed either prospectively or on stored sera. Patients who died before their 100 day evaluation were excluded because response could not be estimated. FLC levels were performed using Freelite™ reagents on a Dade-Behring Nephelometer. In order to pool the data of the monoclonal kappa and lambda patients, the clonal free light chain was considered the involved] immunoglobulin free light chain for the purpose of these analyses and is henceforth referred to as FLC. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were evaluated. Results: Pre-transplant, 94% of patients had an abnormal FLC ratio, with a median involved FLC of 152 mg/L [15.2 mg/dL]. Only 14% of 98 patients had a “measurable” serum M-spike (i.e. ≥ 10 g/L [1 g/dL]) on electrophoresis with a median of 1 g/L [0.1 g/dL]. Ten patients have died of their disease during a median follow-up time of 19.5 months, range 3.3 to 103 months. The 2- year and 4-year estimated survivals are 92% and 76%, respectively. Using the 75th percentile value of pre-PBSCT FLC (382 mg/L [38.2 g/dL]) as a grouping variable, there was a significantly higher risk of death 5.4 (95% confidence interval 1.5–19.3) in the patient quartile with the highest baseline FLC. Baseline FLC correlated with serum cardiac troponin T levels (rho 0.51, p&lt;0.0001), suggesting that high FLC levels are associated with more advanced disease. After PBSCT, the median percent reduction of FLC was 81%. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. The hazard ratio for death for not achieving a post-transplant FLC of 20 mg/L [2 mg/dL] post-transplant was 5.1 (95% confidence interval 1.1–24.1). Of 91 patients evaluable for complete response by EBMT criteria, 45 had a complete hematological response. Sixty-five percent of the patients achieving a FLC level of less than 20 mg/L [2 mg/dL] also had a complete hematologic response. Free light chain response as defined by a post transplant FLC level 20mg/L [2 mg/dL] or lower was a more powerful predictor of survival than complete hematologic response, as defined by the EBMT multiple myeloma criteria. Post-PBSCT FLC level only weakly predicted for organ response, but median follow-up for surviving patients is relatively short at 19.6 months. Conclusion: FLC measurements both pre- and post-PBSCT are important predictors of patient outcome.

Abstract Introduction: The association of amyloidosis with immunoglobulin light chain disorders is well recognized. It is less commonly appreciated that amyloidosis can be associated with IgM monoclonal gammopathies. One of the available therapies for treating amyloidosis is stem cell transplantation. It is unknown whether the clinical outcomes in patients with IgM amyloidosis differs from those patients with light chain amyloidosis. Patients: Among 242 amyloidosis patients receiving stem cell transplants 10 (4%) had an IgM monoclonal protein. Eight were Mλ. One was biclonal Mλ Mκ and one was biclonal Mκ Gλ. The age range was 56 to 71, median 64 years. Seven were men. The monoclonal protein ranged in size from 0.1 to 2.3 g/dL (median 1.2 g/dL). Patients were transplanted from 2 to 8 months (median 4 months) following histologic diagnosis of amyloid. The median time from the recognition of the IgM monoclonal protein to the diagnosis of amyloid was 1.3 months, but 2 patients, both of whom had overt Waldenström’s macroglobulinemia, were diagnosed 45 and 115 months respectively before amyloidosis developed. Of the cohort of 10, 3 fulfilled the criteria for symptomatic Waldenström’s macroglobulinemia. Results: Amyloid syndromes were recognized in the kidney, heart, peripheral nerve and liver in 8, 3, 3 and 1 patient, respectively. Of the 3 peripheral neuropathy patients one also had autonomic failure. Seven of the 8 renal amyloid patients were confirmed with a renal biopsy. Their urinary protein loss ranged from 0.1 to 9.5 g/24h with a median of 4.7 g/24h. Six of the 10 patients had single organ involvement, 3 had 2 organ involvement and 1 had 3 organ involvement. All 3 Waldenström’s patients had prior exposure to cytotoxic chemotherapy. Amyloid deposits were seen in the bone marrow, fat and lymph node in 6, 5 and 1 patient, respectively. Patients underwent from 1 to 7 (median 3) apheresis with a median CD34 yield of 4.5 x 106/kg. Conditioning was Melphalan at 140 and 200 mg/m2 in 2 and 8 patients respectively. Neutrophil engraftment 500/μL occurred between day 11 and 30 (median 14) and for platelets 20,000/μL between day 11 and 406 (median day 16). The median number of hospitalization days ranged from 0 to 32 (median 12). Nine of the 10 patients fulfilled criteria for a hematologic response and to date 3 of these 9 have also achieved an organ response, including normalization of urinary protein loss in 2 nephrotic patients and a greater than 50% reduction in urinary protein loss in the third. None of the patients with amyloid neuropathy responded. One of the patients with cardiac amyloid showed echocardiographic evidence of improvement. At this time 8 survive and 2 died; 1 a treatment-related death (day +40) and 1 of relapse post transplant with progressive amyloid at 45 months. The median follow-up of surviving patients is 29 months. Conclusion: The outcomes in patients with IgM amyloidosis following transplantation do not appear to be different from those with immunoglobulin light chain amyloidosis. There is no suggestion that the response rates are lower or that alternate conditioning schemes such as BEAM should be considered.

Abstract AMD3100, a CXCR4 receptor antagonist, has been studied as a stem cell mobilization agent for the purpose of autologous stem cell transplantation (ASCT) in hematologic malignancies. Lymphocyte subset analysis of peripheral blood in patients treated with AMD3100 has been studied in healthy volunteers. To date, no reports exist describing the lymphocyte subsets of the autograft in patients undergoing AMD3100 stem cell mobilization for the purposes of ASCT in non-Hodgkin lymphoma (NHL). Considering our prior work demonstrating the significant impact of autograft lymphocyte content on clinical outcomes of patients undergoing ASCT for NHL we set out to profile autograft lymphocyte subsets of patients undergoing mobilization with AMD3100. Using flow cytometry, we analyzed aliquots of apheresis products in 7 patients with NHL undergoing AHSCT who received AMD3100 in addition to G-CSF as a part of their mobilization regimen. These results were compared to 29 patients with NHL who had undergone stem cell mobilization with G-CSF alone. There were no significant differences between these two groups of patients in terms of sex, age, performance status, histology, LDH, and number of pretransplant chemotherapeutic regimens. CD34+ cells collected at apheresis did not differ significantly between the groups. However, compared with G-CSF alone, patients that received AMD3100 had an approximate 5-fold increase in CD4+ cells (0.62 x 109 cells/kg vs. 0.12 x 109 cells/kg, p = 0.0004), a 3.5-fold increase in the absolute number of autograft CD3+ cells (1.21 x 109 cells/kg vs. 0.33 x 109 cells/kg, p = 0.0017), and a 2.5-fold increase in CD8+ cells (0.48 x 109 cells/kg vs 0.19 x 109 cells/kg, p = 0.215). A significant increase was also noted in CD4+25+ cell compartment (0.17 x 109 cells/kg vs. 0.006 x 109 cells/kg, p = 0.0001). No significant difference was noted in the absolute number of autograft CD16+56+ NK cells. Finally, an increase in the autograft total absolute lymphocyte count (41.6 x 109 cells/kg vs. 2.88 x 109 cells/kg, p &lt; 0.001) as well as peripheral blood absolute lymphocyte count at day 15 after AHSCT was observed in those patients who had received AMD3100 (0.79 x 109 cells/kg vs. 0.58 x 109 cells/kg, p = 0.04). The increased lymphocyte content of the autograft (total and subset) would suggest the potential of positive impact on clinical outcomes in patients mobilized with AMD3100. Indeed, none of the patients who received AMD3100 had relapsed disease at one year post-transplant (although two of these patients are currently 9 months and 11 months post-transplant respectively), whereas 10 of the 29 control patients had relapsed disease at one year. Further studies are necessary to confirm these observations and ascertain their clinical significance.

Abstract Introduction: Stem cell transplant is an increasingly widely applied technique for managing amyloidosis. As in multiple myeloma, the treatment would not be expected to be curative and patients would be expected to relapse in most instances. In addition, approximately one-third of patients fail to respond to initial therapy. The role of second transplantation in treatment failures or patients who relapse is reviewed. Patients: Of 242 patients undergoing high dose conditioning and stem cell transplantation for amyloidosis (AL) at the Mayo Clinic, 6 subsequently underwent a second transplant. Results: Patient 1, who had single organ renal amyloid nephrotic syndrome responded and relapsed at 73 months, received a second stem cell transplant achieving a hematologic complete response with normalization of a markedly elevated pre transplant free light chain (59 to 1.9 mg/dL) and is alive at 12 months. Patient 2 relapsed 42 months after transplant for single organ renal amyloidosis; the second stem cell transplant, has normalized his free light chain ratio reduced his urinary protein loss from 5450 to 1482 mg/day and he is alive 21 months following his second transplant (63 months overall). Patient 3 relapsed 34 months after a response of renal and cardiac amyloidosis. After transplant two, he failed to achieve a 50% reduction in his free light chain, began hemodialysis 7 months post transplant and died one year post transplant. Patient 4 with single organ cardiac involvement relapsed 30 months following his first transplant and died on day +5 of his second transplant of an acute pulmonary embolus. Patient 5 was a response failure after his first transplant, had a second transplant 35 months later, having failed Dexamethasone followed by Melphalan/Dexamethasone therapy, and died 3 months later of progressive disease. Patient 6 had single organ vascular involvement manifest by calf and thigh claudication and failed to respond with his first transplant with a persistently elevated free light chain. The second transplant was performed six months after the first without further free light chain reduction and persistent claudication at 11 months. Conclusion: Patients who failed to achieve a hematologic response after a first transplant appear not to benefit from a second course of high dose therapy. Among 4 patients who were previously responsive and relapsed, one achieved a hematologic complete response, one achieved a hematologic partial response, and two died. The two patients achieving a second hematologic response had the longest response duration (73 and 42 months) following their first transplant, and the second response presumably reflects favorable (indolent; non proliferative) biology of the underlying plasma cell dyscrasia. High dose therapy and stem cell transplant may be an effective salvage regimen for patients who responded to a first transplant and whose response lasted greater than 36 months.

Abstract Background: Pre-treatment cytogenetics is a known predictor of outcome in haematological malignancies. However, its value in adult ALL is generally limited to the presence of the Philadelphia (Ph) translocation; mostly due to the low incidence of other recurrent chromosomal abnormalities. Methods: Since 1993, cytogenetic data from patients enrolled on a joint MRC/ECOG trial have been collated and reviewed centrally in the UK and US. Karyotype data from patients registered before the Imatinib amendment were pooled using standard cytogenetic definitions and classification criteria. Results: A successful cytogenetic result was achieved in 938/1235 (76%) cases; while 297 (24%) failed with &lt;20 normal metaphases analyzed. Patients were classified into the following mutually exclusive groups: t(9;22)(q34;q11) n=193(21%); t(4;11)(q21;q23) n=50(5%); other MLL translocations n=11(1%), t(8;14)(q24;q32) and variants n=14(1%); t(1;19)(q23;p13) n=23(2%); T cell receptor translocations n=35(4%); low hypodiploidy (30–39 chromosomes) /near triploidy n=23(2%); high hyperdiploidy n=83(9%); tetraploidy n=12(1%); complex karyotype (&gt;=5 aberrations) n=48(5%); other abnormal n=255(27%); normal n=191(20%). MRC and ECOG patients showed similar cytogenetic distributions, except for t(9;22), which was significantly more prevalent in the ECOG cohort (27% v 18%, p&lt;0.001). However, the incidence of t(9;22) increased with age and ECOG patients were significantly older. Overall, the 5 year event free survival (EFS) was 32% (95% CI 30%–35%) with a median follow-up time of 5.1 years and did not differ between the two cohorts. The EFS of t(9;22) patients [15% (11%–21%)] was significantly inferior compared with all other cases [36% (32%–39%)] (p&lt;0.001) and was independent of age and white cell count (WCC). Univariate logrank analyses identified t(4;11) and high hyperdiploidy as indicators of poor and good prognosis, respectively, compared with other Ph negative cases, but neither was independent of age and WCC. Three subgroups were shown to have a significantly worse EFS compared to other Ph negative cases by logrank analyses after adjusting for age and WCC: t(8;14) 14% (2%–37%) v 36% (32%–40%) (p=0.01); low hypodiploidy 22% (8%–40%) v 36% (32%–40%) (p=0.02); complex karyotype 21% (10%–33%) v 32% (29%–35%) (p=0.005). Neither of the latter two subgroups were associated with other poor risk features such as age, WCC or failure to achieve a remission within 4 weeks. Conclusions: This is the largest cytogenetic dataset of adult ALL reported to date and demonstrates the importance of combining cohorts to increase the number of cases available for analysis. The observation that low hypodiploidy and, for the first time, karyotype complexity confer a poor risk, demonstrates that cytogenetic subgroups other than the Ph translocation can and should be used to risk stratify adults with ALL to alternative treatments.

Abstract Background: Overall prognosis in CMML is unfavorable. The only curative option is ASCT, yet the limited data available from the largest reported series, reports 2 year overall (OS) and disease free (DFS) survival of only 21% and 18%, respectively [Kroger et al, BJH 2002, 118: 67]. Data on DLI for CMML are generally restricted to case reports. We retrospectively reviewed our experience of ASCT and DLI for adults with CMML. Patients: Seventeen consecutive patients (11 males) with CMML underwent ASCT from 1992 to 2004. At transplant, median (range) age was 50 years (26–60), duration of disease 7 months (2.5–44), and bone marrow (BM) blast count 6% (1–58%). Prior to transplant, 11 had evolved into acute myeloid leukemia (AML). Of these, 10 received standard induction chemotherapy but only one achieved complete remission (CR); 5 had persistent CMML and 4 refractory AML. Karyotype at transplant was either normal (n=9) or revealed isolated monosomy 7 (n=4), complex (n=1), or single, nonrecurrent abnormalities. ASCT: Conditioning was Cytoxan/Total Body Irradiation in all but one who received a non-myeloablative (NMA) regimen (cladrabine/ATG/thiotepa). Stem cell source was HLA-identical sibling in 14 patients and unrelated in 3 peripheral blood (PB) in 7, BM in 8, or both in 2. Median BM mononuclear cell/kg dose was 2.3 (1.7–4.15) x 108 and PB CD34 cell/kg was 5.12 (0.94–7.29) x 106. Graft versus host disease (GVHD) prophylaxis was cyclosporin alone (n=3), with methotrexate (n=12), or prednisone (n=1) or was tacrolimus/methotrexate (n=1). Post-transplant course: All but one patient who died on day 11 of sepsis engrafted (sustained ANC &gt; 500) at a median of 19.5 days (13–31). CR was documented in 13 (76%) post-ASCT. Acute GVHD was grade II-IV (75%) and III-IV (37.5%) and chronic GVHD was extensive (n=37.5%). Seven (41%) demonstrated relapse or persistent disease at a median of 6 months (3–55.5) and 13 (76%) have died due to disease (n=6) or transplant related mortality (n=7). DLI: Six patients underwent DLI for morphologic (4 recurrent/persistent CMML, 1 early AML with extramedullary disease) or cytogenetic relapse (n=1), at a median of 19.5 days (6–52) post-relapse. Median BM blast count at DLI was 3% (1–22%). The median CD3+ cell dose infused was 30.45 x 107 cells/kg (11.2–45.5), given in a median of 3 infusions (range: 1–3). Four did not respond, but two (one with cytogenetic and one with morphologic relapse) achieved a durable CR of 15 months each, both had extensive CGVHD, from which one died of complications. The other relapsed but failed to respond to a second DLI and died of disease. Survival: For the entire cohort, median DFS and OS were 6 months and 7 months, respectively. At last follow up, 4 remain alive, 3 in continuous CR (18%), at 12, 29 (treated with the NMA regimen) and 116 months, respectively. Of the 3 patients surviving in remission, all had transformed to AML prior to ASCT and only one had achieved CR following induction chemotherapy. Multivariate analysis failed to demonstrate any significant effect of age, duration of disease, BM blast %, karyotype or induction chemotherapy on RFS or OS, likely reflecting the small numbers available for analysis. Conclusion: The current study demonstrates anti-CMML activity of both ASCT and DLI although overall outcome is less than encouraging and unpredictable. Novel approaches are needed.