Low Relapse without Excessive Transplant-Related Mortality following Myeloablative Cord Blood Transplantation for Acute Leukemia in Complete Remission: A Matched Cohort Analysis

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients
  • Statistical Analysis
• Results
  • Matching
  • Relapse
  • TRM
  • GVHD
  • OS and RFS
• Discussion
• Acknowledgments
• References
• Copyright

Growing evidence supports the efficacy of cord blood transplantation (CBT), and the number of CBTs is increasing. Numerous studies confirm the presence of a graft-versus-leukemia (GVL) effect following CBT, and preliminary data suggests that double-unit CBT may be associated with a decreased risk of relapse. We have observed a low relapse rate following CBT among patients with acute leukemias in morphologic complete remission (CR) at the time of myeloablative (MA) transplant. To further assess this observation, we conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving CBTs versus patients receiving matched unrelated donor (MURD) and mismatched unrelated donor (MMURD) transplants at our center. Thirty-one consecutive CBT patients (aged 0.6-42 years, median 22 years), transplanted between April 2006 and June 2008, were compared to matched subjects selected on the basis of disease type and remission number, cytogenetic risk status, minimal residual disease status (MRD), time from diagnosis to first relapse (for patients beyond CR1), use of imatinib for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) patients, age, and date of transplant. With a median follow-up among surviving CBT patients of 21.1 months (range: 6.6-32.6 months), there has been 1 relapse among cord patients versus 8 relapses among MURD patients (P=.018) and 7 relapses among MMURD patients (P=.019). Treatment-related mortality (TRM) between cohorts is comparable. Although we have observed a high incidence of acute graft-versus-host disease (aGVHD) following CBT, the incidence of National Institutes of Health (NIH) consensus criteria chronic GVHD (cGVHD) has been low. These data support increased investigation of the use of CBT.

Key Words: Cord blood transplantation, Relapse, Hematopoietic cell transplantation

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Introduction 

Cord blood transplantation (CBT) is rapidly evolving, and the number of CBTs is increasing. Establishment of thresholds for infused cell doses and requirements for HLA matching have significantly decreased treatment-related mortality (TRM), and the introduction of double-unit transplants has improved engraftment rates and appears to have improved outcomes among adults and large children 1, 2, 3, 4, 5. Growing inventories of higher quality cord units should continue to result in improved outcomes. Reports of lower incidences of chronic graft-versus-host disease (cGVHD) and more treatment responsive GVHD compared to other donor sources further enhance the appeal of CBT 6, 7, 8. Relative delays in immune reconstitution and prolonged time to engraftment, however, remain important challenges.

Despite improvements in TRM following CBT and hematopoietic cell transplantion (HCT) in general, disease relapse remains a prominent cause of death following allogeneic transplant. As nontransplant-based therapies improve, the relapse risk of patients for whom HCT is indicated will likely increase, and strategies to reduce relapse are crucial. Multiple studies confirm the potency of the graft-versus-leukemia (GVL) effect following CBT. Numerous series including patients with heterogeneous status of disease at the time of transplant suggest a comparable if not lower risk of relapse following CBT compared to HCT with other donor sources 7, 9, 10, 11, 12, 13, 14. A growing body of evidences suggests that, especially among patients with good disease control at the time of transplant, double-unit CBT may be associated with particularly low relapse rates 3, 15, 16. To evaluate relapse rates following CBT, we conducted a matched cohort analysis comparing relapse rates and outcomes for patients with acute leukemias in morphologic complete remission (CR) at the time of transplant receiving myeloablative (MA) CBTs, matched unrelated donor (MURD) transplants, and mismatched unrelated donor (MMURD) transplants at our center.

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Patients and Methods 

Patients 

Between April 2006, when our current cord blood protocols opened, and June 2008, 31 consecutive patients underwent MA CBT for acute leukemias in morphologic CR (n=29) or chronic myelogenous leukemia (CML) not in blast crisis (n=2). Results were analyzed through December 2008. To provide cohorts of MURD and MMURD subjects that were as comparable as possible, 1 of each type of patient was selected from our center's database for each CBT patient without knowledge of transplant outcome. Potentially matched subjects were selected first on the basis of disease status including disease type and remission number, cytogenetic risk status, minimal residual disease (MRD) status, time from diagnosis to first relapse (for patients beyond CR1), and use of imatinib for CML and Philadelphia chromosome-positive acute lymphobalstic leukemia (ALL) patients. MRD was defined as the presence of detectable disease by flow cytometry, cytogenetic analysis, or fluorescein in situ hybridization (FISH) in patients with <5% morphologic marrow blasts. From strata of subjects matched on the above characteristics, final cohorts were then selected based on closest possible matching of age, date of transplant, and, for patients in CR1 at the time of transplant, time from diagnosis to transplant. All patients signed consent forms and this study was approved by the center's institutional review board. General patient details are summarized below and in Table 1. Details of individual matched pairs are summarized in Table 2.

Table 1. Patient Characteristics

	Cord	MMURD	MURD
Number	31	31	31
Age	22 (0.6-42)	25 (1-48)	25 (0.9-41)
Disease	AML n=17	AML n=18	AML n=18
	ALL n=13	ALL n=11	ALL n=13
	Biphenotypic n=1	Biphenotypic n=2	Biphenotypic n=0
	CML n=2	CML n=2	CML n=2
Donor source	Cord blood n=31	Bone marrow n=15	Bone marrow n=6
		Peripheral blood n=16	Peripheral blood n=25
Matching	4/6:4/6 n=14	9/10 n=28	10/10 n=31
	4/6:5/6 n=5	8/10 n=3
	5:6:5/6 n=7
	6/6:6/6 n=1
	5/6 n=4
Conditioning	Cy/TBI/Flu n=31	Cy/TBI based n=21	Cy/TBI based n=24
		Bu/Cy based n=10	Bu/Cy based n =5
			TREO/Flu n=2

MURD indicates matched unrelated donor; MMURD, mismatched unrelated donor; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myeloid myelogenous leukemia; Cy, cyclophosphamide; TBI, total body irridiation; Flu, fludarabine; Bu, busulfan; TREO, treosulfan.

Table 2. Individual Cases and Matched Pairs

MURD indicates matched unrelated donor; MMURD, mismatched unrelated donor; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myeloid myelogenous leukemia; CR1, first complete remission; CP1, first chronic phase; Ph+, Philadelphia chromosome; MRD, minimal residual disease.

Among CBT patients, 27 patients received 2 units (6 of whom had 1 of the 2 units CD34⁺ selected and ex vivo expanded) and 4 received single units. Matching was performed at low resolution for HLA-A and -B and high resolution (allele level) for HLA-DRB1. Matching details are summarized in Table 1. For patients receiving CBT with unmanipulated units, single-unit CBT was permitted for 6/6 units with total nucleated cell count (TNC) ≥3.0×10⁷/kg, 5/6 units with TNC ≥4.0×10⁷/kg, and 4/6 units with TNC ≥6.0×10⁷/kg. If these thresholds were not met, double-unit CBT was performed and each unit was required to have a TNC ≥1.5×10⁷/kg. For patients receiving an ex vivo expanded unit, the unmanipulated unit was required to have a TNC ≥2.5×10⁷/kg. Conditioning regimen for 30 patients was 120mg/kg cyclophosphamide (Cy), 75mg/m² fludarabine (Flu), and 13.2Gy total body irradiation (TBI). One CBT patient received decreased Cy dosing of 90mg/kg because of a history of liver abnormalities and esophageal varices. For all CBT patients, GVHD prophylaxis was cyclosporine (CsA) and mycophenolate mofetil (MMF).

For unrelated donors, allele level matching was performed at HLA-A,-B, -C, -DRB1, and -DQ. Among MURD patients, transplants occurred between November 2001 and November 2007 (median May 2005). Conditioning regimen were: 120mg/kg Cy and 12Gy TBI (n=12); 120mg/kg CY, and 13.2Gy TBI (n=9); 120mg/kg CY and oral busulfan (Bu) targeted (targeted Bu) to 800-900 ng/mL (n=4); targeted Cy and 12Gy TBI (n=2); 42g/m² treosulfan (TREO), and 150mg/kg Flu (n=2); targeted Bu, 120mg/m² Flu, and 5.5mg/kg antithymocyte globulin (ATG) (n=1); 95mg/kg Cy and 12Gy TBI (decreased Cy for a patient with a history of liver abnormalities) (n=1). GVHD prophylaxis was CsA and methotrexate (MTX) (n=11), tacrolimus (TAC), and MTX (n=17), and TAC, sirolimus, and MTX (n=3). Among MMURD patients, transplants occurred between October 2002 and February 2008 (median December 2004). Conditioning regimens were: 120mg/kg Cy and 12Gy TBI (n=12); 120mg/kg Cy and 13.2Gy TBI (n=7); 120mg/kg Cy and targeted Bu (n=9); targeted Cy and 12Gy TBI (n=1); 120mg/kg Cy, targeted Bu, and ATG 4.5mg/kg (n=1); 60mg/kg etoposide and 12Gy TBI (etoposide substituted for Cy for a patient with borderline ejection fraction) (n=1). GVHD prophylaxis was CsA and MTX (n=17), and TAC and MTX (n=14).

Statistical Analysis 

Patient characteristics and follow-up times are summarized using standard measures. Cumulative incidence estimates of acute GVHD (aGVHD) and cGVHD, relapse, and TRM were utilized, with death or relapse (for GVHD), TRM (for relapse), and relapse (for TRM) included as competing risk events [17]. Relapse was defined as the presence of >5% morphologic marrow blasts or biopsy proven extramedullary disease. aGVHD was graded according to established criteria [18]. cGVHD was graded according to the 2005 National Institutes of Health (NIH) consensus criteria [19]. Kaplan-Meier estimates were used to evaluate overall survival (OS) and relapse-free survival (RFS). Censoring for all time-to event outcomes occurred at the date of last contact. Estimates are reported at 2 years post-HCT because the maximum follow-up time for the cord blood group was 2.7 years and no deaths or relapses occurred after 2 years in any group. Associated 95% confidence intervals (CIs) are reported for each incidence estimate. Cause-specific hazards are compared between groups using a log rank test, with 2-sided P-values considered significant at the .05 level.

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Results 

Matching 

All patients were matched successfully for all disease criteria, except in the following 3 cases (Table 2): a CBT patient with ALL was in CR1 with MRD (0.05% blasts by flow cytometry), whereas the MMURD matched pair had no MRD; a CBT patient with ALL was in CR3 with MRD (0.01% blasts by flow cytometry and cytogenetic abnormalities), whereas the MURD matched pair had no MRD; and an MMURD ALL patient in CR1 had MRD (flow cytometry negative, cytogenetic positive), whereas the CBT patient had no MRD. For patients with acute leukemias in CR1 at the time of transplant, median time from diagnosis to transplant was 177 days for CBT patients (range: 90-416 days), 151 days for MURD patients (range: 106-300 days), and 186 days for MMURD patients (range: 113-364 days). The 6 patients with either CML or Philadelphia chromosome-positive ALL were all treated with imatinib prior to transplant. Four of 6 patients in the CBT, MURD, and MMURD cohorts were treated with imatinib posttransplant. Median age difference was 3 years between CBT and MURD pairs and 5 years between CBT and MMURD pairs. Median follow-up for surviving CBT patients is 21.1 months (range: 6.6-32.6 months) versus 35.1 months (range: 12.4-75.8 months) for MURD patients and 29.1 months (range: 7-65.1 months) for MMURD patients.

Relapse 

There has been 1 relapse among cord patients versus 8 relapses among MURD patients and 7 relapses among MMURD patients. Two-year cumulative incidence of relapse is 3.2%, 95% CI [0.2-14.1%] for CBT patients versus 25.8%, 95% CI [12.1-41.8%] for MURD patients and 23%, 95% CI [10.1-38.9%] for MMURD patients (Table 3, Figure 1). Cause-specific hazard for relapse is significantly decreased when comparing cord patients to MURD patients (P=.018) and MMURD patients (P=.019) by log rank test.

Table 3. Relapse, TRM, and Survival

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• Figure 1 

  Cumulative incidence of relapse and TRM by cohort. Relapse (A) and TRM (B).

TRM 

There have been 6 deaths because of TRM among CBT patients versus 5 among MURD patients and 9 among MMURD patients. Causes of TRM among CBT patients were infection (n=5) and GVHD (n=1), among MURD patients were infection (n=3), GVHD (n=1), and regimen-related toxicity (RRT; n=1), and among MMURD patients were infection (n=3), GVHD (n=3), RRT (n=2), and GVHD/infection (n=1). Two-year cumulative incidence of TRM is 20.6%, 95% CI [8.2-36.9%] for CBT patients versus 17%, 95% CI [6.2-32.5%] for MURD patients and 29.2%, 95% CI [14.6-45.5%] for MMURD patients (Table 3, Figure 1). Cause-pecific hazard for TRM is nonsignificant when comparing CBT patients to MURD patients (P=.78) and MMURD patients (P=.41) by log rank test.

GVHD 

Cumulative incidence of grade II-IV aGVHD through day 100 among CBT patients is 80.6%, 95% CI [61.9%- 90.8%] versus 67.7%, 95% [48.4%, 81.2%] for MURD patients and 87.1%, 95% CI [69.2%, 95.0%] for MMURD patients. Cumulative incidence of grade III-IV aGVHD among CBT patients is 29.0%, 95% CI [14.5%-45.3%] versus 12.9%, 95% CI [4.1%-27.0%] for MURD patients and 35.5%, 95% CI [19.4%- 51.9%] for MMURD patients. Two-year incidence of the composite endpoint of equal to or greater than moderate cGVHD or grade II-IV late, persistent or relapsing aGVHD, or overlap syndrome is 56.5%, 95% CI [37.0%, 72.1%] for CBT patients versus 49.2%, 95% CI [30.6%-65.3%] for MURD patients and 48.5%, 95% CI [29.8%-65.4%] for MMURD patients (Figure 2). Among CBT patients, only 3 patients with late GVHD developed equal to or greater than moderate cGVHD; 14 patients had late, persistent, or relapsing aGVHD. No cumulative incidences of GVHD are statistically significantly decreased or increased when comparing CBT patients to MURD or MMURD patients.

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• Figure 2 

  Cumulative incidence GVHD by cohort. Grade II-IV GVHD through day 100 (A), grade III-IV GVHD through day 100 (B), and composite endpoint of equal to or greater than moderate cGVHD or grade II-IV late, persistent, or relapsing aGVHD (C).

OS and RFS 

Two-year OS and RFS for CBT patients are 74.5%, 95% CI [53-87.2%] and 76.2%, 95% CI [56-88%] versus 59.7%, 95% CI [39.8-74.9%] and 57.1, 95% CI [37.7-72.5%] for MURD patients and 50%, 95% CI [31-66.2%] and 47.8%, 95% CI [29.5-65%] for MMURD patients (Table 3, Figure 3). Cause-specific hazard for OS and RFS are borderline significantly decreased when comparing CBT patients to MMURD patients (P=.062 and .041, respectively) and nonsignificant when comparing CBT patients to MURD patients (P=.27 and .17, respectively).

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• Figure 3 

  OS and RFS. Kaplan-Meier estimates of OS (A) and RFS (B).

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Discussion 

We have observed a low relapse rate following MA CBT for patients with high-risk acute leukemias or CML in morphologic CR at the time of transplant. A number of factors might contribute to this low relapse rate. The majority of patients in our study (n=22) underwent double-unit CBT with 2 unmanipulated units and 6 additional patients underwent double-unit CBT with 1 unmanipulated and 1 CD34⁺ selected and ex vivo expanded unit. Clinical data suggest that for patients with good disease control at the time of transplant, double-unit CBT may be associated with decreased relapse rates 3, 15, 16. The biologic mechanism underlying this observation is not characterized, but it may be a result of the immunologic interaction between the 2 units and the host and is an area of active investigation. Additionally, the majority of our CBT patients underwent transplant with multiply mismatched units; only 1 patient received 6/6 matched units. In the unrelated donor setting, higher degrees of mismatch are associated with lower relapse risk, but increased TRM, and early data also support this observation in the CBT setting [10]. It is uncertain whether a higher proportion of patients with better matched cord blood units would result in higher rates of relapse. Finally, our CBT conditioning regimen for adult patients contains 13.2Gy TBI. Many TBI based MA noncord blood HCT conditioning regimens for adults, including those at our center, contain 12Gy TBI. Fifteen patients in the MURD cohort and 14 patients in the MMURD cohort received only 12Gy TBI. Higher TBI doses are associated with decreased relapse, although they have also been associated with increases in TRM 20, 21.

To compare this relapse rate to the relapse rate observed in comparable patients undergoing MA MURD and MMURD transplants, we conducted a matched cohort analysis. Because details of the disease and disease status at the time of transplant are the most important predictors of relapse risk, we focused on matching patients very closely for these variables. Our center's large database of MURD and MMURD transplants allowed us to match comparably aged patients who had undergone transplants in a comparable period and received similar supportive care. In the MURD cohort there were 8 relapses and in the MMURD cohort there were 7 relapses, in contrast to 1 relapse in the cord group. The lack of difference in relapse rates between the MURD and MMURD cohorts is likely attributable to the small sample size, but it is possible that unidentified risk factors for relapse in the MMURD cohort may contribute to this finding.

Although the small size of our series precludes definitive conclusions, the homogeneity of the cohorts is important. In larger series of CBT outcomes that have included analysis of relapse rates, many patients are not in morphologic remission at the time of transplant. Moreover, for larger series, disease risk is typically stratified into early (CR1), intermediate (≥CR2), and advanced (morphologic relapse) 9, 12, 14, 22. The advent of MRD monitoring and increasing refinement of cytogenetic and molecular risk markers for prognosis of acute leukemias allows increasingly sophisticated stratification of relapse risk assessment, and data supports the observation that poor risk features, even for patients in morphologic CR at the time of transplant, increase the chance of posttransplant relapse 23, 24, 25, 26, 27, 28, 29, 30. Although many reports comparing outcomes between single-unit CBT and MURD or MMURD HCT find comparable relapse rates even when comparing patients in CR at the time of transplant, it is possible that bias exists. CBT is often reserved for patients with the highest risk disease and is frequently undertaken when transplant is felt to be urgent. These patients, although they may be in CR, may have disease features putting them at greater risk for relapse than patients undergoing URD transplant. Alternatively, however, investigators fearing less GVL effects with cord blood may reserve the technique for those at lower risk.

Importantly, nonrelapse-related outcomes were comparable between cohorts. Regarding GVHD, our observed high incidence of grade II-IV aGVHD among CBT patients is consistent with recent reports suggesting that double-unit CBT is associated with a higher incidence of aGVHD than single unit CBT 4, 5. In contrast to other reports regarding cGVHD, however, we have observed a relatively higher incidence of the composite endpoint of equal to or greater than moderate cGVHD or grade II-IV late, persistent, or relapsing aGVHD, or overlap syndrome in our CBT patients. The majority of CBT patients experiencing this composite endpoint had either late, persistent, or relapsing aGVHD; only 3 patients demonstrated features of equal to or greater than moderate cGVHD. Few studies have graded cGVHD according to the 2005 NIH consensus criteria, and the extent to which late manifestations of GVHD among CBT patients may be different from late manifestations of GVHD in other donor settings requires further investigation. In addition, the prognostic significance of late, persistent, or relapsing aGVHD versus classic cGVHD is uncertain. Larger numbers and longer follow-up will be needed to examine these issues. When comparing the incidence of late GVHD between the CBT, MURD, and MMURD cohorts in this study, it is important to note that the low incidence of the competing risk of relapse among CBT patients may have resulted in an increased cumulative incidence of late GVHD relative to the MURD and MMURD cohorts.

With respect to TRM, all patients were comparably aged and underwent MA conditioning, indicating good performance status and limited comorbidities and decreasing the likelihood of selection bias affecting TRM. Although delayed engraftment and immune reconstitution remain important issues following CBT and CBT patients frequently require intensive supportive care in the early posttransplant period, we did not observe excess TRM in our small cohort of CBT patients.

Our data suggest that patients undergoing MA CBT for high-risk acute leukemias in morphologic CR have low relapse rates with acceptable TRM. The use of double-unit transplants may contribute to these results. These data suggest that consideration should be given to proceeding rapidly to transplants with CBT for patients with high-risk malignancies while disease status is under good control. Although our series is small, and these findings may not hold true for patients in relapse at the time of transplant or for older or infirm patients unable to tolerate MA conditioning, they do support increased investigation of CBT. Larger numbers and longer follow-up will be necessary to confirm these observations.

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Acknowledgments 

The authors Denise Ziegler and Judy Schramm for their assistance in care of the patients.

Financial disclosure: This study was supported by NIH Grant T32 CA 009515-24.

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